Updated on 2025/08/22

写真a

 
TOKINO Takashi
 
Organization
Institute of Cancer Research Department of Medical Genome Sciences Professor
Title
Professor
External link

Degree

  • Ph. D.

Research Interests

  • がんゲノム

  • 分子生物学

Research Areas

  • Life Science / Tumor biology

  • Life Science / Genome biology

Education

Professional Memberships

Papers

  • Dominant inheritance in hereditary angioedema associated with carboxypeptidase N deficiency. International journal

    Tokimasa Hida, Masashi Idogawa, Masae Okura, Takashi Tokino, Hisashi Uhara

    Allergology international : official journal of the Japanese Society of Allergology   2025.4

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  • The genomic landscape of cutaneous squamous cell carcinoma in Japan. International journal

    Junji Kato, Tokimasa Hida, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

    The Journal of dermatology   2024.12

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    Comprehensive studies of the genetic profiles of cutaneous squamous cell carcinoma (cSCC) in Japanese patients have been lacking, although an understanding of these profiles is crucial for improving treatment outcomes. Since 2019, comprehensive genomic profiling (CGP) has been covered by Japan's health insurance, and the resulting data have been compiled into a comprehensive database by the country's Center for Cancer Genomics and Advanced Therapeutics (C-CAT). In this retrospective study, we used CGP data from the C-CAT database to analyze genomic characteristics of cSCC in Japanese patients. The patients' clinical and genomic data, including the chemotherapy regimens, tumor mutational burden (TMB), and survival status, were obtained. We analyzed the cases of 152 patients, with only those evaluated by the FoundationOne® CDx included for accuracy. Among the 152 patients, the most common gene oncogenic alterations were observed in TP53 (67%), CDKN2A (54%), TERT (49%), CDKN2B (33%), and NOTCH1 (18%). TMB-high (≥10 mut/Mb) was observed in 27% (n = 41) of the patients, with a median age of 75 years for this group. TMB-low (<10 mut/Mb) was observed in 73% (n = 111) of the patients; their median age was 67 years.

    DOI: 10.1111/1346-8138.17592

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  • Genetic Characteristics of Cutaneous, Acral, and Mucosal Melanoma in Japan. International journal

    Tokimasa Hida, Masashi Idogawa, Junji Kato, Yukiko Kiniwa, Kohei Horimoto, Sayuri Sato, Masahide Sawada, Shoichiro Tange, Masae Okura, Ryuhei Okuyama, Takashi Tokino, Hisashi Uhara

    Cancer medicine   13 ( 22 )   e70360   2024.11

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    BACKGROUND: Acral and mucosal melanomas are more prevalent in Asians than in Caucasians, unlike cutaneous melanomas, which are predominant in Caucasians. Recent studies have suggested that non-Caucasian cutaneous melanomas responded less to immune checkpoint inhibitors, highlighting the need for genetic profiling across ethnicities. This study aimed to elucidate the genetic characteristics of Japanese melanomas, which is an under-researched topic. METHODS: Single-nucleotide variants, indels, and copy number alterations in 104 Japanese melanoma patients (37 cutaneous, 52 acral, and 15 mucosal) were analyzed using custom panel sequencing. RESULTS: Driver events were detected in 94% of the cases. Among cutaneous melanoma cases, 76% had BRAF mutations, and 8% had NRAS mutations. In acral melanoma, BRAF (9%), NRAS (17%), KRAS (8%), KIT (19%), and NF1 (7%) mutations were detected. Major driver mutations in mucosal melanoma were detected in NRAS, KRAS, NF1, PTEN, GNAQ, and KIT. The median tumor mutational burden across all melanoma types was 4.6 mutations/Mb, with no significant difference between the cutaneous and acral/mucosal types. Of the 21 patients with both primary and metastatic lesions, 11 showed distinct mutations in each. Potentially actionable mutations were detected in 58 patients in addition to BRAF V600E/K mutations in 31. CONCLUSIONS: This study highlights distinct genetic abnormalities and actionable alterations in Japanese melanoma patients. This suggests a lower tumor mutational burden in East Asian cutaneous melanoma, which may affect the efficacy of immune checkpoint inhibitors. The heterogeneity of driver mutations across and within individuals highlights the need for personalized treatment approaches.

    DOI: 10.1002/cam4.70360

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  • A case of familial progressive hyperpigmentation with or without hypopigmentation presenting with hypopigmented striae along the lines of Blaschko. International journal

    Tokimasa Hida, Masashi Idogawa, Aki Ishikawa, Masae Okura, Satoru Sasaki, Takashi Tokino, Hisashi Uhara

    The Journal of dermatology   2024.9

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    Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is an autosomal dominant disorder characterized by widespread skin hyperpigmentation, café-au-lait spots, and hypopigmented circular macules, resulting from KITLG variants. KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis. Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH. However, the mechanisms behind hypopigmented macule formation remain unclear. This report presents a unique FPHH case in a patient with a novel KITLG mutation (Ser78Leu). Notably, the patient showed multiple hypopigmented macules and striae along the lines of Blaschko. Digital polymerase chain reaction analysis of the DNA from skin and blood tissues indicated a copy-neutral loss of heterozygosity at the KITLG locus, only in the hypopigmented macule. These findings suggest that the hypopigmented macules might result from revertant mosaicism. Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis. This case contributes to the understanding of the genetic mechanisms in FPHH.

    DOI: 10.1111/1346-8138.17459

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  • Genomic landscape of cutaneous, acral, mucosal, and uveal melanoma in Japan: analysis of clinical comprehensive genomic profiling data.

    Tokimasa Hida, Junji Kato, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

    International journal of clinical oncology   2024.9

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    BACKGROUND: Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan. METHODS: Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed. RESULTS: A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1. CONCLUSION: The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.

    DOI: 10.1007/s10147-024-02615-y

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  • 口腔がんにおける悪性化関連遺伝子群転写抑制機構の解明(Nuclear protein X represses the transcription of malignancy-related genes in oral cancer cell lines)

    丹下 正一朗, 後藤 生子, 川島 秀器, 井戸川 雅史, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   83回   P - 2241   2024.9

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  • Mosaic SUFU mutation associated with a mild phenotype of multiple hereditary infundibulocystic basal cell carcinoma syndrome. International journal

    Marina Hamada, Tokimasa Hida, Masashi Idogawa, Shoichiro Tange, Takafumi Kamiya, Masae Okura, Toshiharu Yamashita, Takashi Tokino, Hisashi Uhara

    The Journal of dermatology   2024.8

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    Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants.

    DOI: 10.1111/1346-8138.17434

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  • LMNA::NTRK1 Fusion-positive Leiomyosarcoma: Discrepancy between DNA-based Comprehensive Genomic Profiling and RNA Sequencing.

    Norito Suzuki, Masashi Idogawa, Makoto Emori, Kazuyuki Murase, Yohei Arihara, Hajime Nakamura, Makoto Usami, Tomohiro Kubo, Ichiro Kinoshita, Shintaro Sugita, Takashi Tokino, Tadashi Hasegawa, Akihiro Sakurai, Kohichi Takada

    Internal medicine (Tokyo, Japan)   63 ( 15 )   2215 - 2219   2024.8

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    A 26-year-old man presented with a tumor in the left soleus muscle. The tumor was diagnosed as a locally advanced leiomyosarcoma. The patient was treated with irradiation followed by wide resection. One year after surgery, the patient presented with multiple lung metastases. Despite aggressive sequential chemotherapy, systemic metastatic tumors continued to develop. To explore therapeutic options for the patient, we performed DNA-based CGP with FoundationOne® CDx (F1). F1 identified an out-of-strand rearrangement of the NOS1AP::NTRK1 gene, which has not been previously reported. In contrast, RNA sequencing revealed an in-frame LMNA::NTRK1 gene, which is an oncogenic fusion gene.

    DOI: 10.2169/internalmedicine.2879-23

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  • Genomic profiles of Merkel cell carcinoma in Japan. International journal

    Junji Kato, Tokimasa Hida, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

    The Journal of dermatology   2024.7

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    DOI: 10.1111/1346-8138.17401

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  • クローズアップ実験法(series 370) 知っていますか?TCGAの更新状況

    丹下 正一朗, 井戸川 雅史, 時野 隆至

    実験医学   42 ( 9 )   1414 - 1424   2024.6

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  • クローズアップ実験法(series 370) 知っていますか?TCGAの更新状況

    丹下 正一朗, 井戸川 雅史, 時野 隆至

    実験医学   42 ( 9 )   1414 - 1424   2024.6

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  • The Clinical Validity of Urinary Pellet DNA Monitoring for the Diagnosis of Recurrent Bladder Cancer. International journal

    Masakazu Abe, Hayato Hiraki, Takashi Tsuyukubo, Sadahide Ono, Shigekatsu Maekawa, Daichi Tamura, Akiko Yashima-Abo, Renpei Kato, Hiromitsu Fujisawa, Takeshi Iwaya, Woong-Yang Park, Masashi Idogawa, Takashi Tokino, Wataru Obara, Satoshi S Nishizuka

    The Journal of molecular diagnostics : JMD   26 ( 4 )   278 - 291   2024.4

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    The aim of this study was to evaluate the clinical validity of monitoring urine pellet DNA (upDNA) of bladder cancer (BC) by digital PCR (dPCR) as a biomarker for early recurrence prediction, treatment efficacy evaluation, and no-recurrence corroboration. Tumor panel sequencing was first performed to select patient-unique somatic mutations to monitor both upDNA and circulating tumor DNA (ctDNA) by dPCR. For longitudinal monitoring using upDNA as well as plasma ctDNA, an average of 7.2 (range, 2 to 12) time points per case were performed with the dPCR assay for 32 previously treated and untreated patients with BC. Clinical recurrence based on imaging and urine cytology was compared using upDNA variant allele frequency (VAF) dynamics. A continuous increasing trend of upDNA VAF ≥1% was considered to indicate molecular recurrence. Most (30/32; 93.8%) cases showed at least one traceable somatic mutation. In 5 of 7 cases (71.4%) with clinical recurrence, upDNA VAF >1% was detected 7 to 15 months earlier than the imaging diagnosis. The upDNA VAF remained high after initial treatment for locally recurrent cases. The clinical validity of upDNA monitoring was confirmed with the observation that 26 of 30 cases (86.7%) were traceable. Local recurrences were not indicated by ctDNA alone. The results support the clinical validity of upDNA monitoring in the management of recurrent BC.

    DOI: 10.1016/j.jmoldx.2024.01.006

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  • The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population. International journal

    Masashi Idogawa, Tasuku Mariya, Yumi Tanaka, Tsuyoshi Saito, Hiroshi Nakase, Takashi Tokino, Akihiro Sakurai

    Journal of human genetics   2024.2

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    Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

    DOI: 10.1038/s10038-024-01233-w

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  • Long Noncoding RNA RP11-278A23.1, a Potential Modulator of p53 Tumor Suppression, Contributes to Colorectal Cancer Progression. International journal

    Masayo Kamikokura, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino, Masashi Idogawa

    Cancers   16 ( 5 )   2024.2

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    Recently, many studies revealed that long noncoding RNAs (lncRNAs) play important roles in cancers. To identify lncRNAs contributing to colorectal cancers, we screened lncRNAs through expression and survival analyses in datasets from The Cancer Genome Atlas (TCGA). The screen revealed that RP11-278A23.1 expression is significantly increased in colorectal cancer tissues compared with normal tissues and that high RP11-278A23.1 expression correlates with poor prognosis. The knockdown of RP11-278A23.1 inhibited the growth of and promoted apoptosis in colorectal cancer cells. Next, to comprehensively examine differentially expressed genes after RP11-278A23.1 knockdown, RNA sequencing was performed in HCT116 cells. The expression of p21, a p53 target gene, was significantly upregulated, and the expression of several p53 target proapoptotic genes was also altered. RP11-278A23.1 knockdown increased p53 expression at the translational level but not at the transcriptional level. Interestingly, RP11-278A23.1 knockdown also altered the expression of these proapoptotic genes in DLD1 cells with mutated p53 and in p53-knockout HCT116 cells. These results suggest that RP11-278A23.1 modifies the expression of these apoptosis-related genes in p53-dependent and p53-independent manners. In summary, lncRNA RP11-278A23.1 contributes to colorectal cancer progression by promoting cell growth and inhibiting apoptosis, suggesting that this lncRNA may be a useful therapeutic target.

    DOI: 10.3390/cancers16050882

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  • Effects of temozolomide on tumor mutation burden and microsatellite instability in melanoma cells. International journal

    Masahide Sawada, Tokimasa Hida, Takafumi Kamiya, Tomoyuki Minowa, Junji Kato, Masae Okura, Masashi Idogawa, Takashi Tokino, Hisashi Uhara

    The Journal of dermatology   2023.9

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    The efficacy of combination therapy with an immune checkpoint inhibitor (ICI) and cytotoxic chemotherapeutic agents has been investigated in cancer, including melanoma. Before ICIs were introduced, dacarbazine or temozolomide (TMZ) were used to treat melanoma. Several studies using glioma or colorectal cancer cells showed that TMZ can increase the tumor mutation burden (TMB) and induce mismatch repair (MMR) deficiency associated with microsatellite instability (MSI). These could increase immunoreactivity to an ICI, but this has not been evaluated in melanoma cells. We investigated the effects of TMZ on MSI status and TMB in melanoma cells. To evaluate the TMB, we performed whole-exome sequencing using genomic DNA from the human melanoma cell lines Mel18, A375, WM266-4, G361, and TXM18 before and after TMZ treatment. Polymerase chain reaction amplification of five mononucleotide repeat markers, BAT25, BAT26, NR21, NR24, and MONO27, was performed, and we analyzed changes in the MSI status. In all cell lines, the TMB was increased after TMZ treatment (the change amount of TMB with ≤ 5% variant allele frequency [VAF] was 18.0-38.3 mutations per megabase) even in the condition without obvious cytological damage. MSI after TMZ treatment was not observed in any cells. TMZ increased TMB but did not change MSI status in melanoma cells.

    DOI: 10.1111/1346-8138.16925

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  • 長鎖非コードRNA IncAC1はp53標的遺伝子の発現変化を介して大腸癌進展に寄与する(Long non-coding RNA IncAC1 contributes to colorectal cancer progression via the expression change of p53-targeting genes)

    井戸川 雅史, 小泉 昌代, 丹下 正一朗, 平野 朋美, 大久保 陽介, 時野 隆至

    日本癌学会総会記事   82回   1242 - 1242   2023.9

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  • 再発転移頭頸部癌におけるctDNAモニタリングによる治療効果予測(Prediction of treatment response by ctDNA monitoring in recurrent metastatic head and neck cancer)

    古後 龍之介, 真子 知美, 開 勇人, 西塚 哲, 丹下 正一朗, 井戸川 雅史, 時野 隆至, 中川 尚志

    日本癌学会総会記事   82回   1424 - 1424   2023.9

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  • 予後不良の腫瘍と発現が相関する霊長類特異的遺伝子の解析(Analysis of primate-specific genes contributes to malignant cancer)

    丹下 正一朗, 平野 朋美, 井戸川 雅史, 平田 英周, 井本 逸勢, 時野 隆至

    日本癌学会総会記事   82回   1287 - 1287   2023.9

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  • TM4SF1-AS1 inhibits apoptosis by promoting stress granule formation in cancer cells

    Hiroshi Kitajima, Reo Maruyama, Takeshi Niinuma, Eiichiro Yamamoto, Akira Takasawa, Kumi Takasawa, Kazuya Ishiguro, Akihiro Tsuyada, Ryo Suzuki, Gota Sudo, Toshiyuki Kubo, Kei Mitsuhashi, Masashi Idogawa, Shoichiro Tange, Mutsumi Toyota, Ayano Yoshido, Kohei Kumegawa, Masahiro Kai, Kazuyoshi Yanagihara, Takashi Tokino, Makoto Osanai, Hiroshi Nakase, Hiromu Suzuki

    Cell Death &amp; Disease   14 ( 7 )   2023.7

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    Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Long noncoding RNAs (lncRNAs) play pivotal roles in tumor development. To identify dysregulated lncRNAs in gastric cancer (GC), we analyzed genome-wide trimethylation of histone H3 lysine 4 (H3K4me3) to screen for transcriptionally active lncRNA genes in the non-tumorous gastric mucosa of patients with GC and healthy individuals. We found that H3K4me3 at TM4SF1-AS1 was specifically upregulated in GC patients and that the expression of TM4SF1-AS1 was significantly elevated in primary and cultured GC cells. TM4SF1-AS1 contributes to GC cell growth in vitro and in vivo, and its oncogenic function is mediated, at least in part, through interactions with purine-rich element-binding protein α (Pur-α) and Y-box binding protein 1 (YB-1). TM4SF1-AS1 also activates interferon signaling in GC cells, which is dependent on Pur-α and RIG-I. Chromatin isolation by RNA purification (ChIRP)-mass spectrometry demonstrated that TM4SF1-AS1 was associated with several stress granule (SG)-related proteins, including G3BP2, RACK1, and DDX3. Notably, TM4SF1-AS1 promoted SG formation and inhibited apoptosis in GC cells by sequestering RACK1, an activator of the stress-responsive MAPK pathway, within SGs. TM4SF1-AS1-induced SG formation and apoptosis inhibition are dependent on Pur-α and YB-1. These findings suggested that TM4SF1-AS1 contributes to tumorigenesis by enhancing SG-mediated stress adaptation.

    Other Link: https://www.nature.com/articles/s41419-023-05953-3

    DOI: 10.1038/s41419-023-05953-3

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  • メラノーマ細胞におけるtumor mutation burden及びmicrosatellite instabilityに対するtemozolomideの影響

    澤田 匡秀, 肥田 時征, 神谷 崇文, 箕輪 智幸, 加藤 潤史, 黄倉 真恵, 井戸川 雅史, 時野 隆至, 宇原 久

    日本皮膚悪性腫瘍学会学術大会プログラム・抄録集   39回   229 - 229   2023.6

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  • がん遺伝子パネル検査解析支援ソフトウェア「Varporter」の開発と応用

    井戸川 雅史, 田中 佑弥, 櫻井 晃洋, 時野 隆至

    日本遺伝カウンセリング学会誌   44 ( 2 )   92 - 92   2023.6

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  • Prospective observational study of monitoring gene alterations in plasma cell-free DNA using droplet digital PCR system during anti-EGFR antibody treatment in patients with RAS wild-type advanced colorectal cancer.

    Naoki Takahashi, Keishi Nakamura, Yosuke Kito, Eiji Kubota, Masako Asayama, Yosuke Kumekawa, Hiroki Hara, Tomohiro Matsushima, Kunihiro Tsuji, Hiromi Kataoka, Akihiro Tsuyada, Yasushi Sasaki, Masashi Idogawa, Takashi Tokino, Takeshi Sawada

    Journal of Clinical Oncology   41 ( 4_suppl )   172 - 172   2023.2

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    Publishing type:Research paper (scientific journal)   Publisher:American Society of Clinical Oncology (ASCO)  

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    Background: Anti-EGFR antibody is recommended as one of the standard treatments in patients with RAS wild-type advanced colorectal cancer (CRC). Few reports have evaluated low-frequency subclones of alterations in EGFR signaling pathway genes in plasma cell-free DNA (cfDNA) during anti-EGFR treatment in prospective cohort of advanced CRC patients. Methods: Key inclusion criteria of this study was as follows: 20 years old and over, performance status 0 to 2, metastatic or recurrent CRC (adenocarcinoma), RAS wild-type CRC diagnosed by PCR-rSSO using tumor tissue, no prior use of anti-EGFR antibody. Plasma samples were prospectively collected at pre-treatment, at 4, 10 weeks, every 10 weeks thereafter, and at the end of the anti-EGFR treatment. With QX200 Droplet Digital PCR platform, we analyzed hotspot mutations of KRAS, NRAS, BRAF, and PIK3CA and copy number (CN) variant of HER2 and MET using plasma samples of pre- and post-treatment as well as during treatment (limited to patients with any gene alterations at pre- and post-treatment). Results: Total 50 patients were registered in this study, but 3 patients were excluded because inclusion criteria were not met. Finally, 47 patients were included in full analysis set. In 15 patients (31.9%), genetic alterations including KRAS (G12G13: 10.1%, A59Q61: 2.2%), NRAS (G12G13: 2.2%, Q61: 2.1%), BRAF (V600: 6.4%) , PIK3CA (E545: 4.3%, H1047: 4.3%) , and HER2 (amplification: 6.5%) were detected in pre-treatment samples. Analysis of pre-treatment samples showed that response rates of patients with any gene alterations (N = 13) and that without any gene alterations (N = 29) were 30.8% and 58.6%, respectively (p = 0.095). When the cut-off of variant allele frequency (VAF) was set as 0.5% in patients with any gene mutations, the response rates for cases with VAF ≥0.5% (N = 6) and those with VAF &lt; 0.5% (N = 7) were 0% and 57.1%, respectively (p = 0.049). Among 41 patients with detectable target lesions by CT scan, there was significant difference in percentage of best tumor shrinkage between patients with gene alterations and those without gene alterations (32.1% vs 10.5%, p = 0.037), when cut-off VAF of any gene mutations was set as 0.5% and cut-off CN of HER2 or MET was set as 4 at pre-treatment. Due to dynamics of each gene alteration in cfDNA during treatment, mutations of KRAS A59Q61, NRAS Q61, and MET amplification were characterized as acquired alterations which were newly detected after the administration of anti-EGFR antibodies. Conclusions: Our study demonstrated the clinical relevance of minor mutant subclones in EGFR signaling pathway genes in plasma for predicting response to anti-EGFR treatment. Although sample size of this study was small, preferable threshold for distinguishing responders from non-responders may be 0.5% as VAF of these gene mutations. Clinical trial information: 000034923 .

    DOI: 10.1200/jco.2023.41.4_suppl.172

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  • 抗PD-1抗体が著効したNF1変異型末端型メラノーマの1例

    松田 宇充, 加藤 潤史, 肥田 時征, 堀本 浩平, 佐藤 さゆり, 黄倉 真恵, 宇原 久, 井戸川 雅史, 時野 隆至

    日本皮膚科学会雑誌   133 ( 2 )   271 - 272   2023.2

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  • MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway. International journal

    Shoichiro Tange, Tomomi Hirano, Masashi Idogawa, Eishu Hirata, Issei Imoto, Takashi Tokino

    BMC cancer   23 ( 1 )   85 - 85   2023.1

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    BACKGROUND: While molecular targeted drugs and other therapies are being developed for many tumors, pancreatic cancer is still considered to be the malignant tumor with the worst prognosis. We started this study to identify prognostic genes and therapeutic targets of pancreatic cancer. METHODS: To comprehensively identify prognostic genes in pancreatic cancer, we investigated the correlation between gene expression and cancer-specific prognosis using transcriptome and clinical information datasets from The Cancer Genome Atlas (TCGA). In addition, we examined the effects of the suppression of candidate prognostic genes in pancreatic cancer cell lines. RESULT: We found that patients with high expression levels of MYEOV, a primate-specific gene with unknown function, had significantly shorter disease-specific survival times than those with low expression levels. Cox proportional hazards analysis revealed that high expression of MYEOV was significantly associated with poor survival and was an independent prognostic factor for disease-specific survival in pancreatic cancer patients. Analysis of multiple cancer samples revealed that the MYEOV promoter region is methylated in noncancer tissues but is demethylated in tumors, causing MYEOV overexpression in tumors. Notably, the knockdown of MYEOV suppressed the expression of MTHFD2 and other folate metabolism-related enzyme genes required for the synthesis of amino acids and nucleic acids and also restored the expression of c-Myc and mTORC1 repressors. CONCLUSION: There is a significant correlation between elevated MYEOV expression and poor disease-specific survival in pancreatic cancer patients. MYEOV enhances the activation of several oncogenic pathways, resulting in the induction of pancreatic cancer cell proliferation. Overall, MYEOV acts as an oncogene in pancreatic cancer. Furthermore, MYEOV may be a prognostic biomarker and serve as an 'actionable' therapeutic target for pancreatic cancers.

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  • 抗PD-1抗体が著効したNF1-mutant acral melanoma肝転移の1例

    松田 宇充, 加藤 潤史, 肥田 時征, 堀本 浩平, 佐藤 さゆり, 黄倉 真恵, 宇原 久, 井戸川 雅史, 時野 隆至

    日本皮膚科学会雑誌   132 ( 12 )   2699 - 2699   2022.11

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  • がん遺伝子パネル検査解析支援ソフトウェア「Varporter」の開発(The development of Varporter, a software supporting the evaluation of cancer gene panel test.)

    井戸川 雅史, 平野 朋美, 丹下 正一朗, 時野 隆至

    日本癌学会総会記事   81回   J - 2034   2022.9

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  • 膵臓がんにおける新規予後予測遺伝子と1炭素代謝経路の関係(A relationship between the novel prognosticator gene in malignant pancreatic cancer and one-carbon metabolism)

    丹下 正一朗, 平野 朋美, 井戸川 雅史, 平田 英周, 井本 逸勢, 時野 隆至

    日本癌学会総会記事   81回   P - 2314   2022.9

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  • 頭頸部扁平上皮癌におけるctDNAモニタリングの特徴(The characteristics of ctDNA monitoring in head and neck squamous cell carcinoma)

    古後 龍之介, 真子 知美, 岩谷 岳, 開 勇人, 西塚 哲, 井戸川 雅史, 時野 隆至, 中川 尚志

    日本癌学会総会記事   81回   P - 1283   2022.9

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  • CRISPRを用いた遺伝子活性化システムによる腫瘍細胞株におけるlncRNAの網羅的機能スクリーニング(Comprehensive screening of long noncoding RNAs(lncRNAs) based on CRISPR-mediated gene activation in cancer cells)

    平野 朋美, 井戸川 雅史, 丹下 正一朗, 時野 隆至

    日本癌学会総会記事   81回   P - 3096   2022.9

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  • Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. International journal

    Hiroki Murai, Takahiro Kodama, Kazuki Maesaka, Shoichiro Tange, Daisuke Motooka, Yutaka Suzuki, Yasuyuki Shigematsu, Kentaro Inamura, Yoshihiro Mise, Akio Saiura, Yoshihiro Ono, Yu Takahashi, Yota Kawasaki, Satoshi Iino, Shogo Kobayashi, Masashi Idogawa, Takashi Tokino, Tomomi Hashidate-Yoshida, Hideo Shindou, Masanori Miyazaki, Yasuharu Imai, Satoshi Tanaka, Eiji Mita, Kazuyoshi Ohkawa, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Hidetoshi Eguchi, Eiichi Morii, Tetsuo Takehara

    Hepatology (Baltimore, Md.)   77 ( 1 )   77 - 91   2022.5

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    BACKGROUND&AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES&RESULTS: We performed RNA-seq of tumor tissues in 113 nonviral HCC patients and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into 3 molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with CTNNB1 mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T-cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Steatotic HCC patients, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

    DOI: 10.1002/hep.32573

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  • Mutation Analysis of Radioresistant Early-Stage Cervical Cancer. International journal

    Tae Oike, Yoshihito Sekiguchi, Yuya Yoshimoto, Takahiro Oike, Ken Ando, Wenchao Gu, Yasushi Sasaki, Takashi Tokino, Akira Iwase, Tatsuya Ohno

    International journal of molecular sciences   23 ( 1 )   2021.12

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    Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRASmt/SMAD4mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRASmt/SMAD4mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRASmt/SMAD4mt cancer cells. These data indicate that the KRASmt/SMAD4mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRASmt/SMAD4mt signature.

    DOI: 10.3390/ijms23010051

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  • DLEU1 promotes oral squamous cell carcinoma progression by activating interferon-stimulated genes. International journal

    Yui Hatanaka, Takeshi Niinuma, Hiroshi Kitajima, Koyo Nishiyama, Reo Maruyama, Kazuya Ishiguro, Mutsumi Toyota, Eiichiro Yamamoto, Masahiro Kai, Akira Yorozu, Shohei Sekiguchi, Kazuhiro Ogi, Hironari Dehari, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino, Akihiro Miyazaki, Hiromu Suzuki

    Scientific reports   11 ( 1 )   20438 - 20438   2021.10

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    Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.

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  • Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer. International journal

    Ryosuke Fujisawa, Takeshi Iwaya, Fumitaka Endo, Masashi Idogawa, Noriyuki Sasaki, Hayato Hiraki, Shoichiro Tange, Tomomi Hirano, Yuka Koizumi, Masakazu Abe, Tomoko Takahashi, Mizunori Yaegashi, Yuji Akiyama, Mari Masuda, Akira Sasaki, Fumiaki Takahashi, Yasushi Sasaki, Takashi Tokino, Satoshi S Nishizuka

    Carcinogenesis   42 ( 10 )   1239 - 1249   2021.9

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    We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses were evaluated by the ratio of the variant allele frequency (VAF) of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50% or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 vs 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

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  • Dead or alive? Pitfall of survival analysis with TCGA datasets. International journal

    Masashi Idogawa, Masayo Koizumi, Tomomi Hirano, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino

    Cancer biology & therapy   22 ( 10-12 )   1 - 2   2021.9

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    We often encounter situations in which data from the TCGA that have been analyzed in papers we read or reviewed cannot be reproduced, even when TCGA datasets are used, especially in survival analyses. Therefore, we attempted to confirm the data source for TCGA survival analysis and found that several websites used to analyze the survival data of TCGA datasets inappropriately handle the survival data, causing differences in statistical analyses. This causes the misinterpretation of results because figures of survival analysis results in several papers are sometimes exactly as generated by these sites, and the results depend on only the tools provided by these sites. We would like to make this situation widely known and raise the problem for scientific soundness.

    DOI: 10.1080/15384047.2021.1979845

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  • Genetic analyses of a secondary poroma and trichoblastoma in a HRAS-mutated sebaceous nevus. International journal

    Tomoyuki Minowa, Takafumi Kamiya, Tokimasa Hida, Masae Okura, Junji Kato, Masashi Idogawa, Shoichiro Tange, Tomomi Hirano, Takashi Tokino, Hisashi Uhara

    The Journal of dermatology   48 ( 8 )   1268 - 1272   2021.8

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    A sebaceous nevus is a congenital skin hamartoma caused by postzygotic HRAS or KRAS mosaic mutations. With age, affected individuals may develop secondary tumors within a sebaceous nevus. RAS mutations are harbored from the onset of sebaceous nevus, and further mutations can be expected to be required in order to explain the initiation of secondary tumors. However, genetic analyses of the secondary tumors have not been conducted. Herein, we describe the rare coexistence of a poroma and a trichoblastoma arising in a sebaceous nevus. This is the first report of an investigation of multiple genes in a secondary tumor in an SN. First, HRAS c.37G>C, which is the common mutation in sebaceous nevus, was detected in all three lesions (sebaceous nevus, poroma, and trichoblastoma). Next, to elucidate the potential second-hit mutations in the secondary poroma and trichoblastoma, we applied a panel sequencing for skin cancers that was newly developed in our institution. Our comparison of the mutational profile of 95 skin cancer-related genes in each of the three lesions newly revealed TP53 p.R158P in the poroma and NOTCH2 p.G329S in the trichoblastoma. TP53 p.R158P has been determined as a pathogenic mutation in other tumors, and NOTCH2 p.G329S was a novel mutation. We identified two novel mutations that may have contributed to the pathogenesis of the secondary tumor's development. The roles of the mutations remain unclear.

    DOI: 10.1111/1346-8138.15919

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  • Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo. International journal

    Naoki Tanimizu, Norihisa Ichinohe, Yasushi Sasaki, Tohru Itoh, Ryo Sudo, Tomoko Yamaguchi, Takeshi Katsuda, Takafumi Ninomiya, Takashi Tokino, Takahiro Ochiya, Atsushi Miyajima, Toshihiro Mitaka

    Nature communications   12 ( 1 )   3390 - 3390   2021.6

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    In the liver, the bile canaliculi of hepatocytes are connected to intrahepatic bile ducts lined with cholangiocytes, which remove cytotoxic bile from the liver tissue. Although liver organoids have been reported, it is not clear whether the functional connection between hepatocytes and cholangiocytes is recapitulated in those organoids. Here, we report the generation of a hepatobiliary tubular organoid (HBTO) using mouse hepatocyte progenitors and cholangiocytes. Hepatocytes form the bile canalicular network and secrete metabolites into the canaliculi, which are then transported into the biliary tubular structure. Hepatocytes in HBTO acquire and maintain metabolic functions including albumin secretion and cytochrome P450 activities, over the long term. In this study, we establish functional liver tissue incorporating a bile drainage system ex vivo. HBTO enable us to reproduce the transport of hepatocyte metabolites in liver tissue, and to investigate the way in which the two types of epithelial cells establish functional connections.

    DOI: 10.1038/s41467-021-23575-1

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  • カスタムパネルシーケンスを用いた日本人メラノーマのドライバー遺伝子の検出

    肥田 時征, 井戸川 雅史, 堀本 浩平, 加藤 潤史, 佐藤 さゆり, 藤岡 茉生, 丹下 正一朗, 時野 隆至, 宇原 久

    日本皮膚科学会雑誌   131 ( 5 )   1363 - 1363   2021.5

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  • ALK-positive atypical Spitz tumour with conspicuous rosette-like structures. International journal

    Tomoyuki Minowa, Tokimasa Hida, Kohei Horimoto, Junji Kato, Takafumi Kamiya, Shintaro Sugita, Masashi Idogawa, Toshiaki Saida, Tadashi Hasegawa, Takashi Tokino, Hisashi Uhara

    European journal of dermatology : EJD   31 ( 2 )   256 - 258   2021.4

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    DOI: 10.1684/ejd.2021.3997

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  • Circulating tumor DNAの初期変動を用いた食道癌化学療法効果予測に関する検討

    藤澤 良介, 岩谷 岳, 遠藤 史隆, 佐々木 教之, 二階 春香, 馬場 誠朗, 秋山 有史, 開 勇人, 小泉 優香, 阿部 正和, 片桐 弘勝, 木村 聡元, 大塚 幸喜, 井戸川 雅史, 新田 浩幸, 佐々木 章, 佐々木 泰史, 時野 隆至, 西塚 哲

    日本外科学会定期学術集会抄録集   121回   SF - 1   2021.4

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  • Circulating tumor DNAの初期変動を用いた食道癌化学療法効果予測に関する検討

    藤澤 良介, 岩谷 岳, 遠藤 史隆, 佐々木 教之, 二階 春香, 馬場 誠朗, 秋山 有史, 開 勇人, 小泉 優香, 阿部 正和, 片桐 弘勝, 木村 聡元, 大塚 幸喜, 井戸川 雅史, 新田 浩幸, 佐々木 章, 佐々木 泰史, 時野 隆至, 西塚 哲

    日本外科学会定期学術集会抄録集   121回   SF - 1   2021.4

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  • メラノーマに特化したシーケンスパネルの開発

    肥田 時征, 堀本 浩平, 加藤 潤史, 佐藤 さゆり, 藤岡 茉生, 宇原 久, 井戸川 雅史, 丹下 正一朗, 時野 隆至

    日本皮膚科学会雑誌   131 ( 3 )   541 - 542   2021.3

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  • Frequent Tumor Burden Monitoring of Esophageal Squamous Cell Carcinoma With Circulating Tumor DNA Using Individually Designed Digital Polymerase Chain Reaction. International journal

    Takeshi Iwaya, Fumitaka Endo, Fumiaki Takahashi, Takashi Tokino, Yasushi Sasaki, Satoshi S Nishizuka

    Gastroenterology   160 ( 1 )   463 - 465   2021.1

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    DOI: 10.1053/j.gastro.2020.09.035

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  • Mutation profiling of uterine cervical cancer patients treated with definitive radiotherapy. International journal

    Yuya Yoshimoto, Yasushi Sasaki, Kazutoshi Murata, Shin-Ei Noda, Yuhei Miyasaka, Junko Hamamoto, Mio Furuya, Junko Hirato, Yoshiyuki Suzuki, Tatsuya Ohno, Takashi Tokino, Takahiro Oike, Takashi Nakano

    Gynecologic oncology   159 ( 2 )   546 - 553   2020.11

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    OBJECTIVE: To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. METHODS: Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. RESULTS: Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1-4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. CONCLUSIONS: FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.

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  • Neurofibromatosis type 1 without cutaneous neurofibromas: a rare genotype-phenotype correlation? International journal

    Tokimasa Hida, Masashi Idogawa, Aki Ishikawa, Miyako Mizukami, Junji Kato, Yasuyuki Sumikawa, Masae Okura, Takashi Tokino, Hisashi Uhara

    European journal of dermatology : EJD   30 ( 5 )   608 - 609   2020.10

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  • p53標的遺伝子ARVCFはスプライシング変化によりp53の腫瘍抑制能を補助する

    井戸川 雅史, 鈴木 菜摘, 丹下 正一朗, 時野 隆至

    日本癌学会総会記事   79回   OJ4 - 3   2020.10

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  • 予後不良膵臓癌のマーカー候補となる新規上皮特異的遺伝子の特定

    丹下 正一郎, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   79回   PJ15 - 6   2020.10

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  • 非乳頭十二指腸腺腫、粘膜内癌におけるゲノム・エピゲノムの統合解析

    澤田 武, 佐々木 泰史, 太田 亮介, 津山 翔, 八尾 隆史, 中西 宏佳, 山本 英一郎, 久保田 英嗣, 片岡 洋望, 鈴木 拓, 時野 隆至, 源 利成

    日本癌学会総会記事   79回   OJ14 - 5   2020.10

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  • Aggressive variant of splenic marginal zone lymphoma characterized using a cancer panel test and treated with rituximab-containing chemotherapy: A case report. International journal

    Kazuya Ishiguro, Yasushi Sasaki, Yoshitake Takagi, Takeshi Niinuma, Hiromu Suzuki, Takashi Tokino, Toshiaki Hayashi, Tohru Takahashi, Tetsuyuki Igarashi, Yoshihiro Matsuno

    Medicine   99 ( 35 )   e21938   2020.8

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    RATIONALE: Aggressive variant of splenic marginal zone lymphoma (AV-SMZL) is a very rare disease that is often associated with TP53 mutations and has a poor prognosis. On the other hand, recent advances in genome sequencing techniques enable us to understand the molecular characteristics of rare cancers such as AV-SMZL. Here we present a case of AV-SMZL analyzed using a genetic test. PATIENT CONCERNS: A 66-year-old woman was admitted with splenomegaly and lymphocytosis. Computed tomography revealed marked splenomegaly without lymphadenopathy in any other areas. The serum soluble interleukin-2 receptor (sIL-2R) level was significantly elevated. Peripheral and bone marrow blood tests showed an increase in abnormal lymphocytes. DIAGNOSIS: A splenectomy revealed an SMZL pattern with increased numbers of large cells and mitotic cells and a high Ki-67 positivity rate, which led to a diagnosis of AV-SMZL. Although TP53 mutation was not detected, mutations in NOTCH2, NCOA4, PTEN, EPHA3, and KMT2D were identified. Among these, the mutations in NCOA4, PTEN, and EPHA3 were novel pathogenic mutations in SMZL, which suggests they may be related to the aggressiveness and persistence of the disease. INTERVENTIONS: The patient was administered a rituximab-containing regimen and rituximab-maintenance therapy. OUTCOMES: The patient continues to exhibit a complete response. LESSONS: This is a case of AV-SMZL in which a cancer panel test successfully detected genetic alterations that are potentially associated with its pathogenesis. These findings suggest that genetic analysis is useful for making diagnoses as well as for determining treatment strategies in AV-SMZL.

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  • Integrated genetic and epigenetic analysis of cancer-related genes in non-ampullary duodenal adenomas and intramucosal adenocarcinomas. Reviewed International journal

    Ryosuke Ota, Takeshi Sawada, Sho Tsuyama, Yasushi Sasaki, Hiromu Suzuki, Yasuharu Kaizaki, Kenkei Hasatani, Eiichiro Yamamoto, Hiroyoshi Nakanishi, Satoko Inagaki, Shigetsugu Tsuji, Naohiro Yoshida, Hisashi Doyama, Hiroshi Minato, Keishi Nakamura, Satomi Kasashima, Eiji Kubota, Hiromi Kataoka, Takashi Tokino, Takashi Yao, Toshinari Minamoto

    The Journal of pathology   252 ( 3 )   330 - 342   2020.8

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    The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One-hundred seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal and gastric type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear β-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicate the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal type adenomas and intramucosal adenocarcinomas may indicate the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis. This article is protected by copyright. All rights reserved.

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  • Interactive Web-based Graphs of Coronavirus Disease 2019 Cases and Deaths per Population by Country. Reviewed International journal

    Masashi Idogawa, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America   71 ( 15 )   902 - 903   2020.7

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  • Combination of KRAS and SMAD4 mutations in formalin-fixed paraffin-embedded tissues as a biomarker for pancreatic cancer. Reviewed International journal

    Takahiro Yokose, Minoru Kitago, Sachiko Matsuda, Yasushi Sasaki, Yohei Masugi, Yuki Nakamura, Masahiro Shinoda, Hiroshi Yagi, Yuta Abe, Go Oshima, Shutaro Hori, Fujita Yusuke, Yutaka Nakano, Yutaka Endo, Kodai Abe, Takashi Tokino, Yuko Kitagawa

    Cancer science   111 ( 6 )   2174 - 2182   2020.6

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    Formalin-fixed paraffin-embedded (FFPE) tissues used for routine pathological diagnosis are valuable for cancer genomic analysis; however, the association between mutation status derived from these specimens and prognosis in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We analyzed 50 cancer-related gene mutations including driver genes in PDAC, using next-generation sequencing (NGS) to clarify the association between gene mutations and prognosis. DNA was extracted from FFPE tissues obtained from 74 patients with untreated resectable PDAC who underwent surgery at our institution between 2013 and 2018. Fifty of the 74 patients with DNA extracts from FFPE samples suitable for NGS were analyzed. The prevalence of driver gene mutations was as follows: 84% for KRAS, 62% for TP53, 32% for SMAD4, and 18% for CDKN2A. There were no cases of single SMAD4 mutations; its rate of coincidence with KRAS or TP53 mutations was 30% and 2%, respectively. The combination of KRAS and SMAD4 mutations resulted in significantly shorter relapse-free survival (RFS; median survival time [MST], 12.3 vs. 28.9 months, P = .014) and overall survival (OS; MST, 22.3 months vs. not reached, P = .048). On multivariate analysis, the combination of KRAS and SMAD4 mutations was an independent prognostic factor for RFS (hazard ratio [HR] 4.218; 95% confidence interval [CI], 1.77-10.08; P = .001) and OS (HR 6.730; 95% CI, 1.93-23.43; P = .003). The combination of KRAS and SMAD4 mutations in DNA obtained from FFPE tissues is an independent poor prognostic factor in PDAC.

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  • Genetic analyses of mosaic neurofibromatosis type 1 with giant café-au-lait macule, plexiform neurofibroma and multiple melanocytic nevi. Reviewed International journal

    Tokimasa Hida, Masashi Idogawa, Masae Okura, Shintaro Sugita, Taro Sugawara, Yasushi Sasaki, Takashi Tokino, Toshiharu Yamashita, Hisashi Uhara

    The Journal of dermatology   47 ( 6 )   658 - 662   2020.4

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    Neurofibromatosis type 1 (NF1) is a genodermatosis caused by heterozygous germ line variations in the NF1 gene. A second-hit NF1 aberration results in the formation of café-au-lait macules, cutaneous neurofibroma and plexiform neurofibroma (PNF). Mosaic NF1 (mNF1), caused by a postzygotic NF1 mutation, is characterized by localized or generalized NF1-related manifestations. Although NF1 and mNF1 are associated with pigmentary skin lesions, clinically recognizable melanocytic nevi that developed over PNF have not been reported. Here, we report the first case of multiple melanocytic nevi that developed on a giant café-au-lait macule and PNF. The PNF had biallelic NF1 deletions, a whole deletion of NF1 and a novel intragenic deletion involving exons 25-30. The deletions were not detected in the blood, which resulted in the diagnosis of mNF1. Furthermore, the nevus cells had not only biallelic NF1 deletions but also NRAS Q61R, a common mutation found in congenital melanocytic nevi. These analyses revealed the coexistence of the two different mosaic diseases, mNF1 and congenital melanocytic nevi. For a diagnosis of cases with atypical NF1-like symptoms, genetic analyses using blood and lesional tissues are useful and aid in genetic counseling.

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  • Renal angiomyolipoma (AML) harboring a missense mutation of TSC2 with copy-neutral loss of heterozygosity (CN-LOH). Reviewed International journal

    Masashi Idogawa, Tokimasa Hida, Toshiaki Tanaka, Noriaki Ohira, Shoichiro Tange, Yasushi Sasaki, Hisashi Uhara, Naoya Masumori, Takashi Tokino, Hiroshi Natori

    Cancer biology & therapy   21 ( 4 )   315 - 319   2020.4

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    Angiomyolipoma (AML) is classified as a perivascular epithelioid cell neoplasm, mostly occurring in the kidney. Twenty percent of patients with renal AML have tuberous sclerosis complex (TSC) caused by germline variation in the TSC1 or TSC2 gene. In this paper, we report the first case of renal AML harboring somatic missense mutations of the TSC2 gene and concomitant copy-neutral loss of heterozygosity (CN-LOH). The patient presented with solitary renal AML and pulmonary lymphangiomyomatosis and without other findings suggestive of TSC. Exome sequencing analysis of the renal AML, however, identified a pathogenic somatic missense mutation in the TSC2 gene (NM_000548:c.5228G>A:p. R1743Q), although no other somatic mutation was detected. Furthermore, no germline mutation in TSC1 or TSC2 was detected. Interestingly, the mutant allele ratio was too high for a somatic heterozygous mutation without loss of heterozygosity (LOH). Furthermore, no copy number variation was detected around the TSC2 locus (16p13.3). To clarify the allelic status, we analyzed heterozygous single-nucleotide polymorphisms (SNPs) in chromosome 16. In these SNPs, an unbalanced allele ratio was accumulated inside the 16p13.3 region. These results suggested copy-neutral LOH (CN-LOH). Consequently, we concluded that the missense mutation of the TSC2 gene and CN-LOH of the TSC2 locus caused renal AML.

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  • Chemotherapy after progression on nivolumab is essential for responders with genetic alterations of driver gene: Review of two recurrent/metastatic oral squamous cell carcinoma patients. Reviewed International journal

    Kazuhiro Ogi, Junichi Kobayashi, Takafumi Nakagaki, Junya Okamoto, Kazushige Koike, Naoki Hirokawa, Masanori Someya, Hiroki Sakamoto, Kohichi Takada, Takashi Tokino, Yasushi Sasaki, Hiroyoshi Hiratsuka, Akihiro Miyazaki

    Oral oncology   102   104509 - 104509   2020.3

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  • p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53. Reviewed International journal

    Natsumi Suzuki, Masashi Idogawa, Shoichiro Tange, Tomoko Ohashi, Yasushi Sasaki, Hiroshi Nakase, Takashi Tokino

    Oncogene   39 ( 10 )   2202 - 2211   2020.3

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    p53 is one of the most important tumor suppressor genes, and the exploration of p53-target genes is important for elucidation of its functional mechanisms. In this study, we identified Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) as a direct target of p53 through ChIP-sequencing analysis. Activated p53 protein was found to bind to two distinct sites in the ARVCF gene, resulting in induction of ARVCF expression at both the mRNA and protein levels. We revealed that the knockdown of ARVCF inhibited p53-induced apoptosis. Interestingly, ARVCF interacted with hnRNPH2, which is involved in pre-mRNA splicing, and ARVCF knockdown induced dynamic changes in alternative splicing patterns. These results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Thus, we demonstrated that the induction of ARVCF expression contributed to the tumor suppressive function of p53. Recently, it has been reported that many tumors have thousands of alternative splicing events that are not detectable in normal samples. ARVCF may play a role in alternative splicing events in cancer and may provide clues to explore novel approaches for cancer diagnosis and therapy.

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  • 神経線維腫を伴わない神経線維腫症1型2家系の遺伝子解析

    肥田 時征, 井戸川 雅史, 石川 亜貴, 水上 都, 加藤 潤史, 澄川 靖之, 時野 隆至, 宇原 久

    日本レックリングハウゼン病学会学術大会プログラム・抄録集   11回   15 - 15   2020.2

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  • Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis. Reviewed International journal

    Yusuke Fujita, Sachiko Matsuda, Yasushi Sasaki, Yohei Masugi, Minoru Kitago, Hiroshi Yagi, Yuta Abe, Masahiro Shinoda, Takashi Tokino, Michiie Sakamoto, Yuko Kitagawa

    Cancer science   111 ( 2 )   739 - 748   2020.2

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    There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.

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  • Significance of gene mutations in the Wnt signaling pathway in traditional serrated adenomas of the colon and rectum. Reviewed International journal

    Hiroyoshi Nakanishi, Takeshi Sawada, Yasuharu Kaizaki, Ryosuke Ota, Hiromu Suzuki, Eiichiro Yamamoto, Hironori Aoki, Makoto Eizuka, Kenkei Hasatani, Naoki Takahashi, Satoko Inagaki, Masahide Ebi, Hiroyuki Kato, Eiji Kubota, Hiromi Kataoka, Satoru Takahashi, Takashi Tokino, Toshinari Minamoto, Tamotsu Sugai, Yasushi Sasaki

    PloS one   15 ( 2 )   e0229262   2020

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    Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear β-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs.

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  • Whole-exome sequencing of 79 xenografts as a potential approach for the identification of genetic variants associated with sensitivity to cytotoxic anticancer drugs. International journal

    Chihiro Udagawa, Yasushi Sasaki, Yasuhiro Tanizawa, Hiroshi Suemizu, Yasuyuki Ohnishi, Yasukazu Nakamura, Takashi Tokino, Hitoshi Zembutsu

    PloS one   15 ( 9 )   e0239614   2020

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    Chemotherapy response remains unpredictable in most patients with cancer. In this study, we performed whole-exome sequencing of 79 cancer xenografts derived from human cancer tissues to identify genetic predictors of chemosensitivity to nine cytotoxic anticancer drugs. Xenografts were harvested from 12 organs with cancer and implanted into nude mice. The mice were exposed to one of nine cytotoxic anticancer drugs (5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C, methotrexate, vincristine, and vinblastine) to assess the correlation between chemosensitivity response and variant allele frequency. We found 162 candidate variants that were possibly associated with chemosensitivity to one or more of the nine anticancer drugs (P < 0.01). In a subgroup analysis of breast and gastric cancer xenografts, 78 and 67 variants, respectively, were possibly associated with chemosensitivity. This approach may help to contribute to the development of personalized treatments that may allow for the prescription of optimal chemotherapy regimens among patients with cancer.

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  • Genomic characterization for familial cases with urothelial carcinoma. Reviewed International journal

    Tetsuya Shindo, Megumi Hirobe, Yasushi Adachi, Yasushi Sasaki, Takashi Tokino, Naoya Masumori

    International cancer conference journal   8 ( 4 )   185 - 189   2019.10

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    In this report, we present familial cases of urothelial carcinoma. To investigate the possibility of hereditary urothelial cancer, we performed semiconductor-based next-generation DNA sequencing. A woman in her 80s who had bladder and left ureteral cancer was hospitalized in Sapporo Shirakaba-dai Hospital due to consciousness disturbance. Radiographic evaluation revealed multiple liver metastases and she died 38 days later. Needle necropsy was done for a left ureteral tumor that continued to her bladder tumor and for liver metastases. At the same time, her son in his 60s, who also had muscle-invasive bladder cancer, was admitted to Sapporo Medical University Hospital and underwent neoadjuvant chemotherapy followed by laparoscopic radical cystectomy. DNA was isolated from both cancers and normal controls in each case and analyzed by massive parallel sequencing of 409 cancer-related genes using a targeted, multiplex PCR approach followed by semiconductor sequencing. Somatic mutations of KMT2C and KMT2D were detected in the mother's tumor. Copy number gains of FGFR1, IkBKB, NFkB2, FGFR2, and FLT3 and copy number losses of IGF2R and TP53 were also found in her cancer. In her son's tumor, somatic mutations of FGFR3 and EP300 were identified. Copy number gains of IkBKE/MAPK1/PARP1, EGFR, BRAF, IRS2, MAPK2K1, IGF1R, and ERBB2 and copy number loss of TP53 were also found in his cancer. There were no germline gene mutations related to familial urothelial carcinoma. Although somatic mutation of TP53 was a common feature, these cases with urothelial carcinoma might not be the result of a heredity syndrome.

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  • FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy. Reviewed International journal

    Narisa Dewi Maulany Darwis, Ankita Nachankar, Yasushi Sasaki, Toshiaki Matsui, Shin-Ei Noda, Kazutoshi Murata, Tomoaki Tamaki, Ken Ando, Noriyuki Okonogi, Shintaro Shiba, Daisuke Irie, Takuya Kaminuma, Takuya Kumazawa, Mai Anakura, Souichi Yamashita, Takashi Hirakawa, Sangeeta Kakoti, Yuka Hirota, Takashi Tokino, Akira Iwase, Tatsuya Ohno, Atsushi Shibata, Takahiro Oike, Takashi Nakano

    International journal of molecular sciences   20 ( 18 )   2019.9

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    Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

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  • 新規大腸がん線維芽細胞関連遺伝子の同定(Identification of a novel cancer associated fibroblast-related gene in colorectal cancer)

    須藤 豪太, 山本 英一郎, 萬 顕, 新沼 猛, 杉本 亮, 北嶋 洋志, 久保 俊之, 畠中 柚衣, 甲斐 正広, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事   78回   P - 3102   2019.9

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  • 多発性骨髄腫における新規エピジェネティック併用療法の開発(Development of a new combinational epigenetic therapy of multiple myeloma)

    石黒 一也, 北嶋 洋志, 新沼 猛, 石田 禎夫, 丸山 玲緒, 池田 博, 山本 英一郎, 甲斐 正広, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   78回   P - 2241   2019.9

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  • 変異TP53遺伝子との相関が確認された新規遺伝子群の発見(Identification of novel TP53 mutation-associated genes through pan-cancer analysis)

    丹下 正一郎, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   78回   P - 1192   2019.9

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  • 新規p53標的遺伝子ARVCFはスプライシング変化を誘導し腫瘍抑制に寄与する(ARVCF, a novel p53 target, modulates the splicing landscape and supports the tumor suppressive function of p53)

    井戸川 雅史, 鈴木 菜摘, 丹下 正一郎, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   78回   J - 3018   2019.9

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  • UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells. Reviewed International journal

    Takeshi Niinuma, Hiroshi Kitajima, Masahiro Kai, Eiichiro Yamamoto, Akira Yorozu, Kazuya Ishiguro, Hajime Sasaki, Gota Sudo, Mutsumi Toyota, Tomo Hatahira, Reo Maruyama, Takashi Tokino, Hiroshi Nakase, Tamotsu Sugai, Hiromu Suzuki

    Clinical epigenetics   11 ( 1 )   70 - 70   2019.5

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    BACKGROUND: Ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) is a major regulator of epigenetic mechanisms and is overexpressed in various human malignancies. In this study, we examined the involvement of UHRF1 in aberrant DNA methylation and gene silencing in colorectal cancer (CRC). RESULTS: CRC cell lines were transiently transfected with siRNAs targeting UHRF1, after which DNA methylation was analyzed using dot blots, bisulfite pyrosequencing, and Infinium HumanMethylation450 BeadChip assays. Gene expression was analyzed using RT-PCR and gene expression microarrays. Depletion of UHRF1 rapidly induced genome-wide DNA demethylation in CRC cells. Infinium BeadChip assays and bisulfite pyrosequencing revealed significant demethylation across entire genomic regions, including CpG islands, gene bodies, intergenic regions, and repetitive elements. Despite the substantial demethylation, however, UHRF1 depletion only minimally reversed CpG island hypermethylation-associated gene silencing. By contrast, the combination of UHRF1 depletion and histone deacetylase (HDAC) inhibition reactivated the silenced genes and strongly suppressed CRC cell proliferation. The combination of UHRF1 depletion and HDAC inhibition also induced marked changes in the gene expression profiles such that cell cycle-related genes were strikingly downregulated. CONCLUSIONS: Our results suggest that (i) maintenance of DNA methylation in CRC cells is highly dependent on UHRF1; (ii) UHRF1 depletion rapidly induces DNA demethylation, though it is insufficient to fully reactivate the silenced genes; and (iii) dual targeting of UHRF1 and HDAC may be an effective new therapeutic strategy.

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  • A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors. Reviewed International journal

    Hiroshi Fukamachi, Seon-Kyu Kim, Jiwon Koh, Hye Seung Lee, Yasushi Sasaki, Kentaro Yamashita, Taketo Nishikawaji, Shu Shimada, Yoshimitsu Akiyama, Sun-Ju Byeon, Dong-Hyuck Bae, Keisuke Okuno, Masatoshi Nakagawa, Toshiro Tanioka, Mikito Inokuchi, Hiroshi Kawachi, Kiichiro Tsuchiya, Kazuyuki Kojima, Takashi Tokino, Yoshinobu Eishi, Yong Sung Kim, Woo Ho Kim, Yasuhito Yuasa, Shinji Tanaka

    Journal of experimental & clinical cancer research : CR   38 ( 1 )   127 - 127   2019.3

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    BACKGROUND: Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs. METHODS: We established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles. RESULTS: mTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells. CONCLUSION: mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.

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  • DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling. Reviewed International journal

    Kazuya Ishiguro, Hiroshi Kitajima, Takeshi Niinuma, Tadao Ishida, Reo Maruyama, Hiroshi Ikeda, Toshiaki Hayashi, Hajime Sasaki, Hideki Wakasugi, Koyo Nishiyama, Tetsuya Shindo, Eiichiro Yamamoto, Masahiro Kai, Yasushi Sasaki, Takashi Tokino, Hiroshi Nakase, Hiromu Suzuki

    Haematologica   104 ( 1 )   155 - 165   2019.1

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    Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. DOT1L expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation in vitro The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower IRF4/MYC expression were less sensitive to DOT1L inhibition, but with prolonged treatment, anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.

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  • Prognostic Effect of Long Noncoding RNA NEAT1 Expression Depends on p53 Mutation Status in Cancer. Reviewed International journal

    Masashi Idogawa, Hiroshi Nakase, Yasushi Sasaki, Takashi Tokino

    Journal of oncology   2019   4368068 - 4368068   2019

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    Recently, many studies have revealed that long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes. Our previous study reported that lncRNA NEAT1 is a direct transcriptional target of p53. NEAT1 is an essential component of paraspeckles, which have recently been identified as a novel type of nuclear compartment. Although our previous findings indicate that NEAT1 induction contributes to the tumor-suppressor function of p53, the role of NEAT1 in cancer is still controversial. In this study, we comprehensively analyzed the relationship between NEAT1 expression and p53 mutation status. Interestingly, survival analysis based on NEAT1 expression in several cancer tissues revealed that the p53 wild-type group with high NEAT1 expression had a good prognosis, while poor prognosis or no correlation between NEAT1 expression and survival was observed in the p53-mutated group. These results demonstrate that the tumor-suppressive effect of NEAT1 depends on p53 function and is consistent with our previous report showing that NEAT1 supports the tumor-suppressive function of p53. Specifically, NEAT1 seems to play a tumor-suppressive role only in the presence of wild-type p53. These results provide important clues to the roles of NEAT1 in cancer.

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  • Patient-specific circulating tumor DNA monitoring using digital PCR in esophageal squamous cell cancer patients Reviewed

    Iwaya Takeshi, Endo Fumitaka, Sasaki Yasushi, Yaegashi Mizunori, Sato Kei, Sasaki Noriyuki, Akiyama Yuji, Sasaki Akira, Masuda Mari, Tokino Takashi, Nishizuka Satoshi

    CANCER SCIENCE   109   708   2018.12

  • Exome sequence analysis of carcinomatous and sarcomatous elements of an esophageal carcinosarcoma Reviewed

    Sasaki Noriyuki, Iwaya Takeshi, Endo Fumitaka, Konosu Masafumi, Akiyama Yuji, Sasaki Yasushi, Tokino Takashi, Nishizuka Satoshi

    CANCER SCIENCE   109   216   2018.12

  • Surface microstructures are associated with mutational intratumoral heterogeneity in colorectal tumors. Reviewed

    Taku Harada, Eiichiro Yamamoto, Hiro-O Yamano, Hironori Aoki, Hiro-O Matsushita, Kenjiro Yoshikawa, Ryo Takagi, Eiji Harada, Yoshihito Tanaka, Yuko Yoshida, Makoto Eizuka, Akira Yorozu, Gota Sudo, Hiroshi Kitajima, Takeshi Niinuma, Masahiro Kai, Yasushi Sasaki, Takashi Tokino, Tamotsu Sugai, Hiroshi Nakase, Hiromu Suzuki

    Journal of gastroenterology   53 ( 12 )   1241 - 1252   2018.12

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    BACKGROUND: Recent studies revealed that colorectal tumors are composed of genetically diverse subclones. We aimed to clarify whether the surface microstructures of colorectal tumors are associated with genetic intratumoral heterogeneity (ITH). METHODS: The surface microstructures (pit patterns) of colorectal tumors were observed using magnifying endoscopy, and biopsy specimens were obtained from respective areas when tumors exhibited multiple pit patterns. A total of 711 specimens from 477 colorectal tumors were analyzed for BRAF, KRAS and TP53 mutations using pyrosequencing and direct sequencing. A panel of cancer-related genes was analyzed through targeted sequencing in 7 tumors. RESULTS: Colorectal tumors with multiple pit patterns exhibited more advanced pit patterns and higher frequencies of KRAS and/or TP53 mutations than tumors with a single pit pattern. In tumors with multiple pit patterns, mutations were observed as public (common to all areas) or private (specific to certain areas), and private KRAS and/or TP53 mutations were often variable and unrelated to the pit pattern grade. Notably, invasive CRCs frequently exhibited public TP53 mutations, even in adenomatous areas, which is indicative of their early malignant potential. Targeted sequencing revealed additional public and private mutations in tumors with multiple pit patterns, indicating their single clonal origin. CONCLUSIONS: Our results suggest intratumoral pit pattern variation does not simply reflect the process of colorectal tumor evolution, but instead represents genetically diverse subclones, and this diversity may be associated with malignant potential.

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  • Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment. Reviewed International journal

    Hideki Wakasugi, Hideaki Takahashi, Takeshi Niinuma, Hiroshi Kitajima, Ritsuko Oikawa, Naoki Matsumoto, Yuko Takeba, Takehito Otsubo, Masayuki Takagi, Yasushi Ariizumi, Michihiro Suzuki, Chiaki Okuse, Shogo Iwabuchi, Masayuki Nakano, Noriyuki Akutsu, Jong-Hon Kang, Takeshi Matsui, Norie Yamada, Hajime Sasaki, Eiichiro Yamamoto, Masahiro Kai, Yasushi Sasaki, Shigeru Sasaki, Yasuhito Tanaka, Hiroshi Yotsuyanagi, Takeya Tsutsumi, Hiroyuki Yamamoto, Takashi Tokino, Hiroshi Nakase, Hiromu Suzuki, Fumio Itoh

    Cancer letters   434   91 - 100   2018.10

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    Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.

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  • 中枢神経系原発悪性リンパ腫におけるIon Reporterエクソームシーケンシングによる分子マーカー候補の同定(Identification of molecular marker candidate by Ion Reporter exome sequencing in primary central nervous system lymphoma) Reviewed

    高島 康郎, 佐々木 泰史, 早野 あづさ, 本間 順平, 深井 順也, 岩立 康男, 梶原 浩司, 石澤 伸, 本道 洋昭, 時野 隆至, 山中 龍也

    日本癌学会総会記事   77回   2381 - 2381   2018.9

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  • 大腸腫瘍の表面構造が反映する腫瘍内不均一性(Microsurface structures are associated with mutational intratumoral heterogeneity in colorectal tumors)

    山本 英一郎, 山野 泰穂, 青木 敬則, 須藤 豪太, 新沼 猛, 甲斐 正広, 佐々木 泰史, 時野 隆至, 菅井 有, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   77回   2405 - 2405   2018.9

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  • Targeted next-generation sequencing of 50 cancer-related genes in Japanese patients with oral squamous cell carcinoma. Reviewed International journal

    Takafumi Nakagaki, Miyuki Tamura, Kenta Kobashi, Akina Omori, Ryota Koyama, Masashi Idogawa, Kazuhiro Ogi, Hiroyoshi Hiratsuka, Takashi Tokino, Yasushi Sasaki

    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine   40 ( 9 )   1010428318800180 - 1010428318800180   2018.9

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    Somatic mutation analysis is a standard of practice for human cancers to identify therapeutic sensitization and resistance mutations. We performed a multigene sequencing screen to explore mutational hotspots in cancer-related genes using a semiconductor-based sequencer. DNA from oral squamous cell carcinoma samples was used as a template to amplify 207 regions from 50 cancer-related genes. Of the 80 oral squamous cell carcinoma specimens from Japanese patients, including formalin-fixed paraffin-embedded samples, 56 specimens presented at least one somatic mutation among the 50 investigated genes, and 17 of these samples showed multiple gene somatic mutations. TP53 was the most commonly mutated gene (50.0%), followed by CDKN2A (16.3%), PIK3CA (7.5%), HRAS (5.0%), MET (2.5%), and STK11 (2.5%). In total, 32 cases (40.0%) were human papillomavirus positive and they were significantly less likely to have a TP53, mutation than human papillomavirus-negative oral squamous cell carcinomas (8/32, 25.0% vs 32/48, 66.7%, p = 0.00026). We also detected copy number variations, in which segments of the genome could be duplicated or deleted from the sequencing data. We detected the tumor-specific TP53 mutation in the plasma cell-free DNA from two oral squamous cell carcinoma patients, and after surgery, the test for these mutations became negative. Our approach facilitates the simultaneous high-throughput detection of somatic mutations and copy number variations in oral squamous cell carcinoma samples.

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  • 慢性胃炎および胃がんに関連する長鎖non-coding RNAの同定と機能解析(Identification and characterization of a long non-coding RNA associated with chronic gastritis and gastric caner)

    北嶋 洋志, 丸山 玲緒, 山本 英一郎, 新沼 猛, 甲斐 正広, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   77回   512 - 512   2018.9

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  • DOT1L阻害はIRF4-MYCシグナルの抑制を介して多発性骨髄腫細胞の増殖を抑制する(DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling)

    石黒 一也, 北嶋 洋志, 新沼 猛, 石田 禎夫, 丸山 玲緒, 池田 博, 山本 英一郎, 甲斐 正広, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   77回   988 - 988   2018.9

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  • Digital PCRを用いた食道癌患者における症例特異的血漿中遊離DNAモニタリング(Patient-specific circulating tumor DNA monitoring using digital PCR in esophageal squamous cell cancer patients) Reviewed

    岩谷 岳, 遠藤 史隆, 佐々木 泰史, 八重樫 瑞典, 佐藤 慧, 佐々木 教之, 秋山 有史, 佐々木 章, 増田 万里, 時野 隆至, 西塚 哲

    日本癌学会総会記事   77回   930 - 930   2018.9

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  • 大腸がんにおける腫瘍血管内皮関連遺伝子の同定(Identification and characterization of a tumor endothelium-related gene in colorectal cancer)

    萬 顕, 山本 英一郎, 沼田 有斗, 新沼 猛, 北嶋 洋志, 甲斐 正広, 須藤 豪太, 黒瀬 誠, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事   77回   1574 - 1574   2018.9

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  • 新規大腸がん線維芽細胞関連遺伝子の同定(Identification of cancer-associated fibroblast-related genes in colorectal cancer)

    沼田 有斗, 山本 英一郎, 萬 顕, 新沼 猛, 杉本 亮, 北嶋 洋志, 甲斐 正広, 青木 敬則, 須藤 豪太, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事   77回   2189 - 2189   2018.9

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  • 食道癌肉腫の遺伝子変異解析(Exome sequence analysis of carcinomatous and sarcomatous elements of an esophageal carcinosarcoma)

    佐々木 教之, 岩谷 岳, 遠藤 史隆, 鴻巣 正史, 秋山 有史, 佐々木 泰史, 時野 隆至, 西塚 哲

    日本癌学会総会記事   77回   326 - 326   2018.9

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  • 大腸癌における発現ネットワーク解析によるハブ長鎖非コードRNA(hub-lncRNA)の同定と機能解析(Identification of hub-long non-coding RNAs(lncRNAs) by the network analysis of lncRNA expression in colorectal cancers)

    井戸川 雅史, 鈴木 菜摘, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   77回   463 - 463   2018.9

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  • 日本人口腔扁平上皮癌における癌関連50遺伝子を標的とした次世代シークエンサーによる解析(Targeted next-generation sequencing of 50 cancer-related genes in Japanese patients with oral squamous cell carcinoma)

    荻 和弘, 中垣 貴文, 井戸川 雅史, 宮崎 晃亘, 時野 隆至, 佐々木 泰史

    日本癌学会総会記事   77回   784 - 784   2018.9

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  • 新規p53標的遺伝子として同定されたp120カテニンファミリー蛋白の癌における役割(The roles of p120 catenin family protein as a novel p53 target in cancer)

    鈴木 菜摘, 井戸川 雅史, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   77回   1301 - 1301   2018.9

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  • Mutational analysis of uterine cervical cancer that survived multiple rounds of radiotherapy. Reviewed International journal

    Endang Nuryadi, Yasushi Sasaki, Yoshihiko Hagiwara, Tiara Bunga Mayang Permata, Hiro Sato, Shuichiro Komatsu, Yuya Yoshimoto, Kazutoshi Murata, Ken Ando, Nobuteru Kubo, Noriyuki Okonogi, Yosuke Takakusagi, Akiko Adachi, Mototaro Iwanaga, Keisuke Tsuchida, Tomoaki Tamaki, Shin-Ei Noda, Yuka Hirota, Atsushi Shibata, Tatsuya Ohno, Takashi Tokino, Takahiro Oike, Takashi Nakano

    Oncotarget   9 ( 66 )   32642 - 32652   2018.8

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    Radiotherapy is an essential component of cancer therapy. Despite advances in cancer genomics, the mutation signatures of radioresistant tumors have not yet been fully elucidated. To address this issue, we analyzed a unique set of clinical specimens from a uterine cervical cancer that repeatedly locally recurred after multiple rounds of radiotherapy. Exon sequencing of 409 cancer-related genes in the treatment-naïve tumor and the tumors that recurred after initial and secondary radiotherapy identified (i) activating mutations in PIK3CA and KRAS, and putative inactivating mutations in SMAD4, as trunk mutation signatures that persisted over the clinical course; and (ii) mutations in KMT2A, TET1, and NLRP1 as acquired mutation signatures observed only in recurrent tumors after radiotherapy. Comprehensive mining of published in vitro genomics data pertaining to radiosensitivity revealed that simultaneous mutations in KRAS and SMAD4, which have not been described previously in uterine cervical cancer, are associated with cancer cell radioresistance. The association between this mutation signature and radioresistance was validated by isogenic cell-based experiments. These results provide proof-of-principle for the analytical pipeline employed in this study, which explores clinically relevant mutation signatures for radioresistance, and demonstrate that this approach is worth pursuing with larger cohorts in the future.

    DOI: 10.18632/oncotarget.25982

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  • Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1. Reviewed International journal

    Koyo Nishiyama, Reo Maruyama, Takeshi Niinuma, Masahiro Kai, Hiroshi Kitajima, Mutsumi Toyota, Yui Hatanaka, Tomohiro Igarashi, Jun-Ichi Kobayashi, Kazuhiro Ogi, Hironari Dehari, Akihiro Miyazaki, Akira Yorozu, Eiichiro Yamamoto, Masashi Idogawa, Yasushi Sasaki, Tamotsu Sugai, Takashi Tokino, Hiroyoshi Hiratsuka, Hiromu Suzuki

    Cell death & disease   9 ( 8 )   826 - 826   2018.8

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    Recent studies have shown that long noncoding RNAs (lncRNAs) have pivotal roles in human malignancies, although their significance in oral squamous cell carcinoma (OSCC) is not fully understood. In the present study, we identified lncRNAs functionally associated with OSCC. By analyzing RNA-seq datasets obtained from primary head and neck squamous cell carcinoma (HNSCC), we identified 15 lncRNAs aberrantly expressed in cancer tissues. We then validated their expression in 18 OSCC cell lines using qRT-PCR and identified 6 lncRNAs frequently overexpressed in OSCC. Among those, we found that knocking down DLEU1 (deleted in lymphocytic leukemia 1) strongly suppressed OSCC cell proliferation. DLEU1 knockdown also suppressed migration, invasion, and xenograft formation by OSCC cells, which is suggestive of its oncogenic functionality. Microarray analysis revealed that DLEU1 knockdown significantly affects expression of a number of cancer-related genes in OSCC cells, including HAS3, CD44, and TP63, suggesting that DLEU1 regulates HA-CD44 signaling. Expression of DLEU1 was elevated in 71% of primary OSCC tissues, and high DLEU1 expression was associated with shorter overall survival of HNSCC patients. These data suggest that elevated DLEU1 expression contributes to OSCC development, and that DLEU1 may be a useful therapeutic target in OSCC.

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  • Target amplicon exome-sequencing identifies promising diagnosis and prognostic markers involved in RTK-RAS and PI3K-AKT signaling as central oncopathways in primary central nervous system lymphoma. Reviewed International journal

    Yasuo Takashima, Yasushi Sasaki, Azusa Hayano, Jumpei Homma, Junya Fukai, Yasuo Iwadate, Koji Kajiwara, Shin Ishizawa, Hiroaki Hondoh, Takashi Tokino, Ryuya Yamanaka

    Oncotarget   9 ( 44 )   27471 - 27486   2018.6

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    Exome-sequencing for somatic mutation detection and copy number variation analysis are effective and valid methods for evaluating human cancers in current molecular medicine. We conducted target amplicon exome-sequencing analyses using PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Twenty-seven primary central nervous system lymphoma (PCNSL) specimens and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverages of the entire coding regions of 409 cancer-related genes. The average of the total numbers of somatic mutations including single-nucleotide variations and insertion/deletion mutations in each specimen was 13.3. Of these, the average of the ratios of nonsynonymous substitutions in each specimen was 74.8%. The most frequent mutations in 27 specimens were in PIM1, MYD88, CD79B, DST, IRF4, ERBB3, MYH11, DCC, and KMT2D. Furthermore, somatic mutations of MYH11 were related to poor prognoses in PCNSL patients. Copy number variations were also duplicated and/or deleted from deep-sequencing in segmental genomic islands. In addition to these prognostic marker candidates, analysis of RTK-RAS-MAPK signaling and the PTEN-PI3K-AKT proapoptotic pathway showed that somatic activations and aberrations, respectively, may be involved in a promising central oncopathway harboring mTOR, c-Myc, FOXO1, and p53. This study provides a foundation for molecular targeted therapies based on genome diagnostics and prognosis in PCNSL.

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  • Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer. Reviewed International journal

    Tetsuya Shindo, Takeshi Niinuma, Naotaka Nishiyama, Nobuo Shinkai, Hiroshi Kitajima, Masahiro Kai, Reo Maruyama, Takashi Tokino, Naoya Masumori, Hiromu Suzuki

    Oncotarget   9 ( 36 )   24457 - 24469   2018.5

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    In this study, we identified microRNAs (miRNAs) involved in cisplatin (CDDP) resistance in bladder cancer (BCa). After establishing CDDP-resistant BCa cell lines (T24RC and EJ138RC), TaqMan arrays revealed that members of the miR-200 family (miR-200b, miR-200a and miR-429) were downregulated in T24RC as compared to parental T24 cells. miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2'-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2'-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. These results suggest downregulation of miR-200b is associated with CDDP resistance in BCa. Epigenetic silencing of miR-200b may be a marker of CDDP resistance and a useful therapeutic target for overcoming CDDP resistance in BCa.

    DOI: 10.18632/oncotarget.25326

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  • Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs. Reviewed International journal

    Chihiro Udagawa, Yasushi Sasaki, Hiroshi Suemizu, Yasuyuki Ohnishi, Hiroshi Ohnishi, Takashi Tokino, Hitoshi Zembutsu

    Experimental and therapeutic medicine   15 ( 2 )   1339 - 1359   2018.2

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    Although there has been progress moving from a 'one-size-fits-all' cytotoxic approach to personalized molecular medicine, the majority of patients with cancer receive chemotherapy using cytotoxic anticancer drugs. The sequencing analysis of 409 genes associated with cancer was conducted in the present study using 59 DNA sequences extracted from human cancer xenografts implanted into nude mice, of which sensitivity to 9 cytotoxic anticancer drugs [5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C (MMC), methotrexate, vincristine (VCR), and vinblastine] was examined. The present study investigated the association between the sensitivities of the xenografts to the 9 anticancer drugs and the frequency of single nucleotide variants (SNV). The correlation between the expression level of the genes and sensitivities to the 9 drugs in the above xenografts was also estimated. In the screening study using 59 xenografts, 3 SNVs (rs1805321, rs62456182 in PMS1 Homolog 2, Mismatch Repair System Component and rs13382825 in LDL Receptor Related Protein 1B), were associated with sensitivity to VCR and MMC, respectively (P<0.001). A replication study of 596 SNVs was subsequently performed, which indicated P<0.05 in the screening study using independent samples of 20 xenografts. A combined result of the screening and replication studies indicated that 35 SNVs were potentially associated with sensitivities to one or more of the nine anticancer drugs (Pcombined=0.0011-0.035). Of the 35 SNVs, rs16903989 and rs201432181 in Leukemia Inhibitory Factor Receptor α and Adhesion G Protein-Coupled Receptor A2 were commonly associated with sensitivity to 2 or 4 anticancer drugs, respectively. These findings provide novel insights which may benefit the development of personalized anticancer therapy for patients with cancer in the future.

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  • Profiling cancer-related gene mutations in oral squamous cell carcinoma from Japanese patients by targeted sequencing Reviewed

    Nakagaki Takafumi, Sasaki Yasushi, Idogawa Masashi, Koyama Ryouta, Tamura Miyuki, Fukushima Hisayo, Ogi Kazuhiro, Hiratsuka Hiroyoshi, Tokino Takashi

    CANCER SCIENCE   109   57   2018.1

  • Exploitation of a liquid biopsy system using circulating tumor DNA in esophageal cancer patients. Reviewed

    Iwaya Takeshi, Endo Fuinitaka, Sasaki Yasushi, Yaegashi Mizunori, Chiba Takehiro, Akiyama Yuji, Masuda Mar, Yamada Tesshi, Tokino Takashi, Nishizuka Satoshi

    CANCER SCIENCE   109   953   2018.1

  • Exploration of p53-targeting long non-coding RNAs (lncRNAs) and network analysis of lncRNA expression in cancers Reviewed

    Idogawa Masashi, Ohashi Tomoko, Sasaki Yasushi, Tokino Takashi

    CANCER SCIENCE   109   82   2018.1

  • Identification of genomic alterations in oral squamous cell carcinomas using amplicon-based whole-exome sequencing Reviewed

    Sasaki Yasushi, Tamura Miyuki, Nakagaki Takafumi, Koyama Ryota, Idogawa Masashi, Ogi Kazuhiro, Hiratsuka Hiroyoshi, Nakase Hiroshi, Tokino Takashi

    CANCER SCIENCE   109   990   2018.1

  • Identification and characterization of a metastatic suppressor BRMS1L as a target gene of p53 Reviewed

    Ryota Koyama, Miyuki Tamura, Takafumi Nakagaki, Tomoko Ohashi, Masashi Idogawa, Hiromu Suzuki, Takashi Tokino, Yasushi Sasaki

    CANCER SCIENCE   108 ( 12 )   2413 - 2421   2017.12

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    Other Link: http://orcid.org/0000-0002-8507-1726

    DOI: 10.1111/cas.13420

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  • p53標的遺伝子BRMS1Lの同定と機能解析

    佐々木 泰史, 小山 良太, 田村 みゆき, 中垣 貴文, 大箸 智子, 井戸川 雅史, 鈴木 拓, 時野 隆至

    生命科学系学会合同年次大会   2017年度   [1LBA - 057]   2017.12

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  • Identification and characterization of a metastatic suppressor BRMS1L as a target gene of p53. Reviewed International journal

    Ryota Koyama, Miyuki Tamura, Takafumi Nakagaki, Tomoko Ohashi, Masashi Idogawa, Hiromu Suzuki, Takashi Tokino, Yasushi Sasaki

    Cancer science   108 ( 12 )   2413 - 2421   2017.12

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    The tumor suppressor p53 and its family members, p63 and p73, play a pivotal role in the cell fate determination in response to diverse upstream signals. As transcription factors, p53 family proteins regulate a number of genes that are involved in cell cycle arrest, apoptosis, senescence, and maintenance of genomic stability. Recent studies revealed that p53 family proteins are important for the regulation of cell invasion and migration. Microarray analysis showed that breast cancer metastasis suppressor 1-like (BRMS1L) is upregulated by p53 family proteins, specifically p53, TAp63γ, and TAp73β. We identified two responsive elements of p53 family proteins in the first intron and upstream of BRMS1L. These response elements are well conserved among mammals. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effect. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. Together, these results strongly indicate that BRMS1L is one of the mediators downstream of the p53 pathway, and that it inhibits cancer cell invasion and migration, which are essential steps in cancer metastasis. Collectively, our results indicate that BRMS1L is involved in cancer cell invasion and migration, and could be a therapeutic target for cancer.

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  • 新規p53標的である蛋白コード遺伝子LIMA1と長鎖非コードRNA(IncRNA)NEAT1のp53機能における役割

    鈴木 菜摘, 井戸川 雅史, 大箸 智子, 佐々木 泰史, 時野 隆至

    生命科学系学会合同年次大会   2017年度   [1P - 0990]   2017.12

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  • Downregulation of miR-186 is associated with metastatic recurrence of gastrointestinal stromal tumors. Reviewed International journal

    Takeshi Niinuma, Masahiro Kai, Hiroshi Kitajima, Eiichiro Yamamoto, Taku Harada, Reo Maruyama, Takayuki Nobuoka, Toshirou Nishida, Tatsuo Kanda, Tadashi Hasegawa, Takashi Tokino, Tamotsu Sugai, Yasuhisa Shinomura, Hiroshi Nakase, Hiromu Suzuki

    Oncology letters   14 ( 5 )   5703 - 5710   2017.11

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    Although dysregulation of microRNAs (miRNAs/miRs) is a common feature of human malignancies, its involvement in gastrointestinal stromal tumors (GISTs) is not fully understood. The present study aimed to identify the miRNAs that perform a role in GIST metastasis. miRNA expression profiles from a series of 32 primary GISTs were analyzed using microarrays, and miR-186 was observed to be downregulated in tumors exhibiting metastatic recurrence. Reverse transcription-quantitative polymerase chain reaction analysis of an independent cohort of 100 primary GISTs revealed that low miR-186 expression is associated with metastatic recurrence and a poor prognosis. Inhibition of miR-186 in GIST-T1 cells promoted cell migration. Gene expression microarray analysis demonstrated that miR-186 inhibition upregulated a set of genes implicated in cancer metastasis, including insulin-like growth factor-binding protein 3, AKT serine/threonine kinase 2, hepatocyte growth factor receptor, CXC chemokine receptor 4 and epidermal growth factor-containing fibulin-like extracellular matrix protein 1. These results suggest that the downregulation of miR-186 is involved in the metastatic recurrence of GISTs, and that miR-186 levels could potentially be a predictive biomarker for clinical outcome.

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  • 口腔扁平上皮癌の全エクソン解析

    佐々木 泰史, 田村 みゆき, 中垣 貴文, 小山 良太, 井戸川 雅史, 荻 和弘, 平塚 博義, 仲瀬 裕志, 時野 隆至

    日本癌学会総会記事   76回   P - 3044   2017.9

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  • 癌におけるp53標的長鎖非コードRNA(lncRNA)の探索と発現ネットワーク解析

    井戸川 雅史, 大箸 智子, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   76回   J - 1077   2017.9

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  • 口腔扁平上皮癌に関与する長鎖非コードRNAの同定

    西山 廣陽, 丸山 玲緒, 新沼 猛, 北嶋 洋志, 荻 和弘, 出張 裕也, 宮崎 晃亘, 甲斐 正広, 佐々木 泰史, 時野 隆至, 平塚 博義, 鈴木 拓

    日本癌学会総会記事   76回   P - 1292   2017.9

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  • ヒストンメチル化酵素DOT1Lは多発性骨髄腫の治療標的となりうる

    石黒 一也, 佐々木 基, 若杉 英樹, 北嶋 洋志, 新沼 猛, 丸山 玲緒, 甲斐 正広, 池田 博, 石田 禎夫, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   76回   P - 2244   2017.9

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  • 次世代シークエンサーによる日本人 口腔扁平上皮癌におけるがん関連409遺伝子の変異解析

    中垣 貴文, 佐々木 泰史, 井戸川 雅史, 小山 良太, 田村 みゆき, 福島 久代, 荻 和弘, 平塚 博義, 時野 隆至

    日本癌学会総会記事   76回   J - 1063   2017.9

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  • Profiling cancer-related gene mutations in oral squamous cell carcinoma from Japanese patients by targeted amplicon sequencing. Reviewed International journal

    Takafumi Nakagaki, Miyuki Tamura, Kenta Kobashi, Ryota Koyama, Hisayo Fukushima, Tomoko Ohashi, Masashi Idogawa, Kazuhiro Ogi, Hiroyoshi Hiratsuka, Takashi Tokino, Yasushi Sasaki

    Oncotarget   8 ( 35 )   59113 - 59122   2017.8

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    Somatic mutation analysis is a standard practice in the study of human cancers to identify mutations that cause therapeutic sensitization and resistance. We performed comprehensive genomic analyses that used PCR target enrichment and next-generation sequencing on Ion Proton semiconductor sequencers. Forty-seven oral squamous cell carcinoma (OSCC) samples and their corresponding noncancerous tissues were used for multiplex PCR amplification to obtain targeted coverage of the entire coding regions of 409 cancer-related genes (covered regions: 95.4% of total, 1.69 megabases of target sequence). The number of somatic mutations in 47 patients with OSCC ranged from 1 to 20 with a mean of 7.60. The most frequent mutations were in TP53 (61.7%), NOTCH1 (25.5%), CDKN2A (19.1%), SYNE1 (14.9%), PIK3CA (10.6%), ROS1 (10.6%), and TAF1L (10.6%). We also detected copy number variations (CNVs) in the segments of the genome that could be duplicated or deleted from deep sequencing data. Pathway assessment showed that the somatic aberrations within OSCC genomes are mainly involved in several important pathways, including cell cycle regulation and RTK-MAPK-PI3K. This study may enable better selection of therapies and deliver improved outcomes for OSCC patients when combined with clinical diagnostics.

    DOI: 10.18632/oncotarget.19262

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  • Fledglings in p53 signaling network. Reviewed International journal

    Takashi Tokino, Masashi Idogawa, Yasushi Sasaki

    Oncotarget   8 ( 34 )   55768 - 55769   2017.8

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  • Mutation detection by target sequence analyses using tissue-specific panels in esophageal squamous cell carcinoma Reviewed

    Iwaya Takeshi, Endo Fumitaka, Kume Kohei, Sasaki Yasushi, Tokino Takashi, Nishizuka Satoshi

    CANCER RESEARCH   77   2017.7

  • Long non-coding RNA NEAT1 is a transcriptional target of p53 and modulates p53-induced transactivation and tumor-suppressor function. Reviewed International journal

    Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Hiroshi Nakase, Takashi Tokino

    International journal of cancer   140 ( 12 )   2785 - 2791   2017.6

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    p53 is one of the most important tumor suppressor genes, and the direct transcriptional targets of p53 must be explored to elucidate its functional mechanisms. Thus far, the p53 targets that have been primarily studied are protein-coding genes. Our previous study revealed that several long non-coding RNAs (lncRNAs) are direct transcriptional targets of p53, and knockdown of specific lncRNAs modulates p53-induced apoptosis. In this study, analysis of next-generation chromatin immunoprecipitation-sequencing (ChIP-seq) data for p53 revealed that the lncRNA NEAT1 is a direct transcriptional target of p53. The suppression of NEAT1 induction by p53 attenuates the inhibitory effect of p53 on cancer cell growth and also modulates gene transactivation, including that of many lncRNAs. Furthermore, low expression of NEAT1 is related to poor prognosis in several cancers. These results indicate that the induction of NEAT1 expression contributes to the tumor-suppressor function of p53 and suggest that p53 and NEAT1 constitute a transcriptional network contributing to various biological functions and tumor suppression.

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  • p53 mediates the suppression of cancer cell invasion by inducing LIMA1/EPLIN. Reviewed International journal

    Tomoko Ohashi, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino

    Cancer letters   390   58 - 66   2017.4

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    Language:English  

    The tumor suppressor gene p53 is frequently mutated in human cancer. p53 executes various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. In this study, LIM domain and Actin-binding protein 1 (LIMA1) was identified as a target of the p53 family using a cDNA microarray. We also evaluated genome-wide occupancy of the p53 protein by performing chromatin immunoprecipitation-sequencing (ChIP-seq) and identified two p53 response elements in the LIMA1 gene. LIMA1 protein levels were increased by treatment with nutlin-3a, a small molecule that activates endogenous p53. In addition, LIMA1 expression was significantly downregulated in cancers compared with normal tissues. Knockdown of LIMA1 significantly enhanced cancer cell invasion and partially inhibited p53-induced suppression of cell invasion. Furthermore, low expression of LIMA1 in cancer patients correlated with decreased survival and poor prognosis. Thus, p53-induced LIMA1 inhibits cell invasion, and the downregulation of LIMA1 caused by p53 mutation results in decreased survival in cancer patients. Collectively, this study reveals the molecular mechanism of LIMA1 downregulation in various cancers and suggests that LIMA1 may be a novel prognostic predictor and a therapeutic target for cancer.

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  • The effect of forced expression of mutated K-RAS gene on gastrointestinal cancer cell lines and the IGF-1R targeting therapy. Reviewed International journal

    Yasutaka Matsunaga, Yasushi Adachi, Yasushi Sasaki, Hideyuki Koide, Masayo Motoya, Katsuhiko Nosho, Hideyasu Takagi, Hiroyuki Yamamoto, Shigeru Sasaki, Yoshiaki Arimura, Takashi Tokino, David P Carbone, Kohzoh Imai, Yasuhisa Shinomura

    Molecular carcinogenesis   56 ( 2 )   515 - 526   2017.2

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    Mutation in K-RAS (K-RAS-MT) plays important roles in both cancer progression and resistance to anti-epidermal growth factor receptor (EGFR) therapy in gastrointestinal tumors. Insulin-like growth factor-1 receptor (IGF-1R) signaling is required for carcinogenicity and progression of many tumors as well. We have previously shown successful therapy for gastrointestinal cancer cell lines bearing a K-RAS mutation using an anti-IGF-1R monoclonal antibody. In this study, we sought to evaluate effects of forced K-RAS-MT expression on gastrointestinal cancer cell lines representing a possible second resistance mechanism for anti-EGFR therapy and IGF-1R-targeted therapy for these transfectants. We made stable transfectants of K-RAS-MT in two gastrointestinal cancer cell lines, colorectal RKO and pancreatic BxPC-3. We assessed the effect of forced expression of K-RAS-MT on proliferation, apoptosis, migration, and invasion in gastrointestinal cancer cells. Then we assessed anti-tumor effects of dominant negative IGF-1R (IGF-1R/dn) and an IGF-1R inhibitor, picropodophyllin, on the K-RAS-MT transfectants. Overexpression of K-RAS-MT in gastrointestinal cancer cell lines led to more aggressive phenotypes, with increased proliferation, decreased apoptosis, and increased motility and invasion. IGF-1R blockade suppressed cell growth, colony formation, migration, and invasion, and up-regulated chemotherapy-induced apoptosis of gastrointestinal cancer cells, even when K-RAS-MT was over-expressed. IGF-1R blockade inhibited the Akt pathway more than the extracellular signal-regulated kinase (ERK) pathway in the K-RAS-MT transfectants. IGF-1R/dn, moreover, inhibited the growth of murine xenografts expressing K-RAS-MT. Thus, K-RAS-MT might be important for progressive phonotype observed in gastrointestinal cancers. IGF-1R decoy is a candidate molecular therapeutic approach for gastrointestinal cancers even if K-RAS is mutated. © 2016 Wiley Periodicals, Inc.

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  • Assessment of the quality of DNA from various formalin-fixed paraffin-embedded (FFPE) tissues and the use of this DNA for next-generation sequencing (NGS) with no artifactual mutation. Reviewed International journal

    Naoki Einaga, Akio Yoshida, Hiroko Noda, Masaaki Suemitsu, Yuki Nakayama, Akihisa Sakurada, Yoshiko Kawaji, Hiromi Yamaguchi, Yasushi Sasaki, Takashi Tokino, Mariko Esumi

    PloS one   12 ( 5 )   e0176280   2017

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    Formalin-fixed, paraffin-embedded (FFPE) tissues used for pathological diagnosis are valuable for studying cancer genomics. In particular, laser-capture microdissection of target cells determined by histopathology combined with FFPE tissue section immunohistochemistry (IHC) enables precise analysis by next-generation sequencing (NGS) of the genetic events occurring in cancer. The result is a new strategy for a pathological tool for cancer diagnosis: 'microgenomics'. To more conveniently and precisely perform microgenomics, we revealed by systematic analysis the following three details regarding FFPE DNA compared with paired frozen tissue DNA. 1) The best quality of FFPE DNA is obtained by tissue fixation with 10% neutral buffered formalin for 1 day and heat treatment of tissue lysates at 95°C for 30 minutes. 2) IHC staining of FFPE tissues decreases the quantity and quality of FFPE DNA to one-fourth, and antigen retrieval (at 120°C for 15 minutes, pH 6.0) is the major reason for this decrease. 3) FFPE DNA prepared as described herein is sufficient for NGS. For non-mutated tissue specimens, no artifactual mutation occurs during FFPE preparation, as shown by precise comparison of NGS of FFPE DNA and paired frozen tissue DNA followed by validation. These results demonstrate that even FFPE tissues used for routine clinical diagnosis can be utilized to obtain reliable NGS data if appropriate conditions of fixation and validation are applied.

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  • 次世代シークエンサーを用いた多発性骨髄腫における遺伝子変異とコピー数異常の解析

    福島 久代, 佐々木 泰史, 田村 みゆき, 池田 博, 石黒 一也, 櫻井 晃洋, 時野 隆至

    日本癌学会総会記事   75回   P - 1024   2016.10

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  • 多発性骨髄腫に有効なヒストンメチル化阻害薬の探索

    石黒 一也, 北嶋 洋志, 新沼 猛, 丸山 玲緒, 甲斐 正広, 西山 廣陽, 進藤 哲哉, 池田 博, 石田 禎夫, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   75回   P - 2096   2016.10

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  • 癌におけるp53および長鎖非コードRNA(IncRNA)による転写ネットワーク解析

    井戸川 雅史, 大箸 智子, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   75回   J - 3026   2016.10

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  • 新規p53標的遺伝子LIMA1は癌細胞浸潤を抑制し低発現が予後不良と相関する

    大箸 智子, 井戸川 雅史, 田村 みゆき, 中垣 貴文, 小山 良太, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   75回   J - 3027   2016.10

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  • 口腔扁平上皮癌に関与する長鎖非コードRNAの同定

    西山 廣陽, 粂川 昴平, 丸山 玲緒, 新沼 猛, 北嶋 洋志, 荻 和弘, 出張 裕也, 甲斐 正広, 宮崎 晃亘, 佐々木 泰史, 時野 隆至, 平塚 博義, 鈴木 拓

    日本癌学会総会記事   75回   J - 2018   2016.10

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  • がん関連遺伝子のエクソーム解析による細胞傷害性抗がん剤感受性マーカーの探索

    宇田川 智野, 時野 隆至, 佐々木 泰史, 塩谷 文章, 大西 保行, 末水 洋志, 前佛 均

    日本癌学会総会記事   75回   J - 3043   2016.10

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  • 次世代半導体シーケンサーを用いた口腔扁平上皮癌におけるがん関連遺伝子の網羅的解析

    中垣 貴文, 佐々木 泰史, 井戸川 雅史, 小山 良太, 田村 みゆき, 大箸 智子, 荻 和弘, 平塚 博義, 時野 隆至

    日本癌学会総会記事   75回   P - 2297   2016.10

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  • がん関連遺伝子target sequenceによる食道扁平上皮癌の解析

    岩谷 岳, 遠藤 史隆, 久米 浩平, 佐々木 泰史, 時野 隆至, 澤田 元太, 新井田 厚司, 三森 功士, 西塚 哲

    日本癌学会総会記事   75回   J - 2024   2016.10

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  • 口腔扁平上皮癌におけるがん関連50遺伝子の変異解析

    佐々木 泰史, 中垣 貴文, 田村 みゆき, 小山 良太, 福島 久代, 大箸 智子, 井戸川 雅史, 荻 和弘, 平塚 博義, 時野 隆至

    日本癌学会総会記事   75回   P - 1032   2016.10

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  • 半導体シーケンサーを用いた口腔扁平上皮癌の全エクソームシーケンス

    田村 みゆき, 佐々木 泰史, 中垣 貴文, 小山 良太, 大箸 智子, 井戸川 雅史, 荻 和弘, 平塚 博義, 時野 隆至

    日本癌学会総会記事   75回   P - 1033   2016.10

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  • p53ファミリー遺伝子の標的としてのBRMS1L(breast cancer metastasis suppressor 1 like、BRMS1-like)の同定と機能解析

    小山 良太, 佐々木 泰史, 田村 みゆき, 中垣 貴文, 大箸 智子, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   75回   P - 2059   2016.10

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  • Identification and characterization of the intercellular adhesion molecule-2 gene as a novel p53 target. Reviewed International journal

    Yasushi Sasaki, Miyuki Tamura, Kousuke Takeda, Kazuhiro Ogi, Takafumi Nakagaki, Ryota Koyama, Masashi Idogawa, Hiroyoshi Hiratsuka, Takashi Tokino

    Oncotarget   7 ( 38 )   61426 - 61437   2016.9

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    The p53 tumor suppressor inhibits cell growth through the activation of both cell cycle arrest and apoptosis, which maintain genome stability and prevent cancer development. Here, we report that intercellular adhesion molecule-2 (ICAM2) is transcriptionally activated by p53. Specifically, ICAM2 is induced by the p53 family and DNA damage in a p53-dependent manner. We identified a p53 binding sequence located within the ICAM2 gene that is responsive to wild-type p53, TAp73, and TAp63. In terms of function, we found that the ectopic expression of ICAM2 inhibited cancer cell migration and invasion. In addition, we demonstrated that silencing endogenous ICAM2 in cancer cells caused a marked increase in extracellular signal-regulated kinase (ERK) phosphorylation levels, suggesting that ICAM2 inhibits migration and invasion of cancer cells by suppressing ERK signaling. Moreover, ICAM2 is underexpressed in human cancer tissues containing mutant p53 as compared to those with wild-type p53. Notably, the decreased expression of ICAM2 is associated with poor survival in patients with various cancers. Our findings demonstrate that ICAM2 induction by p53 has a key role in inhibiting migration and invasion.

    DOI: 10.18632/oncotarget.11366

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  • Plasticity of lung cancer stem-like cells is regulated by the transcription factor HOXA5 that is induced by oxidative stress. Reviewed International journal

    Hiroshi Saijo, Yoshihiko Hirohashi, Toshihiko Torigoe, Ryota Horibe, Akari Takaya, Aiko Murai, Terufumi Kubo, Toshimitsu Kajiwara, Tsutomu Tanaka, Yosuke Shionoya, Eri Yamamoto, Reo Maruyama, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Yasuaki Tamura, Yasushi Sasaki, Takashi Tokino, Hiromu Suzuki, Toru Kondo, Hiroki Takahashi, Noriyuki Sato

    Oncotarget   7 ( 31 )   50043 - 50056   2016.8

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    Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are reasonable targets for cancer therapy. However, recent studies have revealed that some non-CSCs/CICs have plastic ability and can dedifferentiate into CSCs/CICs. Therefore, an understanding of the molecular mechanisms that control the plasticity is essential to achieve CSC/CIC-targeting therapy. In this study, we analyzed the plasticity of lung cancer cells and found that lung non-CSCs/CICs can dedifferentiate into CSCs/CICs in accordance with the expression of stem cell transcription factor SOX2. SOX2 expression was induced by the transcription factor HOXA5. Oxidative stress repressed the expression of HDAC8 and then induced histone 3 acetylation and increased the expression of HOXA5 and SOX2. These findings indicate that lung cancer cells have plasticity under a condition of oxidative stress and that HOAX5 has a critical role in dedifferentiation.

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  • The identification of p53 target genes and noncoding RNAs through the combined analysis of RNA-seq and ChIP-seq data Reviewed

    Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Takashi Tokino

    CANCER RESEARCH   76   2016.7

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  • p53 downregulates CRKL oncogene through miR-200 Reviewed

    Takashi Tokino, Miyuki Tamura, Masashi Idogawa, Yasushi Sasaki

    CANCER RESEARCH   76   2016.7

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  • Semiconductor-based next-generation sequencing analysis of 409 cancer-related genes for mutations and copy-number variations in oral squamous cell carcinoma Reviewed

    Takafumi Nakagaki, Yasushi Sasaki, Masashi Idogawa, Ryota Koyama, Kenta Kobashi, Miyuki Tamura, Tomoko Ohashi, Kazuhiro Ogi, Hiroyoshi Hiratsuka, Takashi Tokino

    CANCER RESEARCH   76   2016.7

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  • Targeted sequencing of 409 cancer related genes for somatic mutations and copy number variations in human cancer using the semiconductor sequencers Reviewed

    Yasushi Sasaki, Ryota Koyama, Takafumi Nakagaki, Miyuki Tamura, Masashi Idogawa, Takashi Tokino

    CANCER RESEARCH   76   2016.7

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  • A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer. Reviewed International journal

    Kohei Kumegawa, Reo Maruyama, Eiichiro Yamamoto, Masami Ashida, Hiroshi Kitajima, Akihiro Tsuyada, Takeshi Niinuma, Masahiro Kai, Hiro-O Yamano, Tamotsu Sugai, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Hiromu Suzuki

    Scientific reports   6   26699 - 26699   2016.5

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    Long noncoding RNAs (lncRNAs) have emerged as key components in multiple cellular processes, although their physiological and pathological functions are not fully understood. To identify cancer-related lncRNAs, we screened for those that are epigenetically silenced in colorectal cancer (CRC). Through a genome-wide analysis of histone modifications in CRC cells, we found that the transcription start sites (TSSs) of 1,027 lncRNA genes acquired trimethylation of histone H3 lysine 4 (H3K4me3) after DNA demethylation. Integrative analysis of chromatin signatures and the DNA methylome revealed that the promoter CpG islands (CGIs) of 66 lncRNA genes contained cancer-specific methylation. By validating the expression and methylation of lncRNA genes in CRC cells, we ultimately identified 20 lncRNAs, including ZNF582-AS1, as targets of epigenetic silencing in CRC. ZNF582-AS1 is frequently methylated in CRC cell lines (87.5%), primary CRCs (77.2%), colorectal adenomas (44.7%) and advanced adenomas (87.8%), suggesting that this methylation is an early event during colorectal tumorigenesis. Methylation of ZNF582-AS1 is associated with poor survival of CRC patients, and ectopic expression of ZNF582-AS1 suppressed colony formation by CRC cells. Our findings offer insight into the association between epigenetic alterations and lncRNA dysregulation in cancer and suggest that ZNF582-AS1 may be a novel tumor-suppressive lncRNA.

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  • Low-grade mucoepidermoid carcinoma with regional lymph node metastasis: A case report and genetic review of criteria for grading Reviewed

    Takafumi Nakagaki, Kazuhiro Ogi, Masato Abe, Hironari Dehari, Akihiro Miyazaki, Tadashi Hasegawa, Takashi Tokino, Hiroyoshi Hiratsuka

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   28 ( 2 )   189 - 192   2016.3

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    DOI: 10.1016/j.ajoms.2015.08.006

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  • Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing. Reviewed International journal

    Yasushi Sasaki, Miyuki Tamura, Ryota Koyama, Takafumi Nakagaki, Yasushi Adachi, Takashi Tokino

    World journal of gastroenterology   22 ( 7 )   2284 - 93   2016.2

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    Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett's esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma (ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing (NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53, CDKN2A, FAT1, NOTCH1, PIK3CA, KMT2D and NFE2L2, which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC.

    DOI: 10.3748/wjg.v22.i7.2284

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  • TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells. Reviewed International journal

    Masahiro Kai, Takeshi Niinuma, Hiroshi Kitajima, Eiichiro Yamamoto, Taku Harada, Hironori Aoki, Reo Maruyama, Mutsumi Toyota, Yasushi Sasaki, Tamotsu Sugai, Takashi Tokino, Hiroshi Nakase, Hiromu Suzuki

    PloS one   11 ( 12 )   e0168281   2016

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    Aberrant DNA methylation is commonly observed in colorectal cancer (CRC), but the underlying mechanism is not fully understood. 5-hydroxymethylcytosine levels and TET1 expression are both reduced in CRC, while epigenetic silencing of TET1 is reportedly associated with the CpG island methylator phenotype. In the present study, we aimed to clarify the relationship between loss of TET1 and aberrant DNA methylation in CRC. Stable TET1 knockdown clones were established using Colo320DM cells, which express high levels of TET1, and HCT116 cells, which express TET1 at a level similar to that in normal colonic tissue. Infinium HumanMethylation450 BeadChip assays revealed increased levels of 5-methylcytosine at more than 10,000 CpG sites in TET1-depleted Colo320DM cells. Changes in DNA methylation were observed at various positions within the genome, including promoters, gene bodies and intergenic regions, and the altered methylation affected expression of a subset of genes. By contrast, TET1 knockdown did not significantly affect DNA methylation in HCT116 cells. However, TET1 depletion was associated with attenuated effects of 5-aza-2'-deoxycytidine on gene expression profiles in both cell lines. These results suggest that loss of TET1 may induce aberrant DNA methylation and may attenuate the effect of 5-aza-2'-deoxycytidine in CRC cells.

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  • 新規p53標的遺伝子LIMA1の発現誘導は癌細胞浸潤の抑制に必要である

    大箸 智子, 井戸川 雅史, 梅田 璃子, 佐々木 泰史, 時野 隆至

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [4T18 - 03(3P1065)]   2015.12

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  • 癌細胞におけるゲノムワイドRNAiスクリーニングを用いたp53誘導アポトーシス抵抗性を解除するshRNAの探索

    梅田 璃子, 井戸川 雅史, 大箸 智子, 佐々木 泰史, 時野 隆至

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2LBA040] - [2LBA040]   2015.12

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  • 次世代シーケンサーを用いたがん関連409遺伝子のターゲットシーケンス解析

    佐々木 泰史, 小山 良太, 中垣 貴文, 田村 みゆき, 大箸 智子, 井戸川 雅史, 時野 隆至

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [3LBA004] - [3LBA004]   2015.12

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  • Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors. Reviewed International journal

    Seiko Kamimae, Eiichiro Yamamoto, Masahiro Kai, Takeshi Niinuma, Hiro-o Yamano, Masanori Nojima, Kennjiro Yoshikawa, Tomoaki Kimura, Ryo Takagi, Eiji Harada, Taku Harada, Reo Maruyama, Yasushi Sasaki, Takashi Tokino, Yasuhisa Shinomura, Tamotsu Sugai, Kohzoh Imai, Hiromu Suzuki

    Oncotarget   6 ( 30 )   29975 - 90   2015.10

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    Our aim was to identify DNA methylation changes associated with the growth pattern and invasiveness of colorectal cancers (CRCs). Comparison of the methylation statuses of large (≥ 20 mm in diameter along the colonic surface) noninvasive tumors (NTs) and small (<20 mm in diameter along the colonic surface) invasive tumors (ITs) using CpG island microarray analysis showed neurotensin receptor 1 (NTSR1) to be hypermethylated in large NTs. Quantitative bisulfite pyrosequencing revealed that NTSR1 is frequently methylated in colorectal tumors, with large NTs exhibiting the highest methylation levels. The higher NTSR1 methylation levels were associated with better prognoses. By contrast, NTSR1 copy number gains were most frequent among small ITs. Methylation of NTSR1 was associated with the gene's silencing in CRC cell lines, whereas ectopic expression of NTSR1 promoted proliferation and invasion by CRC cells. Analysis of primary tumors composed of adenomatous and malignant portions revealed that NTSR1 is frequently methylated in the adenomatous portion, while methylation levels are generally lower in the cancerous portions. These results suggest that NTSR1 methylation is associated with lateral and noninvasive growth of colorectal tumors, while low levels of methylation may contribute to the malignant potential through activation of NTSR1. Our data also indicate that NTSR1 methylation may be a prognostic biomarker in CRC.

    DOI: 10.18632/oncotarget.5034

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  • CRKLはmiR-200ファミリーを介してp53により発現抑制される

    田村 みゆき, 佐々木 泰史, 竹田 康佑, 中垣 貴文, 大箸 智子, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   74回   P - 3013   2015.10

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  • 消化器癌における変異kRAS遺伝子の影響の解析およびIGF-1R阻害

    松永 康孝, 足立 靖, 佐々木 泰史, 能正 勝彦, 高木 秀安, 山本 博幸, 佐々木 茂, 有村 佳昭, 遠藤 高夫, 加藤 康夫, 時野 隆至, 篠村 恭久

    日本癌学会総会記事   74回   J - 1204   2015.10

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  • 薬剤耐性を示した多発性骨髄腫患者の次世代シークエンサーを用いた遺伝子解析

    池田 博, 石黒 一也, 青木 由佳, 石田 禎夫, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   74回   P - 3191   2015.10

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  • 半導体シーケンサーを用いたがん関連遺伝子のターゲットシーケンス解析

    佐々木 泰史, 中垣 貴文, 田村 みゆき, 竹田 康佑, 大箸 智子, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   74回   P - 1156   2015.10

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  • p53による癌細胞浸潤の抑制には新規標的遺伝子LIMA1の発現誘導が必要である

    大箸 智子, 井戸川 雅史, 田村 みゆき, 竹田 康佑, 中垣 貴文, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   74回   J - 1280   2015.10

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  • RNA-seqとChIP-seqの複合解析による非コードRNAを含むp53標的遺伝子の同定

    井戸川 雅史, 大箸 智子, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   74回   J - 1294   2015.10

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  • 次世代半導体シーケンサーを用いた口腔扁平上皮癌におけるがん関連遺伝子の網羅的解析

    中垣 貴文, 佐々木 泰史, 井戸川 雅史, 竹田 康佑, 田村 みゆき, 大箸 智子, 荻 和弘, 平塚 博義, 時野 隆至

    日本癌学会総会記事   74回   J - 1330   2015.10

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  • ホルマリン固定パラフィン包埋(FFPE)組織DNAのゲノム解析に問題はないか?

    栄永 直樹, 山口 裕美, 中山 裕貴, 川路 美子, 佐々木 泰史, 時野 隆至, 江角 眞理子

    日本癌学会総会記事   74回   P - 1157   2015.10

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  • Analysis of the molecular features of rectal carcinoid tumors to identify new biomarkers that predict biological malignancy. Reviewed International journal

    Kei Mitsuhashi, Itaru Yamamoto, Hiroyoshi Kurihara, Shinichi Kanno, Miki Ito, Hisayoshi Igarashi, Keisuke Ishigami, Yasutaka Sukawa, Mami Tachibana, Hiroaki Takahashi, Takashi Tokino, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Yasuhisa Shinomura, Hiroyuki Yamamoto, Katsuhiko Nosho

    Oncotarget   6 ( 26 )   22114 - 25   2015.9

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    Although gastrointestinal carcinoid tumors are relatively rare in the digestive tract, a quarter of them are present in the rectum. In the absence of specific tumor biomarkers, lymphatic or vascular invasion is generally used to predict the risk of lymph node metastasis. We, therefore, examined the genetic and epigenetic alterations potentially associated with lymphovascular invasion among 56 patients with rectal carcinoid tumors. We also conducted a microRNA (miRNA) array analysis. Our analysis failed to detect mutations in BRAF, KRAS, NRAS, or PIK3CA or any microsatellite instability (MSI); however, we did observe CpG island methylator phenotype (CIMP) positivity in 13% (7/56) of the carcinoid tumors. The CIMP-positive status was significantly correlated with lymphovascular invasion (P = 0.036). The array analysis revealed that microRNA-885 (miR-885)-5p was the most up-regulated miRNA in the carcinoid tumors with lymphovascular invasion compared with that in those without invasion. In addition, high miR-885-5p expression was independently associated with lymphovascular invasion (P = 0.0002). In conclusion, our findings suggest that miR-885-5p and CIMP status may be useful biomarkers for predicting biological malignancy in patients with rectal carcinoid tumors.

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  • One-Dimensional Sliding of p53 Along DNA Is Accelerated in the Presence of Ca(2+) or Mg(2+) at Millimolar Concentrations. Reviewed International journal

    Agato Murata, Yuji Ito, Risa Kashima, Saori Kanbayashi, Kei Nanatani, Chihiro Igarashi, Masaki Okumura, Kenji Inaba, Takashi Tokino, Satoshi Takahashi, Kiyoto Kamagata

    Journal of molecular biology   427 ( 16 )   2663 - 78   2015.8

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    One-dimensional (1D) sliding of the tumor suppressor p53 along DNA is an essential dynamics required for its efficient search for the binding sites in the genome. To address how the search process of p53 is affected by the changes in the concentration of Mg(2+) and Ca(2+) after the cell damages, we investigated its sliding dynamics at different concentrations of the divalent cations. The 1D sliding trajectories of p53 along the stretched DNA were measured by using single-molecule fluorescence microscopy. The averaged diffusion coefficient calculated from the mean square displacement of p53 on DNA increased significantly at the higher concentration of Mg(2+) or Ca(2+), indicating that the divalent cations accelerate the sliding likely by weakening the DNA-p53 interaction. In addition, two distributions were identified in the displacement of the observed trajectories of p53, demonstrating the presence of the fast and slow sliding modes having large and small diffusion coefficients, respectively. A coreless mutant of p53, in which the core domain was deleted, showed only a single mode whose diffusion coefficient is about twice that of the fast mode for the full-length p53. Thus, the two modes are likely the result of the tight and loose interactions between the core domain of p53 and DNA. These results demonstrated clearly that the 1D sliding dynamics of p53 is strongly dependent on the concentration of Mg(2+) and Ca(2+), which maintains the search distance of p53 along DNA in cells that lost homeostatic control of the divalent cations.

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  • CRKL oncogene is downregulated by p53 through miR-200s Reviewed

    Miyuki Tamura, Yasushi Sasaki, Kenta Kobashi, Kousuke Takeda, Takafumi Nakagaki, Masashi Idogawa, Takashi Tokino

    CANCER SCIENCE   106 ( 8 )   1033 - 1040   2015.8

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    DOI: 10.1111/cas.12713

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  • CRKL oncogene is downregulated by p53 through miR-200s. Reviewed International journal

    Miyuki Tamura, Yasushi Sasaki, Kenta Kobashi, Kousuke Takeda, Takafumi Nakagaki, Masashi Idogawa, Takashi Tokino

    Cancer science   106 ( 8 )   1033 - 40   2015.8

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    Tumor suppressive miRNAs that target oncogenes are frequently downregulated in cancers, and this downregulation leads to oncogene pathway activation. Thus, tumor suppressive miRNAs and their target oncogenes have been proposed as useful targets in cancer treatment. miR-200 family downregulation has been reported in cancer progression and metastasis. The miR-200 family consists of two gene clusters, miR-200b/200a/429 and miR-200c/141, which are located on human chromosomes 1 and 12, respectively. Here, we identified that p53 response elements are located around both clusters of the miR-200 family and confirmed that miR-200s are transcriptional targets of the p53 family. In silico analyses of miRNA targets established the CRKL oncogene as a potential target for miR-200b/200c/429. Moreover, miR-200b/200c/429 inhibited CRKL mRNA and protein expression by directly targeting its 3'-UTR region. Importantly, endogenous CRKL expression was decreased in cancer cells through the introduction of p53 family and endogenous p53 activation. Moreover, the downregulation of CRKL by siRNA inhibited cancer cell growth. The Oncomine database demonstrates that CRKL is overexpressed in a subset of cancer types. Furthermore, CRKL is significantly overexpressed in primary breast cancer tissues harboring mutant TP53. Our results demonstrate that the p53 target miR-200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.

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  • p53 downregulates CRKL proto-oncogene protein through miR-200 family Reviewed

    Yasushi Sasaki, Miyuki Tamura, Kenta Kobashi, Kousuke Takeda, Takafumi Nakagaki, Masashi Idogawa, Takashi Tokino

    CANCER RESEARCH   75   2015.8

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  • Comprehensive genomic analyses of oral squamous cell carcinoma tissues by semiconductor-based next-generation sequencing Reviewed

    Takafumi Nakagaki, Yasushi Sasaki, Kenta Kobashi, Kousuke Takeda, Miyuki Tamura, Tomoko Ohashi, Kazuhiro Ogi, Masashi Idogawa, Hiroyoshi Hiratsuka, Takashi Tokino

    CANCER RESEARCH   75   2015.8

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  • Relation between Ku80 and microRNA-99a expression and late rectal bleeding after radiotherapy for prostate cancer. Reviewed International journal

    Masanori Someya, Hiroyuki Yamamoto, Masanori Nojima, Masakazu Hori, Kunihiko Tateoka, Kensei Nakata, Masaru Takagi, Masato Saito, Naoki Hirokawa, Takashi Tokino, Koh-Ichi Sakata

    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology   115 ( 2 )   235 - 9   2015.5

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    BACKGROUND AND PURPOSE: Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment. MATERIALS AND METHODS: Four patients each with grade 0-1 or grade 2-3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo. RESULTS: In the discovery cohort, grade 2-3 rectal bleeding was significantly higher in the Ku80 <1.09 expression group compared with ⩾1.09 group (P=0.011). In radiation-induced expression of miR-99a, grade 2-3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(-) >0.93 group compared with ⩽0.93 group (P=0.013). Most patients with grade 2-3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained. CONCLUSION: A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy.

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  • Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing. Reviewed International journal

    Hiroshi Ikeda, Kazuya Ishiguro, Tetsuyuki Igarashi, Yuka Aoki, Toshiaki Hayashi, Tadao Ishida, Yasushi Sasaki, Takashi Tokino, Yasuhisa Shinomura

    OncoTargets and therapy   8   2805 - 15   2015

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    A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients.

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  • A Screen for Epigenetically Silenced microRNA Genes in Gastrointestinal Stromal Tumors. Reviewed International journal

    Mai Isosaka, Takeshi Niinuma, Masanori Nojima, Masahiro Kai, Eiichiro Yamamoto, Reo Maruyama, Takayuki Nobuoka, Toshirou Nishida, Tatsuo Kanda, Takahiro Taguchi, Tadashi Hasegawa, Takashi Tokino, Koichi Hirata, Hiromu Suzuki, Yasuhisa Shinomura

    PloS one   10 ( 7 )   e0133754   2015

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    BACKGROUND: Dysregulation of microRNA (miRNA) has been implicated in gastrointestinal stromal tumors (GISTs) but the mechanism is not fully understood. In this study, we aimed to explore the involvement of epigenetic alteration of miRNA genes in GISTs. METHODS: GIST-T1 cells were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which miRNA expression profiles were analyzed using TaqMan miRNA arrays. DNA methylation was then analyzed using bisulfite pyrosequencing. The functions of miRNAs were examined using MTT assays, wound-healing assays, Boyden chamber assays and Matrigel invasion assays. Gene expression microarrays were analyzed to assess effect of ectopic miRNA expression in GIST-T1 cells. RESULTS: Of the 754 miRNAs analyzed, 61 were significantly upregulated in GIST-T1 cells treated with 5-aza-dC plus PBA. Among those, 21 miRNA genes were associated with an upstream CpG island (CGI), and the CGIs of miR-34a and miR-335 were frequently methylated in GIST-T1 cells and primary GIST specimens. Transfection of miR-34a or miR-335 mimic molecules into GIST-T1 cells suppressed cell proliferation, and miR-34a also inhibited migration and invasion by GIST-T1 cells. Moreover, miR-34a downregulated a number of predicted target genes, including PDGFRA. RNA interference-mediated knockdown of PDGFRA in GIST-T1 cells suppressed cell proliferation, suggesting the tumor suppressive effect of miR-34a is mediated, at least in part, through targeting PDGFRA. CONCLUSIONS: Our results suggest that miR-34a and miR-335 are candidate tumor suppressive miRNAs in GISTs, and that they are frequent targets of epigenetic silencing in GISTs.

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  • MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions. Reviewed International journal

    Miki Ito, Kei Mitsuhashi, Hisayoshi Igarashi, Katsuhiko Nosho, Takafumi Naito, Shinji Yoshii, Hiroaki Takahashi, Masahiro Fujita, Yasutaka Sukawa, Eiichiro Yamamoto, Taiga Takahashi, Yasushi Adachi, Masanori Nojima, Yasushi Sasaki, Takashi Tokino, Yoshifumi Baba, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura

    International journal of cancer   135 ( 11 )   2507 - 15   2014.12

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    The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p = 0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR-31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum.

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  • 口腔扁平上皮癌における50の癌関連遺伝子についての次世代シークエンス分析(A Next-Generation Sequencing for 50 Cancer-Related Genes in Oral Squamous Carcinoma)

    Nakagaki Takafumi, Sasaki Yasushi, Idogawa Masashi, Takeda Kousuke, Tamura Miyuki, Ohashi Tomoko, Ogi Kazuhiro, Hiratsuka Hiroyoshi, Tokino Takashi

    Personalized Medicine Universe. Japanese Edition   3 ( Suppl.2 )   61 - 61   2014.11

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  • Forkhead transcription factor FOXF1 is a novel p53 target gene and regulates cancer cell migration and invasion Reviewed

    Takashi Tokino, Miyuki Tamura, Masashi Idogawa, Yasushi Sasaki

    CANCER RESEARCH   74 ( 19 )   2014.10

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  • Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness

    M. Tamura, Y. Sasaki, R. Koyama, K. Takeda, M. Idogawa, T. Tokino

    ONCOGENE   33 ( 40 )   4837 - 4846   2014.10

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  • Array-based genome-wide RNAi screening to identify shRNAs that enhance p53-related apoptosis in human cancer cells. Reviewed International journal

    Masashi Idogawa, Tomoko Ohashi, Jun Sugisaka, Yasushi Sasaki, Hiromu Suzuki, Takashi Tokino

    Oncotarget   5 ( 17 )   7540 - 8   2014.9

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    p53 transduction is a potentially effective cancer therapy but does not result in a good therapeutic response in all human cancers due to resistance to apoptosis. To discover factors that overcome resistance to p53-induced apoptosis, we attempted to identify RNAi sequences that enhance p53-induced apoptosis. We screened a genome-wide lentiviral shRNA library in liver cancer Huh-7 and pancreatic cancer Panc-1 cells, both of which resist p53-induced apoptosis. After the infection of adenovirus expressing p53 or LacZ as a control, shRNA-treated populations were analyzed by microarray. We identified shRNAs that were significantly decreased in p53-infected cells compared with control cells. Among these shRNAs, shRNA-58335 was markedly decreased in both cancer cell lines tested. shRNA-58335 enhanced p53-related apoptosis in vitro and augmented the inhibitory effect of adenoviral p53 transduction on tumor growth in vivo. Furthermore, the enhanced apoptotic response by shRNA-58335 was also confirmed by treatment with PRIMA-1, which reactivates mutant p53, instead of adenoviral p53 transduction. We found that shRNA-58335 evokes the apoptotic response following p53 transduction or functional restoration of p53 with a small molecule drug in cancer cells resistant to p53-induced apoptosis. The combination of p53 restoration and RNAi-based drugs is expected to be a promising novel cancer therapy.

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  • 次世代半導体シーケンサーを用いた口腔扁平上皮癌におけるがん関連遺伝子の変異解析(A Next-Generation Sequencing Screen for Mutational Hotspots in 50 Cancer-Related Genes using Semiconductor Sequencer)

    中垣 貴文, 佐々木 泰史, 井戸川 雅史, 竹田 康佑, 田村 みゆき, 大箸 智子, 荻 和弘, 平塚 博義, 時野 隆至

    日本癌学会総会記事   73回   P - 3270   2014.9

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  • 多発性骨髄腫における単球と骨髄ストローマ細胞の関連性(The interaction between monocyte and bone marrow stroma cell in the pathogenesis of myeloma)

    池田 博, 五十嵐 哲祥, 青木 由佳, 林 敏昭, 石田 禎夫, 佐々木 泰史, 時野 隆至, 篠村 恭久

    日本癌学会総会記事   73回   P - 2277   2014.9

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  • 口腔扁平上皮癌の発生や進展において重要な役割を果たす長鎖非コードRNAの同定(Identification of long non-coding RNAs potentially involved in oral squamous cell carcinoma)

    西山 廣陽, 丸山 玲緒, 竹田 康佑, 中垣 貴文, 新沼 猛, 荻 和弘, 出張 裕也, 甲斐 正広, 宮崎 晃亘, 佐々木 泰史, 時野 隆至, 平塚 博義, 鈴木 拓

    日本癌学会総会記事   73回   P - 3277   2014.9

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  • p53のmiR-200ファミリーを介したCRKLの発現抑制(Proto-oncogene CRKL is downregulated by p53 family through miR-200 family)

    田村 みゆき, 佐々木 泰史, 竹田 康佑, 中垣 貴文, 大箸 智子, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   73回   P - 2065   2014.9

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  • p53標的遺伝子AKR1B10は大腸癌で発現減少し予後不良と相関する(AKR1B10, a Transcriptional Target of p53, is Downregulated in Colorectal Cancers Associated with Poor Prognosis)

    大箸 智子, 井戸川 雅史, 田村 みゆき, 竹田 康佑, 中垣 貴文, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   73回   P - 2072   2014.9

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  • ゲノム網羅的p53結合領域解析とマイクロアレイを組み合わせたp53ファミリー標的長鎖非コードRNA(lincRNA)の同定と解析(Identification of p53 target long non-coding RNAs (lincRNAs) through ChIP-seq, in silico motif analysis and microarray)

    井戸川 雅史, 大箸 智子, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   73回   P - 2079   2014.9

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  • 半導体シーケンサーを用いたがん関連遺伝子の網羅的解析(Comprehensive genomic analyses of cancer tissues by semiconductor-based next-generation sequencing)

    佐々木 泰史, 中垣 貴文, 田村 みゆき, 竹田 康佑, 井戸川 雅史, 大箸 智子, 鈴木 拓, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   73回   P - 2146   2014.9

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  • Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites. Reviewed International journal

    Masashi Idogawa, Tomoko Ohashi, Yasushi Sasaki, Reo Maruyama, Lisa Kashima, Hiromu Suzuki, Takashi Tokino

    Human molecular genetics   23 ( 11 )   2847 - 57   2014.6

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    p53 is one of the most important known tumor suppressor genes, and it is inactivated in approximately half of human cancers. p53 family members execute various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. Therefore, the direct transcriptional targets of the p53 family must be explored to elucidate the functional mechanisms of family members. To identify the direct transcriptional targets of p53 family members, we performed chromatin immunoprecipitation together with next-generation sequencing (ChIP-seq) and searched for p53-binding motifs across the entire human genome. Among the identified ChIP-seq peaks, approximately half were located in an intergenic region. Therefore, we assumed large intergenic non-coding RNAs (lincRNAs) to be major targets of the p53 family. Recent reports have revealed that lincRNAs play an important role in various biological and pathological processes, such as development, differentiation, stemness and carcinogenesis. Through a combination of ChIP-seq and in silico analyses, we found 23 lincRNAs that are upregulated by the p53 family. Additionally, knockdown of specific lincRNAs modulated p53-induced apoptosis and promoted the transcription of a gene cluster. Our results suggest that p53 family members, and lincRNAs constitute a complex transcriptional network involved in various biological functions and tumor suppression.

    DOI: 10.1093/hmg/ddt673

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  • AKR1B10, a transcriptional target of p53, is downregulated in colorectal cancers associated with poor prognosis. Reviewed International journal

    Tomoko Ohashi, Masashi Idogawa, Yasushi Sasaki, Hiromu Suzuki, Takashi Tokino

    Molecular cancer research : MCR   11 ( 12 )   1554 - 63   2013.12

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    UNLABELLED: p53 is one of the most important tumor suppressor genes, and it is frequently inactivated in various cancers. p53 modulates various cellular functions, such as apoptosis and cell-cycle arrest via transcriptional regulation. Recently, p53 has been reported to be involved in a wide range of cellular metabolic pathways, including glycolysis, oxidative phosphorylation, glutaminolysis, and the antioxidant response. To understand the functional mechanism of p53, it is important to find out the direct transcriptional targets of p53. In this study, aldo-keto reductase family 1, member B10 (AKR1B10) was identified as a direct target of the p53 family by cDNA microarray analysis after comparing the mRNA expression of control and H1299 cells that overexpressed with p53 family members. In addition, we found that the expression of AKR1B10 was significantly decreased in colorectal cancers and adenomas as compared with normal colon tissues. Knockdown of AKR1B10 significantly inhibited p53-induced apoptosis in colorectal cancer cells, whereas the overexpression of AKR1B10 enhanced p53-induced apoptosis and inhibited tumor proliferation in vivo. Furthermore, low expression of AKR1B10 in colon cancer patients was correlated with decreased survival and poor prognosis. These results suggest that decreased expression of AKR1B10 could disrupt the tumor suppressive function of p53, which result in decreased survival in colorectal cancer patients. In summary, AKR1B10 may be a novel prognostic predictor and a novel therapeutic target for colorectal cancer. IMPLICATIONS: AKR1B10, a transcriptional target of p53, is also a novel prognostic and therapeutic molecule in colorectal cancer.

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  • p53によるXPO1の抑制機構とその意義(p53 negatively regulates the expression of the nuclear export protein XPO1, establishing a positive feedback loop)

    佐々木 泰史, 田村 みゆき, 竹田 康佑, 井戸川 雅史, 丸山 玲緒, 鈴木 拓, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   72回   105 - 105   2013.10

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  • p53はmiR-200ファミリーを介してCRKLの発現を抑制する(p53 family members activate the miR-200 family leading to downregulation of the CRKL proto-oncogene protein)

    田村 みゆき, 佐々木 泰史, 竹田 康佑, 大箸 智子, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   72回   253 - 253   2013.10

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  • p53ファミリーの新規標的ICAM2の同定 がん細胞の接着・遊走能への関与(Identification and characterization of the intercellular adhesion molecule-2 gene as a novel p53 family target)

    竹田 康佑, 佐々木 泰史, 田村 みゆき, 井戸川 雅史, 荻 和弘, 平塚 博義, 時野 隆至

    日本癌学会総会記事   72回   253 - 253   2013.10

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  • AKR1B10はp53ファミリーの直接転写標的でありp53誘導アポトーシスを促進する(AKR1B10 is a direct transcriptional target of p53 family members and promotes p53-induced apoptosis)

    大箸 智子, 井戸川 雅史, 田村 みゆき, 竹田 康佑, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   72回   253 - 253   2013.10

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  • ゲノム網羅的p53結合領域解析によるp53ファミリーの転写標的となる大型介在性非コードRNA(LincRNA)の同定と機能解析(Identification of large intergenic non-coding RNAs regulated by p53 through a genome-wide analysis of p53 binding sites)

    井戸川 雅史, 大箸 智子, 佐々木 泰史, 丸山 玲緒, 鈴木 拓, 時野 隆至

    日本癌学会総会記事   72回   104 - 104   2013.10

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  • Methylation of a panel of microRNA genes is a novel biomarker for detection of bladder cancer. Reviewed International journal

    Takashi Shimizu, Hiromu Suzuki, Masanori Nojima, Hiroshi Kitamura, Eiichiro Yamamoto, Reo Maruyama, Masami Ashida, Tomo Hatahira, Masahiro Kai, Naoya Masumori, Takashi Tokino, Kohzoh Imai, Taiji Tsukamoto, Minoru Toyota

    European urology   63 ( 6 )   1091 - 100   2013.6

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    BACKGROUND: Dysregulation of microRNAs (miRNAs) has been implicated in bladder cancer (BCa), although the mechanism is not fully understood. OBJECTIVE: We aimed to explore the involvement of epigenetic alteration of miRNA expression in BCa. DESIGN, SETTING, AND PARTICIPANTS: Two BCa cell lines (T24 and UM-UC-3) were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which their miRNA expression profiles were analyzed using a TaqMan array (Life Technologies, Carlsbad, CA, USA). Bisulfite pyrosequencing was used to assess miRNA gene methylation in 5 cancer cell lines, 83 primary tumors, and 120 preoperative and 47 postoperative urine samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of the miRNA gene panel. RESULTS AND LIMITATIONS: Of 664 miRNAs examined, 146 were upregulated by 5-aza-dC plus PBA. CpG islands were identified in the proximal upstream of 23 miRNA genes, and 12 of those were hypermethylated in cell lines. Among them, miR-137, miR-124-2, miR-124-3, and miR-9-3 were frequently and tumor-specifically methylated in primary cancers (miR-137: 68.7%; miR-124-2: 50.6%; miR-124-3: 65.1%; miR-9-3: 45.8%). Methylation of the same four miRNAs in urine specimens enabled BCa detection with 81% sensitivity and 89% specificity; the area under the ROC curve was 0.916. Ectopic expression of silenced miRNAs in BCa cells suppressed growth and cell invasion. CONCLUSIONS: Our results indicate that epigenetic silencing of miRNA genes may be involved in the development of BCa and that methylation of miRNA genes could be a useful biomarker for cancer detection.

    DOI: 10.1016/j.eururo.2012.11.030

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  • DNA methyltransferase 1 is essential for initiation of the colon cancers. Reviewed International journal

    Rena Morita, Yoshihiko Hirohashi, Hiromu Suzuki, Akari Takahashi, Yasuaki Tamura, Takayuki Kanaseki, Hiroko Asanuma, Satoko Inoda, Toru Kondo, Satoshi Hashino, Tadashi Hasegawa, Takashi Tokino, Minoru Toyota, Masahiro Asaka, Toshihiko Torigoe, Noriyuki Sato

    Experimental and molecular pathology   94 ( 2 )   322 - 9   2013.4

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    DNA methyltransferase 1 (Dnmt1) is essential for the maintenance of hematopoietic and somatic stem cells in mice; however, its roles in human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are still elusive. In the present study, we investigated DNMT1 functions in the maintenance of human colon CSCs/CICs using the human colon cancer cell line HCT116 (HCT116 w/t) and its DNMT1 knockout cell line (DNMT1(-/-)). The rates of CSCs/CICs were evaluated by side population (SP) analysis, ALDEFLUOR assay and expression of CD44 and CD24. SP, ALDEFLUOR-positive (ALDEFLUOR(+)) and CD44-positive and CD24-positive (CD44(+)CD24(+)) cell rates were lower in DNMT1(-/-) cells than in HCT116 w/t cells. Since CSCs/CICs have higher tumor-initiating ability than that of non-CSCs/CICs, the tumor-initiating abilities were addressed by injecting immune deficient (NOD/SCID) mice. DNMT1(-/-) cells showed less tumor-initiating ability than did HCT116 w/t cells, whereas the growing rate of DNMT1(-/-) cells showed no significant difference from that of HCT116 cells both in vitro and in vivo. Similar results were obtained for cells in which DNMT1 had been transiently knocked-down using gene-specific siRNAs. Taken together, these results indicate that DNMT1 is essential for maintenance of colon CSCs/CICs and that short-term suppression of DNMT1 might be sufficient to disrupt CSCs/CICs.

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  • 2P026 Direct observation of the multiple sliding modes of a tumor suppressor p53(01B. Protein: Structure & Function,Poster)

    Murata Agato, Kashima Risa, Itoh Yuji, Tokino Takashi, Takahashi Satoshi, Kamagata Kiyoto

    Seibutsu Butsuri   53 ( 1 )   S163   2013

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    DOI: 10.2142/biophys.53.S163_2

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  • CLCA2, a target of the p53 family, negatively regulates cancer cell migration and invasion. Reviewed International journal

    Yasushi Sasaki, Ryota Koyama, Reo Maruyama, Takehiro Hirano, Miyuki Tamura, Jun Sugisaka, Hiromu Suzuki, Masashi Idogawa, Yasuhisa Shinomura, Takashi Tokino

    Cancer biology & therapy   13 ( 14 )   1512 - 21   2012.12

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    The tumor suppressor p53 transcriptionally regulates a number of genes that are involved in cell-cycle inhibition, apoptosis and the maintenance of genetic stability. Recent studies suggest that p53 also contributes to the regulation of cell migration and invasion. Here, we show that human chloride channel accessory-2 (CLCA2) is a target gene of the p53 family (p53, p73 and p63). CLCA2 is induced by DNA damage in a p53-dependent manner. The p53 family proteins activate the CLCA2 promoter by binding directly to the conserved consensus p53-binding site present in the CLCA2 promoter. In terms of function, ectopic expression of CLCA2 inhibited cancer cell migration. In contrast, silencing CLCA2 with siRNA stimulated cancer cell migration and invasion. We also found that inactivation of CLCA2 enhanced the expression of focal adhesion kinase (FAK), as well as its promoter activation. A small-molecule FAK inhibitor reduced the effect of CLCA2 siRNA on cell migration and invasion, suggesting that CLCA2 inhibits cancer cell migration and invasion through suppression of the FAK signaling pathway. Furthermore, there was an inverse correlation between CLCA2 and FAK expression in 251 human breast cancer tissues. These results strongly suggest that CLCA2 is involved in the p53 tumor suppressor network and has a significant effect on cell migration and invasion.

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  • A novel approach to cancer treatment using structural hybrids of the p53 gene family

    Y. Sasaki, Y. Oshima, R. Koyama, M. Tamura, L. Kashima, M. Idogawa, T. Yamashita, M. Toyota, K. Imai, Y. Shinomura, T. Tokino

    CANCER GENE THERAPY   19 ( 11 )   749 - 756   2012.11

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    DOI: 10.1038/cgt.2012.51

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  • Molecular dissection of premalignant colorectal lesions reveals early onset of the CpG island methylator phenotype. Reviewed International journal

    Eiichiro Yamamoto, Hiromu Suzuki, Hiro-o Yamano, Reo Maruyama, Masanori Nojima, Seiko Kamimae, Takeshi Sawada, Masami Ashida, Kenjiro Yoshikawa, Tomoaki Kimura, Ryo Takagi, Taku Harada, Ryo Suzuki, Akiko Sato, Masahiro Kai, Yasushi Sasaki, Takashi Tokino, Tamotsu Sugai, Kohzoh Imai, Yasuhisa Shinomura, Minoru Toyota

    The American journal of pathology   181 ( 5 )   1847 - 61   2012.11

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    The concept of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) is widely accepted, although the timing of its occurrence and its interaction with other genetic defects are not fully understood. Our aim in this study was to unravel the molecular development of CIMP cancers by dissecting their genetic and epigenetic signatures in precancerous and malignant colorectal lesions. We characterized the methylation profile and BRAF/KRAS mutation status in 368 colorectal tissue samples, including precancerous and malignant lesions. In addition, genome-wide copy number aberrations, methylation profiles, and mutations of BRAF, KRAS, TP53, and PIK3CA pathway genes were examined in 84 colorectal lesions. Genome-wide methylation analysis of CpG islands and selected marker genes revealed that CRC precursor lesions are in three methylation subgroups: CIMP-high, CIMP-low, and CIMP-negative. Interestingly, a subset of CIMP-positive malignant lesions exhibited frequent copy number gains on chromosomes 7 and 19 and genetic defects in the AKT/PIK3CA pathway genes. Analysis of mixed lesions containing both precancerous and malignant components revealed that most aberrant methylation is acquired at the precursor stage, whereas copy number aberrations are acquired during the progression from precursor to malignant lesion. Our integrative genomic and epigenetic analysis suggests early onset of CIMP during CRC development and indicates a previously unknown CRC development pathway in which epigenetic instability associates with genomic alterations.

    DOI: 10.1016/j.ajpath.2012.08.007

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  • Heat shock enhances the expression of cytotoxic granule proteins and augments the activities of tumor-associated antigen-specific cytotoxic T lymphocytes. Reviewed International journal

    Akari Takahashi, Toshihiko Torigoe, Yasuaki Tamura, Takayuki Kanaseki, Tomohide Tsukahara, Yasushi Sasaki, Hidekazu Kameshima, Tetsuhiro Tsuruma, Koichi Hirata, Takashi Tokino, Yoshihiko Hirohashi, Noriyuki Sato

    Cell stress & chaperones   17 ( 6 )   757 - 63   2012.11

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    Focal inflammation causes systemic fever. Cancer hyperthermia therapy results in shrinkage of tumors by various mechanisms, including induction of adaptive immune response. However, the physiological meaning of systemic fever and mechanisms of tumor shrinkage by hyperthermia have not been completely understood. In this study, we investigated how heat shock influences the adaptive immune system. We established a cytotoxic T lymphocyte (CTL) clone (#IM29) specific for survivin, one of the tumor-associated antigens (TAAs), from survivin peptide-immunized cancer patients' peripheral blood, and the CTL activities were investigated in several temperature conditions (37-41 °C). Cytotoxicity and IFN-γ secretion of CTL were greatest under 39 °C condition, whereas they were minimum under 41 °C. To address the molecular mechanisms of this phenomenon, we investigated the apoptosis status of CTLs, expression of CD3, CD8, and TCRαβ by flow cytometry, and expression of perforin, granzyme B, and Fas ligand by western blot analysis. The expression of perforin and granzyme B were upregulated under temperature conditions of 39 and 41 °C. On the other hand, CTL cell death was induced under 41 °C condition with highest Caspase-3 activity. Therefore, the greatest cytotoxicity activity at 39 °C might depend on upregulation of cytotoxic granule proteins including perforin and granzyme B. These results suggest that heat shock enhances effector phase of the adaptive immune system and promotes eradication of microbe and tumor cells.

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  • Aberrant methylation of RASGRF1 is associated with an epigenetic field defect and increased risk of gastric cancer. Reviewed International journal

    Hiroyuki Takamaru, Eiichiro Yamamoto, Hiromu Suzuki, Masanori Nojima, Reo Maruyama, Hiro-O Yamano, Kenjiro Yoshikawa, Tomoaki Kimura, Taku Harada, Masami Ashida, Ryo Suzuki, Hiroyuki Yamamoto, Masahiro Kai, Takashi Tokino, Tamotsu Sugai, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

    Cancer prevention research (Philadelphia, Pa.)   5 ( 10 )   1203 - 12   2012.10

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    Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P < 0.001; 8.3% vs. 19.4%, P < 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer.

    DOI: 10.1158/1940-6207.CAPR-12-0056

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  • Genome-wide analysis of DNA methylation identifies novel cancer-related genes in hepatocellular carcinoma. Reviewed International journal

    Masahiro Shitani, Shigeru Sasaki, Noriyuki Akutsu, Hideyasu Takagi, Hiromu Suzuki, Masanori Nojima, Hiroyuki Yamamoto, Takashi Tokino, Koichi Hirata, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine   33 ( 5 )   1307 - 17   2012.10

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    Aberrant DNA methylation has been implicated in the development of hepatocellular carcinoma (HCC). Our aim was to clarify its molecular mechanism and to identify useful biomarkers by screening for DNA methylation in HCC. Methylated CpG island amplification coupled with CpG island microarray (MCAM) analysis was carried out to screen for methylated genes in primary HCC specimens [hepatitis B virus (HBV)-positive, n = 4; hepatitis C virus (HCV)-positive, n = 5; HBV/HCV-negative, n = 7]. Bisulfite pyrosequencing was used to analyze the methylation of selected genes and long interspersed nuclear element (LINE)-1 in HCC tissue (n = 57) and noncancerous liver tissue (n = 50) from HCC patients and in HCC cell lines (n = 10). MCAM analysis identified 332, 342, and 259 genes that were methylated in HBV-positive, HCV-positive, and HBV/HCV-negative HCC tissues, respectively. Among these genes, methylation of KLHL35, PAX5, PENK, and SPDYA was significantly higher in HCC tissue than in noncancerous liver tissue, irrespective of the hepatitis virus status. LINE-1 hypomethylation was also prevalent in HCC and correlated positively with KLHL35 and SPDYA methylation. Receiver operating characteristic curve analysis revealed that methylation of the four genes and LINE-1 strongly discriminated between HCC tissue and noncancerous liver tissue. Our data suggest that aberrant hyper- and hypomethylation may contribute to a common pathogenesis mechanism in HCC. Hypermethylation of KLHL35, PAX, PENK, and SDPYA and hypomethylation of LINE-1 could be useful biomarkers for the detection of HCC.

    DOI: 10.1007/s13277-012-0378-3

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  • DNAメチル化の網羅的解析により同定された新規肝癌関連遺伝子

    志谷 真啓, 鈴木 拓, 阿久津 典之, 高木 秀安, 佐々木 茂, 野島 正寛, 山本 博幸, 時野 隆至, 平田 公一, 篠村 恭久

    日本消化器病学会雑誌   109 ( 臨増大会 )   A700 - A700   2012.9

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  • ゲノム網羅的p53応答配列解析とクロマチン免疫沈降シーケンシング(ChIP-seq)を組み合わせた新規p53標的遺伝子の同定(Identification of novel p53 target genes by ChIP-seq combined with genome-wide p53-binding motif analysis in silico)

    井戸川 雅史, 大箸 智子, 佐々木 泰史, 篠村 恭久, 今井 浩三, 時野 隆至

    日本癌学会総会記事   71回   257 - 258   2012.8

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  • 多発性骨髄腫の発生におけるDNAメチロームの意義 MBDシーケンシング法によるアプローチ(The significance of DNA methylome for tumor progression in multiple myeloma: An MBD-sequencing-based approach)

    野島 正寛, 青木 由佳, 安井 寛, 丸山 玲緒, 麻奥 英毅, 石田 禎夫, 時野 隆至, 森 満, 鈴木 拓, 篠村 恭久

    日本癌学会総会記事   71回   385 - 385   2012.8

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  • p53ファミリーとがん p53ファミリーネットワークと腫瘍抑制(p53 family and cancer research p53 family network and tumor suppression)

    佐々木 泰史, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   71回   41 - 41   2012.8

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  • p53ファミリーの新規標的FOXF1の同定と機能解析 がん細胞の浸潤・遊走能への関与(Forkhead box F1 is a novel target gene of the p53 family and regulates cancer cell migration and invasiveness)

    田村 みゆき, 佐々木 泰史, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   71回   175 - 176   2012.8

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  • ゲノム網羅的shRNAライブラリースクリーニングによるp53誘導アポトーシス阻害遺伝子の同定(The identification of target genes inhibiting p53-induced apoptosis by the screening of genome-wide shRNA library)

    大箸 智子, 井戸川 雅史, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   71回   176 - 176   2012.8

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  • CHFR protein regulates mitotic checkpoint by targeting PARP-1 protein for ubiquitination and degradation. Reviewed International journal

    Lisa Kashima, Masashi Idogawa, Hiroaki Mita, Miki Shitashige, Tesshi Yamada, Kazuhiro Ogi, Hiromu Suzuki, Minoru Toyota, Hiroyoshi Ariga, Yasushi Sasaki, Takashi Tokino

    The Journal of biological chemistry   287 ( 16 )   12975 - 84   2012.4

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    The mitotic checkpoint gene CHFR (checkpoint with forkhead-associated (FHA) and RING finger domains) is silenced by promoter hypermethylation or mutated in various human cancers, suggesting that CHFR is an important tumor suppressor. Recent studies have reported that CHFR functions as an E3 ubiquitin ligase, resulting in the degradation of target proteins. To better understand how CHFR suppresses cell cycle progression and tumorigenesis, we sought to identify CHFR-interacting proteins using affinity purification combined with mass spectrometry. Here we show poly(ADP-ribose) polymerase 1 (PARP-1) to be a novel CHFR-interacting protein. In CHFR-expressing cells, mitotic stress induced the autoPARylation of PARP-1, resulting in an enhanced interaction between CHFR and PARP-1 and an increase in the polyubiquitination/degradation of PARP-1. The decrease in PARP-1 protein levels promoted cell cycle arrest at prophase, supporting that the cells expressing CHFR were resistant to microtubule inhibitors. In contrast, in CHFR-silenced cells, polyubiquitination was not induced in response to mitotic stress. Thus, PARP-1 protein levels did not decrease, and cells progressed into mitosis under mitotic stress, suggesting that CHFR-silenced cancer cells were sensitized to microtubule inhibitors. Furthermore, we found that cells from Chfr knockout mice and CHFR-silenced primary gastric cancer tissues expressed higher levels of PARP-1 protein, strongly supporting our data that the interaction between CHFR and PARP-1 plays an important role in cell cycle regulation and cancer therapeutic strategies. On the basis of our studies, we demonstrate a significant advantage for use of combinational chemotherapy with PARP inhibitors for cancer cells resistant to microtubule inhibitors.

    DOI: 10.1074/jbc.M111.321828

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  • Identification of p53 target genes by ChIP-Seq and transcriptome analysis combined with genome-wide p53-binding motif analysis in silico Reviewed

    Masashi Idogawa, Yasushi Sasaki, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino

    CANCER RESEARCH   72   2012.4

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  • p53により発現抑制される分泌性増殖因子HDGFの同定とがん組織における発現解析

    佐々木 泰史, 根岸 秀明, 小山 良太, 井戸川 雅史, 鈴木 拓, 今井 浩三, 篠村 恭久, 時野 隆至

    日本臨床分子医学会学術総会プログラム・抄録集   49回   133 - 133   2012.4

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  • Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Reviewed International journal

    Takeshi Niinuma, Hiromu Suzuki, Masanori Nojima, Katsuhiko Nosho, Hiroyuki Yamamoto, Hiroyuki Takamaru, Eiichiro Yamamoto, Reo Maruyama, Takayuki Nobuoka, Yasuaki Miyazaki, Toshirou Nishida, Takeo Bamba, Tatsuo Kanda, Yoichi Ajioka, Takahiro Taguchi, Satoshi Okahara, Hiroaki Takahashi, Yasunori Nishida, Masao Hosokawa, Tadashi Hasegawa, Takashi Tokino, Koichi Hirata, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

    Cancer research   72 ( 5 )   1126 - 36   2012.3

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    Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXC and HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference-mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs.

    DOI: 10.1158/0008-5472.CAN-11-1803

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  • Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma. Reviewed International journal

    Yuka Aoki, Masanori Nojima, Hiromu Suzuki, Hiroshi Yasui, Reo Maruyama, Eiichiro Yamamoto, Masami Ashida, Mitsuhiro Itagaki, Hideki Asaoku, Hiroshi Ikeda, Toshiaki Hayashi, Kohzoh Imai, Mitsuru Mori, Takashi Tokino, Tadao Ishida, Minoru Toyota, Yasuhisa Shinomura

    Genome medicine   4 ( 12 )   101 - 101   2012

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    BACKGROUND: The aim of this study was to clarify the role of global hypomethylation of repetitive elements in determining the genetic and clinical features of multiple myeloma (MM). METHODS: We assessed global methylation levels using four repetitive elements (long interspersed nuclear element-1 (LINE-1), Alu Ya5, Alu Yb8, and Satellite-α) in clinical samples comprising 74 MM samples and 11 benign control samples (7 cases of monoclonal gammopathy of undetermined significance (MGUS) and 4 samples of normal plasma cells (NPC)). We also evaluated copy-number alterations using array-based comparative genomic hybridization, and performed methyl-CpG binding domain sequencing (MBD-seq). RESULTS: Global levels of the repetitive-element methylation declined with the degree of malignancy of plasma cells (NPC>MGUS>MM), and there was a significant inverse correlation between the degree of genomic loss and the LINE-1 methylation levels. We identified 80 genomic loci as common breakpoints (CBPs) around commonly lost regions, which were significantly associated with increased LINE-1 densities. MBD-seq analysis revealed that average DNA-methylation levels at the CBP loci and relative methylation levels in regions with higher LINE-1 densities also declined during the development of MM. We confirmed that levels of methylation of the 5' untranslated region of respective LINE-1 loci correlated strongly with global LINE-1 methylation levels. Finally, there was a significant association between LINE-1 hypomethylation and poorer overall survival (hazard ratio 2.8, P = 0.015). CONCLUSION: Global hypomethylation of LINE-1 is associated with the progression of and poorer prognosis for MM, possibly due to frequent copy-number loss.

    DOI: 10.1186/gm402

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  • 2E1412 Single-molecule structural analysis of tumor suppressor p53 using scanning probe microscopes(Proteins:Property II,Oral Presentation,The 50th Annual Meeting of the Biophysical Society of Japan)

    Takahashi Seiya, Sainoo Yasuyuki, Kashima Risa, Tokino Takashi, Komeda Tadahiro, Takahashi Satoshi, Kamagata Kiyoto

    Seibutsu Butsuri   52   S45 - S46   2012

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    DOI: 10.2142/biophys.52.S45_5

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  • Erratum

    Tomita M, Toyota M, Ishikawa C, Nakazato T, Okudaira T, Matsuda T, Uchihara J. N, Taira N, Ohshiro K, Senba M, Tanaka Y, Ohshima K, Saya H, Tokino T, Mori N

    International Journal of Cancer   129 ( 11 )   2763   2011.12

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    DOI: 10.1002/ijc.26389

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  • p53 negatively regulates the hepatoma growth factor HDGF. Reviewed International journal

    Yasushi Sasaki, Hideaki Negishi, Masashi Idogawa, Ikuko Yokota, Ryota Koyama, Masanobu Kusano, Hiromu Suzuki, Masahiro Fujita, Reo Maruyama, Minoru Toyota, Tsuyoshi Saito, Takashi Tokino

    Cancer research   71 ( 22 )   7038 - 47   2011.11

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    Hepatoma-derived growth factor (HDGF) is a secreted heparin-binding growth factor that has been implicated in cancer development and progression. Here, we report that HDGF is a critical target for transcriptional repression by the tumor suppressor p53. Endogenous HDGF expression was decreased in cancer cells with introduction of wild-type p53, which also downregulated HDGF expression after DNA damage. In support of the likelihood that HDGF is a critical driver of cancer cell growth, addition of neutralizing HDGF antibodies to culture media was sufficient to block cell growth, migration, and invasion. Similarly, these effects were elicited by conditioned culture medium from p53-expressing cells, and they could be reversed by the addition of recombinant human HDGF. Interestingly, we found that HDGF was overexpressed also in primary gastric, breast, and lung cancer tissues harboring mutant p53 genes. Mechanistic investigations revealed that p53 repressed HDGF transcription by altering HDAC-dependent chromatin remodeling. Taken together, our results reveal a new pathway in which loss of p53 function contributes to the aggressive pathobiological potential of human cancers by elevating HDGF expression.

    DOI: 10.1158/0008-5472.CAN-11-1053

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  • Genome-wide profiling of chromatin signatures reveals epigenetic regulation of MicroRNA genes in colorectal cancer. Reviewed International journal

    Hiromu Suzuki, Shintaro Takatsuka, Hirofumi Akashi, Eiichiro Yamamoto, Masanori Nojima, Reo Maruyama, Masahiro Kai, Hiro-O Yamano, Yasushi Sasaki, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Minoru Toyota

    Cancer research   71 ( 17 )   5646 - 58   2011.9

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    Altered expression of microRNAs (miRNA) occurs commonly in human cancer, but the mechanisms are generally poorly understood. In this study, we examined the contribution of epigenetic mechanisms to miRNA dysregulation in colorectal cancer by carrying out high-resolution ChIP-seq. Specifically, we conducted genome-wide profiling of trimethylated histone H3 lysine 4 (H3K4me3), trimethylated histone H3 lysine 27 (H3K27me3), and dimethylated histone H3 lysine 79 (H3K79me2) in colorectal cancer cell lines. Combining miRNA expression profiles with chromatin signatures enabled us to predict the active promoters of 233 miRNAs encoded in 174 putative primary transcription units. By then comparing miRNA expression and histone modification before and after DNA demethylation, we identified 47 miRNAs encoded in 37 primary transcription units as potential targets of epigenetic silencing. The promoters of 22 transcription units were associated with CpG islands (CGI), all of which were hypermethylated in colorectal cancer cells. DNA demethylation led to increased H3K4me3 marking at silenced miRNA genes, whereas no restoration of H3K79me2 was detected in CGI-methylated miRNA genes. DNA demethylation also led to upregulation of H3K4me3 and H3K27me3 in a number of CGI-methylated miRNA genes. Among the miRNAs we found to be dysregulated, many of which are implicated in human cancer, miR-1-1 was methylated frequently in early and advanced colorectal cancer in which it may act as a tumor suppressor. Our findings offer insight into the association between chromatin signatures and miRNA dysregulation in cancer, and they also suggest that miRNA reexpression may contribute to the effects of epigenetic therapy.

    DOI: 10.1158/0008-5472.CAN-11-1076

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  • 多発性骨髄腫におけるDNAメチロームと染色体異常 メチル化DNA結合蛋白を利用した次世代シーケンシングによる検討(DNA methylome and chromosomal aberrations in multiple myeloma: an integrated analysis based on MBD-sequencing)

    野島 正寛, 青木 由佳, 安井 寛, 丸山 玲緒, 鈴木 拓, 石田 禎夫, 時野 隆至, 篠村 恭久, 豊田 実

    日本癌学会総会記事   70回   47 - 47   2011.9

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  • 多発性骨髄腫におけるDNA繰り返し配列の低メチル化と染色体異常の関連(The relationship between DNA hypomethylation of repetitive elements and chromosomal aberrations in multiple myeloma)

    青木 由佳, 野島 正寛, 安井 寛, 丸山 玲緒, 鈴木 拓, 石田 禎夫, 麻奥 英毅, 時野 隆至, 豊田 実, 篠村 恭久

    日本癌学会総会記事   70回   137 - 137   2011.9

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  • ゲノム網羅的shRNAライブラリースクリーニングに基づく人工miRNA/p53共発現による癌治療(Cancer therapy by the transduction of p53 and artificial miRNAs based on the screening of genome-wide shRNA library)

    井戸川 雅史, 佐々木 泰史, 鹿島 理沙, 篠村 恭久, 今井 浩三, 時野 隆至

    日本癌学会総会記事   70回   52 - 52   2011.9

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  • p53により発現抑制される分泌性増殖因子HDGFの同定とがんの浸潤・遊走への関与(Negative regulation of hepatoma-derived growth factor by p53)

    佐々木 泰史, 根岸 秀明, 横田 育子, 鹿島 理沙, 井戸川 雅史, 丸山 玲緒, 鈴木 拓, 豊田 実, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   70回   153 - 153   2011.9

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  • p53ファミリーの新規標的ICAM2の同定 がん細胞の接着・遊走能への関与(Identification and characterizatio n of the intercellular adhesion molecule-2 gene as a novel p53 family target)

    横田 育子, 佐々木 泰史, 田村 みゆき, 鹿島 理沙, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   70回   153 - 153   2011.9

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  • p53ファミリーの新規標的遺伝子FOXF1の同定と機能解析(Forkhead transcription factor FOXF1 is a novel target gene of the p53 family and regulates cancer cell invasiveness)

    田村 みゆき, 佐々木 泰史, 横田 育子, 鹿島 理沙, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   70回   153 - 153   2011.9

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  • Cysteine-rich intestinal protein 2 (CRIP2) acts as a repressor of NF-kappaB-mediated proangiogenic cytokine transcription to suppress tumorigenesis and angiogenesis. Reviewed International journal

    Arthur Kwok Leung Cheung, Josephine M Y Ko, Hong Lok Lung, Kwok Wah Chan, Eric J Stanbridge, Eugene Zabarovsky, Takashi Tokino, Lisa Kashima, Toshiharu Suzuki, Dora Lai-Wan Kwong, Daniel Chua, Sai Wah Tsao, Maria Li Lung

    Proceedings of the National Academy of Sciences of the United States of America   108 ( 20 )   8390 - 5   2011.5

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    Chromosome 14 was transferred into tumorigenic nasopharyngeal carcinoma and esophageal carcinoma cell lines by a microcell-mediated chromosome transfer approach. Functional complementation of defects present in the cancer cells suppressed tumor formation. A candidate tumor-suppressor gene, cysteine-rich intestinal protein 2 (CRIP2), located in the hot spot for chromosomal loss at 14q32.3, was identified as an important candidate gene capable of functionally suppressing tumor formation. Previous studies have shown that CRIP2 is associated with development. To date, no report has provided functional evidence supporting a role for CRIP2 in tumor development. The present study provides unequivocal evidence that CRIP2 can functionally suppress tumorigenesis. CRIP2 is significantly down-regulated in nasopharyngeal carcinoma cell lines and tumors. CRIP2 reexpression functionally suppresses in vivo tumorigenesis and angiogenesis; these effects are induced by its transcription-repressor capability. It interacts with the NF-κB/p65 to inhibit its DNA-binding ability to the promoter regions of the major proangiogenesis cytokines critical for tumor progression, including IL6, IL8, and VEGF. In conclusion, we provide compelling evidence that CRIP2 acts as a transcription repressor of the NF-κB-mediated proangiogenic cytokine expression and thus functionally inhibits tumor formation and angiogenesis.

    DOI: 10.1073/pnas.1101747108

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  • Epigenetic alteration of DNA in mucosal wash fluid predicts invasiveness of colorectal tumors. Reviewed International journal

    Seiko Kamimae, Eiichiro Yamamoto, Hiro-o Yamano, Masanori Nojima, Hiromu Suzuki, Masami Ashida, Tomo Hatahira, Akiko Sato, Tomoaki Kimura, Kenjiro Yoshikawa, Taku Harada, Seiko Hayashi, Hiroyuki Takamaru, Reo Maruyama, Masahiro Kai, Morie Nishiwaki, Tamotsu Sugai, Yasushi Sasaki, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Minoru Toyota

    Cancer prevention research (Philadelphia, Pa.)   4 ( 5 )   674 - 83   2011.5

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    Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors. We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC = 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors.

    DOI: 10.1158/1940-6207.CAPR-10-0214

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  • The functional relationship between CHFR and PARP-1 controls the antephase checkpoint and tumor development Reviewed

    Lisa Kashima, Hiroaki Mita, Masashi Idogawa, Minoru Toyota, Yasushi Sasaki, Takashi Tokino

    CANCER RESEARCH   71   2011.4

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  • Apoptosis induction in cancer cells by the simultaneous transduction of p53 and artificial miRNAs based on the screening of genome-wide shRNA library Reviewed

    Masashi Idogawa, Yasushi Sasaki, Lisa Kashima, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino

    CANCER RESEARCH   71   2011.4

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  • p53ファミリーの新規標的ICAM2の同定 がん細胞の接着・遊走能への関与(Identification and characterization of the intercellular adhesion molecule-2 gene as a novel p53 family target)

    平野 雄大, 佐々木 泰史, 横田 育子, 杉坂 淳, 鹿島 理紗, 井戸川 雅史, 時野 隆至

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   3P - 0982   2010.12

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  • Identification and characterization of early growth response 2, a zinc-finger transcription factor, as a p53-regulated proapoptotic gene. Reviewed International journal

    Ikuko Yokota, Yasushi Sasaki, Lisa Kashima, Masashi Idogawa, Takashi Tokino

    International journal of oncology   37 ( 6 )   1407 - 16   2010.12

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    Tumor suppressor p53 is a transcription factor that induces growth arrest and/or apoptosis in response to cellular stress. In recent years, many genes have been identified as p53-regulated genes; however, no single target gene has been shown to be required for the apoptotic effect. Using microarray analysis, we have identified the transcription factor early growth response 2 (EGR2) as a target of the p53 family, specifically p53, p63 and p73. EGR2 expression was up-regulated by DNA damage-induced p53 activity, as well as by overexpression of p53 family genes. Furthermore, we identified a responsive element to p53, TAp63, and TAp73 within the EGR2 gene. This response element is highly conserved between human and rodents. We also found that overexpression of EGR2 induced apoptosis when combined with anticancer agents. Conversely, inactivation of EGR2 attenuated p53-mediated apoptosis. The results presented here suggest that EGR2 is a direct transcriptional target of p53 family that can in part mediate the p53-dependent apoptotic pathway.

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  • CHFRとPARP-1の機能的関連が有糸分裂チェックポイントおよび腫瘍発生をコントロールする(The functional relationship between CHFR and PARP-1 controls the mitotic checkpoint and tumor development)

    鹿島 理沙, 見田 裕章, 井戸川 雅史, 豊田 実, 佐々木 泰史, 時野 隆至

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   3T4 - 4   2010.12

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  • Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. Reviewed International journal

    Hiromu Suzuki, Eiichiro Yamamoto, Masanori Nojima, Masahiro Kai, Hiro-O Yamano, Kenjiro Yoshikawa, Tomoaki Kimura, Toyoki Kudo, Eiji Harada, Tamotsu Sugai, Hiroyuki Takamaru, Takeshi Niinuma, Reo Maruyama, Hiroyuki Yamamoto, Takashi Tokino, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

    Carcinogenesis   31 ( 12 )   2066 - 73   2010.12

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    Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that the silencing of some miRNAs is associated with CpG island hypermethylation. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by treatment with 5-aza-2'-deoxycytidine and 4-phenylbutyrate. We found that miR-34b and miR-34c are epigenetically silenced in GC and that their downregulation is associated with hypermethylation of the neighboring CpG island. Methylation of the miR-34b/c CpG island was frequently observed in GC cell lines (13/13, 100%) but not in normal gastric mucosa from Helicobacter pylori-negative healthy individuals. Transfection of a precursor of miR-34b and miR-34c into GC cells induced growth suppression and dramatically changed the gene expression profile. Methylation of miR-34b/c was found in a majority of primary GC specimens (83/118, 70%). Notably, analysis of non-cancerous gastric mucosae from GC patients (n = 109) and healthy individuals (n = 85) revealed that methylation levels are higher in gastric mucosae from patients with multiple GC than in mucosae from patients with single GC (27.3 versus 20.8%; P < 0.001) or mucosae from H. pylori-positive healthy individuals (27.3 versus 20.7%; P < 0.001). These results suggest that miR-34b and miR-34c are novel tumor suppressors frequently silenced by DNA methylation in GC, that methylation of miR-34b/c is involved in an epigenetic field defect and that the methylation might be a predictive marker of GC risk.

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  • アデノウイルスを用いたアポトーシス阻害的p53標的遺伝子に対する人工miRNAとp53の導入による癌細胞でのアポトーシス誘導(Apoptosis induction in cancer cells by the adenovirus-mediated transduction of p53 and artificial miRNAs targeting anti-apoptotic p53 target genes)

    杉坂 淳, 井戸川 雅史, 佐々木 泰史, 鹿島 理沙, 篠村 恭久, 今井 浩三, 時野 隆至

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   83回・33回   4P - 0967   2010.12

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  • p53 family network and human cancer Reviewed

    Sasaki Y, Idogawa M, Yokota I, Kashima L, Tokino T

    Tumor Research   45   33 - 44   2010.12

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  • A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors. Reviewed International journal

    Shinichi Igarashi, Hiromu Suzuki, Takeshi Niinuma, Haruo Shimizu, Masanori Nojima, Hiroyuki Iwaki, Takayuki Nobuoka, Toshirou Nishida, Yasuaki Miyazaki, Hiroyuki Takamaru, Eiichiro Yamamoto, Hiroyuki Yamamoto, Takashi Tokino, Tadashi Hasegawa, Koichi Hirata, Kohzoh Imai, Minoru Toyota, Yasuhisa Shinomura

    Clinical cancer research : an official journal of the American Association for Cancer Research   16 ( 21 )   5114 - 23   2010.11

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    PURPOSE: Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy. EXPERIMENTAL DESIGN: A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens. RESULTS: LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations. CONCLUSIONS: Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations.

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  • p53ファミリーの標的遺伝子EGR2の同定と機能解析(Identification and characterization of early growth response gene-2 as a p53-regulated proapoptotic gene)

    横田 育子, 佐々木 泰史, 安保 直樹, 鹿島 理沙, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   69回   303 - 304   2010.8

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  • がん抑制分子CHFRおよびPARP-1相互作用による細胞周期制御(Functional association between CHFR and PARP-1 controls the mitotic checkpoint)

    鹿島 理沙, 見田 裕章, 井戸川 雅史, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   69回   312 - 312   2010.8

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  • p53とアポトーシス阻害的標的に対するmiRNAの単一アデノウイルス発現による癌治療(Cancer Therapy by single adenovirus-mediated expression of p53 and microRNAs targeting anti-apoptotic p53 target genes)

    井戸川 雅史, 佐々木 泰史, 鹿島 理沙, 篠村 恭久, 今井 浩三, 時野 隆至

    日本癌学会総会記事   69回   322 - 322   2010.8

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  • Genomic screening for genes upregulated by demethylation revealed novel targets of epigenetic silencing in breast cancer. Reviewed International journal

    Tomoko Fujikane, Noriko Nishikawa, Minoru Toyota, Hiromu Suzuki, Masanori Nojima, Reo Maruyama, Masami Ashida, Mutsumi Ohe-Toyota, Masahiro Kai, Toshihiko Nishidate, Yasushi Sasaki, Tousei Ohmura, Koichi Hirata, Takashi Tokino

    Breast cancer research and treatment   122 ( 3 )   699 - 710   2010.8

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    Breast cancer arises through the accumulation of multiple genetic alterations and epigenetic changes such as methylation, which silences gene expression in a variety of cancers. In the present study, we applied genomic screening to identify genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine (DAC) in a human breast cancer cell line (MCF7). We identified 288 genes upregulated and 29 genes downregulated more than fivefold after treatment with DAC, and gene ontology analyses revealed the genes to be involved in immune responses, apoptosis, and cell differentiation. In addition, real-time PCR analysis of ten genes silenced in MCF7 cells confirmed that they are upregulated by DAC, while bisulfite-pyrosequencing analysis confirmed that nine of those genes were silenced by methylation. We also found that treating MCF7 cells with DAC restored induction of DFNA5 by p53, as well as by two other p53 family genes, p63gamma and p73beta. Introduction of NTN4 into MCF7 cells suppressed cell growth, indicating that NTN4 has tumor suppressive activity. In primary breast cancers, we detected cancer-specific methylation of NTN4, PGP9.5, and DKK3, suggesting that methylation of these genes could be useful markers for diagnosis of breast cancer. Thus, DNA methylation appears to be a common event in breast cancer, and the genes silenced by methylation could be useful targets for both diagnosis and therapy.

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  • 次世代シークエンサーを用いた遺伝子転写開始点予測とエピゲノム解析への応用(Prediction of transcription start sites using next-generation sequencer and its application to epigenome analysis)

    豊田 実, 鈴木 拓, 野島 正寛, 佐々木 泰史, 篠村 恭久, 時野 隆至, 今井 浩三

    日本癌学会総会記事   69回   417 - 417   2010.8

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  • p53により発現抑制される分泌性増殖因子HDGFの同定(Negative regulation of hepatoma-derived growth factor by p53)

    佐々木 泰史, 根岸 秀明, 横田 育子, 鹿島 理沙, 井戸川 雅史, 鈴木 拓, 豊田 実, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   69回   303 - 303   2010.8

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  • DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae. Reviewed International journal

    Masaki Yamashita, Minoru Toyota, Hiromu Suzuki, Masanori Nojima, Eiichiro Yamamoto, Seiko Kamimae, Yoshiyuki Watanabe, Masahiro Kai, Hirofumi Akashi, Reo Maruyama, Yasushi Sasaki, Hiroo Yamano, Tamotsu Sugai, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino, Fumio Itoh

    Cancer science   101 ( 7 )   1708 - 16   2010.7

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    Interferon regulatory factors (IRFs) are transcription factors known to play key roles in innate and adaptive immune responses, cell growth, apoptosis, and development. Their function in tumorigenesis of gastric cancer remains to be determined, however. In the present study, therefore, we examined epigenetic inactivation of IRF1-9 in a panel of gastric cancer cell lines. We found that expression of IRF4, IRF5, and IRF8 was frequently suppressed in gastric cancer cell lines; that methylation of the three genes correlated with their silencing; and that treating the cells with the demethylating agent 5-aza-2'-deoxycytidine (DAC) restored their expression. Expression of IRF5 in cancer cells was enhanced by the combination of DAC treatment and adenoviral vector-mediated expression of p53, p63, or p73. Interferon-gamma-induced expression of IRF8 was also enhanced by DAC. Moreover, treating gastric cancer cells with DAC enhanced the suppressive effects of interferon-alpha, interferon-beta, and interferon-gamma on cell growth. Among a cohort of 455 gastric cancer and noncancerous gastric tissue samples, methylation of IRF4 was frequently observed in both gastric cancer specimens and noncancerous specimens of gastric mucosa from patients with multiple gastric cancers, which suggests IRF4 methylation could be a useful molecular marker for diagnosing recurrence of gastric cancers. Our findings indicate that epigenetic IRF inactivation plays a key role in tumorigenesis of gastric cancer, and that inhibition of DNA methylation may restore the antitumor activity of interferons through up-regulation of IRFs.

    DOI: 10.1111/j.1349-7006.2010.01581.x

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  • IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. Reviewed International journal

    Hiromu Suzuki, Shinichi Igarashi, Masanori Nojima, Reo Maruyama, Eiichiro Yamamoto, Masahiro Kai, Hirofumi Akashi, Yoshiyuki Watanabe, Hiroyuki Yamamoto, Yasushi Sasaki, Fumio Itoh, Kohzoh Imai, Tamotsu Sugai, Lanlan Shen, Jean-Pierre J Issa, Yasuhisa Shinomura, Takashi Tokino, Minoru Toyota

    Carcinogenesis   31 ( 3 )   342 - 9   2010.3

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    A subset of colorectal cancers (CRCs) show simultaneous methylation of multiple genes; these tumors have the CpG island methylator phenotype (CIMP). CRCs with CIMP show a specific pattern of genetic alterations, including a high frequency of BRAF mutations and a low frequency of p53 mutations. We therefore hypothesized that genes inactivated by DNA methylation are involved in the BRAF- and p53-signaling pathways. Among those, we examined the epigenetic inactivation of insulin-like growth factor-binding protein 7 (IGFBP7) expression in CRCs. We found that in CRC cell lines, the silencing of IGFBP7 expression was correlated with high levels of DNA methylation and low levels of histone H3K4 methylation. Luciferase and chromatin immunoprecipitation assays in unmethylated cells revealed that p53 induces expression of IGFBP7 upon binding to a p53 response element within intron 1 of the gene. Treating methylated CRC cell lines with 5-aza-2'-deoxycytidine restored p53-induced IGFBP7 expression. Levels of IGFBP7 methylation were also significantly higher in primary CRC specimens than in normal colonic tissue (P < 0.001). Methylation of IGFBP7 was correlated with BRAF mutations, an absence of p53 mutations and the presence of CIMP. Thus, epigenetic inactivation of IGFBP7 appears to play a key role in tumorigenesis of CRCs with CIMP by enabling escape from p53-induced senescence.

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  • N-Propionyl-Cysteaminylphenol-Magnetite Conjugate (NPrCAP/M) Is a Nanoparticle for the Targeted Growth Suppression of Melanoma Cells Reviewed

    Makito Sato, Toshiharu Yamashita, Masae Ohkura, Yasue Osai, Akiko Sato, Tomoaki Takada, Hidenobu Matsusaka, Ichiro Ono, Yasuaki Tamura, Noriyuki Sato, Yasushi Sasaki, Akira Ito, Hiroyuki Honda, Kazumasa Wakamatsu, Shosuke Ito, Kowichi Jimbow

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   129 ( 9 )   2233 - 2241   2009.9

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    DOI: 10.1038/jid.2009.39

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  • p53誘導性膜貫通蛋白質hCLCA2は癌細胞移動/接着を制御する(hCLCA2, a p53 inducible transmembrane protein regulates cancer cell migration and adhesion)

    佐々木 泰史, 安保 直樹, 鹿島 理沙, 井戸川 雅史, 鈴木 拓, 豊田 実, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   68回   140 - 140   2009.8

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  • p53ファミリーの標的遺伝子ICAM2の同定と機能解析(Identification and characterization of the intercellular adhesion molecule-2 gene as a novel p53 family target)

    石田 勢津子, 安保 直樹, 鹿島 理沙, 井戸川 雅史, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   68回   141 - 141   2009.8

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  • 潜在的腫瘍抑制因子CHFRはNFκB抑制を介してインターロイキン-8を下方制御する(CHFR, a potential tumor suppressor, downregulates interleukin-8 via inhibition of NF-kappaB)

    鹿島 理沙, 豊田 実, 見田 裕章, 鈴木 拓, 井戸川 雅史, 荻 和弘, 佐々木 泰史, 時野 隆至

    日本癌学会総会記事   68回   155 - 155   2009.8

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  • アデノウイルスを用いたp53蛋白とp21発現抑制人工miRNAの共発現による癌治療効果の改善(A single adenovirus expressing p53 protein and p21-targeting artificial microRNAs improves therapeutic outcome in cancer)

    井戸川 雅史, 佐々木 泰史, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   68回   492 - 492   2009.8

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  • DNAメチル化の網羅的解析によって解明された、多発性骨髄腫におけるRASD1遺伝子不活化とデキサメサゾン耐性の相関(Genomic Screening by DNA Methylation Revealed an Association between RASD 1 Inactivation and Dex Resistance in MM)

    野島 正寛, 丸山 玲緒, 安井 寛, 鈴木 拓, 佐々木 泰史, 麻奥 英毅, 酒井 基, 石田 禎夫, 森 満, 今井 浩三, 時野 隆至, 豊田 実, 篠村 恭久

    日本癌学会総会記事   68回   224 - 224   2009.8

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  • p53応答配列のゲノム網羅的in silico解析によるp53誘導性non-coding RNAの同定(Genome wide in silico analysis of p53 response elements identified non-coding RNA regulated by p53)

    高丸 博之, 丸山 玲緒, 豊田 実, 鈴木 拓, 佐々木 泰史, 野島 正寛, 明石 浩史, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   68回   141 - 141   2009.8

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  • p53ファミリーの標的遺伝子EGR2の同定と機能解析(Identification and characterization of early growth response gene-2 as a p53-regulated proapoptotic gene)

    横田 育子, 佐々木 泰史, 安保 直樹, 鹿島 理沙, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   68回   141 - 141   2009.8

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  • Genomic screening for genes silenced by DNA methylation revealed an association between RASD1 inactivation and dexamethasone resistance in multiple myeloma. Reviewed International journal

    Masanori Nojima, Reo Maruyama, Hiroshi Yasui, Hiromu Suzuki, Yumiko Maruyama, Isao Tarasawa, Yasushi Sasaki, Hideki Asaoku, Hajime Sakai, Toshiaki Hayashi, Mitsuru Mori, Kohzoh Imai, Takashi Tokino, Tadao Ishida, Minoru Toyota, Yasuhisa Shinomura

    Clinical cancer research : an official journal of the American Association for Cancer Research   15 ( 13 )   4356 - 64   2009.7

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    PURPOSE: Epigenetic changes such as DNA methylation play a key role in the development and progression of multiple myeloma. Our aim in the present study was to use genomic screening to identify genes targeted for epigenetic inactivation in multiple myeloma and assess their role in the development of resistance to dexamethasone. EXPERIMENTAL DESIGN: Gene expression was examined using microarray screening, reverse transcription-PCR, and real-time quantitative PCR. DNA methylation was examined using bisulfite PCR, bisulfite sequencing, and bisulfite pyrosequencing in 14 multiple myeloma cell lines, 87 multiple myeloma specimens, and 12 control bone marrow samples. WST-8 assays were used to assess cell viability after treatment with 5-aza-2'-deoxycytidine and/or dexamethasone. RESULTS: Microarray analysis was done to screen for genes up-regulated by 5-aza-2'-deoxycytidine. In RPMI8226 cells, 128 genes were up-regulated, whereas 83 genes were up-regulated in KMS12PE cells. Methylation of 22 genes with CpG islands in their 5' regions, including RASD1, was confirmed. Methylation of RASD1 was associated with its inactivation, which correlated with resistance to dexamethasone. Treating multiple myeloma cells with 5-aza-2'-deoxycytidine restored sensitivity to dexamethasone. Methylation of RASD1 was also detected in a subset of primary multiple myeloma specimens, and the levels of methylation were increased after repeated antitumor treatments. Gene signature analysis revealed various genes to be synergistically induced by treatment with a combination of 5-aza-2'-deoxycytidine plus dexamethasone. CONCLUSION: Our findings indicate that epigenetic inactivation of genes, including RASD1, plays a key role in the development of dexamethasone resistance in multiple myeloma. Moreover, they show the utility of demethylation therapy in cases of advanced multiple myeloma.

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  • CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-kappa B

    L. Kashima, M. Toyota, H. Mita, H. Suzuki, M. Idogawa, K. Ogi, Y. Sasaki, T. Tokino

    ONCOGENE   28 ( 29 )   2643 - 2653   2009.7

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  • A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth. Reviewed International journal

    Hiroaki Mita, Minoru Toyota, Fumio Aoki, Hirofumi Akashi, Reo Maruyama, Yasushi Sasaki, Hiromu Suzuki, Masashi Idogawa, Lisa Kashima, Kazuyoshi Yanagihara, Masahiro Fujita, Masao Hosokawa, Masanobu Kusano, Sorin Vasile Sabau, Haruyuki Tatsumi, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    BMC cancer   9   198 - 198   2009.6

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    BACKGROUND: Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS), which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. METHODS: DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. RESULTS: DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20) of gastric cancer cell lines (8-18-fold amplification) and 4.7% (4/86) of primary gastric tumors (8-50-fold amplification). KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild-type KRAS resulted in the inhibition of cell growth and suppression of p44/42 MAP kinase and AKT activity. CONCLUSION: Our study highlights the utility of DGS for identification of copy-number alterations. Using DGS, we identified KRAS as a gene that is amplified in human gastric cancer. We demonstrated that gene amplification likely forms the molecular basis of overactivation of KRAS in gastric cancer. Additional studies using a larger cohort of gastric cancer specimens are required to determine the diagnostic and therapeutic implications of KRAS amplification and overexpression.

    DOI: 10.1186/1471-2407-9-198

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  • A single recombinant adenovirus expressing p53 and p21-targeting artificial microRNAs efficiently induces apoptosis in human cancer cells. Reviewed International journal

    Masashi Idogawa, Yasushi Sasaki, Hiromu Suzuki, Hiroaki Mita, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    Clinical cancer research : an official journal of the American Association for Cancer Research   15 ( 11 )   3725 - 32   2009.6

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    PURPOSE: Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. The activation of p53 induces either cell cycle arrest or apoptosis. Cell cycle arrest in response to p53 activation is mediated primarily through the induction of the cyclin-dependent kinase inhibitor p21. Because p21 also has an inhibitory effect on p53-mediated apoptosis, the suppression of p53-induced p21 expression would be expected to result in the preferential induction of apoptosis. However, p21 also has tumor-suppressive properties. In this study, we developed an adenovirus vector that expresses p53 and suppresses p21 simultaneously to enhance p53-mediated apoptosis. EXPERIMENTAL DESIGN: We constructed a replication-deficient recombinant adenovirus (Ad-p53/miR-p21) that enabled cocistronic expression of the p53 protein and artificial microRNAs that targeted p21, and examined the therapeutic effectiveness of this vector in vitro and in vivo. RESULTS: The levels of p21 were significantly attenuated following infection with Ad-p53/miR-p21. In colorectal and hepatocellular carcinoma cells, infection with Ad-p53/miR-p21 augmented apoptosis as compared with an adenovirus that expressed p53 alone (Ad-p53/miR-control). Ad-p53/miR-p21 also significantly increased the chemosensitivity of cancer cells to adriamycin (doxorubicin). In a xenograft tumor model in nude mice, tumor volume was significantly decreased following the direct injection of Ad-p53/miR-p21 into the tumor, as compared with the injection of Ad-p53/miR-control. CONCLUSION: These results suggest that adenovirus-mediated transduction of p53 and p21-specific microRNAs may be useful for gene therapy of human cancers.

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  • Overexpression of Aurora A by loss of CHFR gene expression increases the growth and survival of HTLV-1-infected T cells through enhanced NF-kappaB activity. Reviewed International journal

    Mariko Tomita, Minoru Toyota, Chie Ishikawa, Tetsuro Nakazato, Taeko Okudaira, Takehiro Matsuda, Jun-Nosuke Uchihara, Naoya Taira, Kazuiku Ohshiro, Masachika Senba, Yuetsu Tanaka, Koichi Ohshima, Hideyuki Saya, Takashi Tokino, Naoki Mori

    International journal of cancer   124 ( 11 )   2607 - 15   2009.6

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    Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia (ATL). Aurora A, a mitotic checkpoint protein, is overexpressed in human cancer cells. The cell cycle-dependent turnover of Aurora A is regulated by E3 ubiquitin ligases such as checkpoint with fork head-associated and ring finger (CHFR). Here, we found overexpression of Aurora A protein in HTLV-1-infected T-cell lines and primary ATL cells. The expression of CHFR mRNA was reduced in these cells by abnormal methylation of CHFR promoter region. Knockdown of Aurora A using small interfering RNA suppressed the growth of HTLV-1-infected T-cell line. Transfection of Aurora A expression plasmid enhanced Tax-induced nuclear factor-kappaB (NF-kappaB) reporter activity. Transfection of CHFR expression plasmid into an HTLV-1-infected T-cell line reduced cell growth, Aurora A protein level and constitutive NF-kappaB reporter activity. Aurora kinase inhibitor suppressed the growth and survival of HTLV-1-infected T-cell lines and primary ATL cells. It also reduced constitutive NF-kappaB activity in an HTLV-1-infected T-cell line by reducing IkappaB kinase beta phosphorylation and the expression of antiapoptotic protein survivin. Our results suggested that loss of CHFR expression resulted to accumulation of Aurora A, which increased NF-kappaB activity. These findings highlight the critical role of Aurora A in HTLV-1-infected T cells, making this molecule a potentially suitable target for future therapies for ATL.

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  • A novel biomarker for cervical cancer. Reviewed International journal

    Takashi Tokino

    Cancer biology & therapy   8 ( 12 )   1154 - 5   2009.6

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  • miRNAによるp21発現誘導抑制能を付加したp53発現ベクターによる癌治療効果の増強

    井戸川 雅史, 佐々木 泰史, 篠村 恭久, 今井 浩三, 時野 隆至

    Drug Delivery System   24 ( 3 )   332 - 332   2009.6

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  • ヒストン脱アセチル化酵素阻害剤の併用によるp53遺伝子治療の作用増強

    佐々木 泰史, 今井 浩三, 篠村 恭久, 時野 隆至

    Drug Delivery System   24 ( 3 )   319 - 319   2009.6

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  • Cancer epigenomics: implications of DNA methylation in personalized cancer therapy. Reviewed International journal

    Minoru Toyota, Hiromu Suzuki, Toshiharu Yamashita, Koichi Hirata, Kohzoh Imai, Takashi Tokino, Yasuhisa Shinomura

    Cancer science   100 ( 5 )   787 - 91   2009.5

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    Genetic alterations in cancer can provide information for predicting a tumor's sensitivity to chemotherapeutic drugs. But although such information is certainly useful, the relatively low frequency of mutations seen in many cancers limits the utility of pharmacogenomics in large numbers of cancer patients, necessitating consideration of other approaches. Epigenetic changes such as DNA methylation are a hallmark of human cancers. Methylation of genes involved in DNA repair and maintaining genome integrity (e.g. MGMT, hMLH1, WRN, and FANCF), and cell-cycle checkpoint genes (e.g. CHFR and 14-3-3 sigma, CDK10, and p73), all reportedly influence the sensitivity to chemotherapeutic drugs, suggesting that DNA methylation could serve as a molecular marker for predicting the responsiveness of tumors to chemotherapy. However, the comprehensive study of pharmacoepigenomics awaits the advent of genome-wide analysis of DNA methylation using microarrays and next-generation sequencers.

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  • A single recombinant adenovirus expressing p53 and p21-targeting artificial microRNAs efficiently induces apoptosis in human cancer cells. Reviewed

    Masashi Idogawa, Yasushi Sasaki, Kohzoh Mai, Yasuhisa Shinomura, Takashi Tokino

    CANCER RESEARCH   69   2009.5

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  • p53 family members regulate the expression of the apolipoprotein D gene Reviewed

    Yasushi Sasaki, Naoki Anbo, Masashi Idogawa, Hiroaki Mita, Minoru Toyota, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    CANCER RESEARCH   69   2009.5

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  • p53 family members regulate the expression of the apolipoprotein D gene. Reviewed International journal

    Yasushi Sasaki, Hideaki Negishi, Ryota Koyama, Naoki Anbo, Kanae Ohori, Masashi Idogawa, Hiroaki Mita, Minoru Toyota, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    The Journal of biological chemistry   284 ( 2 )   872 - 83   2009.1

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    p73 and p63 are members of the p53 gene family that play an important role in development and homeostasis, mainly by regulating transcription of a variety of genes. We report here that apolipoprotein D (apoD), a member of the lipocalin superfamily of lipid transport proteins, is a direct transcriptional target of the p53 family member genes. We found that the expression of apoD was specifically up-regulated by either TAp73 or TAp63 but not significantly by p53. In addition, apoD transcription is activated in response to cisplatin in a manner dependent on endogenous p73. By using small interference RNA designed to target p73, we demonstrated that silencing endogenous p73 abolishes induction of apoD transcription following cisplatin treatment. We also identified a p73/p63-binding site in the promoter of the apoD gene that is responsive to the p53 family members. The ectopic expression of TAp73 as well as the addition of recombinant human apoD to culture medium induced the osteoblastic differentiation of the human osteosarcoma cell line Saos-2, as assessed by alkaline phosphatase activity. Importantly, apoD knockdown abrogated p73-mediated alkaline phosphatase induction. Moreover, TAp73-mediated apoD expression was able to induce morphological differentiation, as well as expression of neuronal markers, in the human neuroblastoma cell line SH-SY5Y. These results suggest that apoD induction may mediate the activity of p73 in normal development.

    DOI: 10.1074/jbc.M807185200

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  • Prediction of p53 target genes based on integrative analysis of chromatin- immunoprecipitated and sequenced tags,by using Galaxy,a web-based interactive platform for large-scale genome analysis Reviewed

    Mita H, Sasaki Y, Suzuki H, Idogawa M, Kashima L, Anbo N, Akashi H, Tatsumi H, Toyota M, Tokino T

    Tumor Research   43   1 - 23   2008.12

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    Other Link: http://orcid.org/0000-0002-8507-1726

    DOI: 10.15114/tr.43.1

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  • DNA methylation and cancer pathways in gastrointestinal tumors. Reviewed International journal

    Hiromu Suzuki, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Minoru Toyota

    Pharmacogenomics   9 ( 12 )   1917 - 28   2008.12

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    Cancer is fundamentally a genetic and epigenetic disease that requires the accumulation of genomic alterations that inactivate tumor suppressors and activate proto-oncogenes. In addition to genetic mutation or allelic loss, epigenetic gene silencing associated with DNA methylation is now recognized as an alternative mechanism by which tumor suppressor genes are inactivated. In gastrointestinal cancers, for example, DNA methylation frequently alters the activity in a number of important signaling pathways by silencing expression of genes encoding Wnt antagonists, negative Ras effectors and p53 targets. Indeed, the list of genes aberrantly methylated in cancer is growing, and methylation of a p53 target micoRNA gene has recently been demonstrated. Sites of DNA methylation could be promising markers and targets for risk assessment, early detection and treatment of cancer.

    DOI: 10.2217/14622416.9.12.1917

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  • LINE-1 hypomethylation is associated with increased CpG island methylation in Helicobacter pylori-related enlarged-fold gastritis. Reviewed International journal

    Eiichiro Yamamoto, Minoru Toyota, Hiromu Suzuki, Yutaka Kondo, Tamana Sanomura, Yoko Murayama, Mutsumi Ohe-Toyota, Reo Maruyama, Masanori Nojima, Masami Ashida, Kyoko Fujii, Yasushi Sasaki, Norio Hayashi, Mitsuru Mori, Kohzoh Imai, Takashi Tokino, Yasuhisa Shinomura

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology   17 ( 10 )   2555 - 64   2008.10

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    BACKGROUND: The molecular mechanism by which Helicobacter pylori infection leads to gastric cancer is not fully understood. Similarly, patients with enlarged-fold (EF+) gastritis, one cause of which is H. pylori infection, have an increased risk for gastric cancer, although again molecular mechanism is unclear. In the present study, we analyzed the methylation status of long interspersed nucleotide elements (LINE-1) and three cancer-related genes in a panel of gastric mucosae, with or without EF+ gastritis. METHODS: We used bisulfite pyrosequencing to assess the levels of LINE-1, CDH1, CDH13, and PGP9.5 methylation in 78 gastric mucosa specimens from 48 patients. RESULTS: Levels of LINE-1 methylation were significantly reduced in mucosae from patients with EF+ gastritis. This hypomethylation of LINE-1 was associated with increased methylation of the 5' CpG islands of the genes, which suggests that, in EF+ gastritis, the methylation of the promoter regions of certain genes is accompanied by global demethylation of repetitive sequences. CONCLUSIONS: Our results indicate that genomewide hypomethylation and regional hypermethylation occur in EF+ gastritis and may contribute to the tumorigenesis of diffuse-type gastric cancers.

    DOI: 10.1158/1055-9965.EPI-08-0112

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  • p53による肝癌由来増殖因子(HDGF)の抑制機構(Negative regulation of hepatoma-derived growth factor by p53)

    安保 直樹, 佐々木 泰史, 根岸 秀明, 井戸川 雅史, 小山 良太, 豊田 実, 鈴木 拓, 時野 隆至

    日本癌学会総会記事   67回   136 - 136   2008.9

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  • 口腔扁平上皮癌におけるSFRP遺伝子のエピジェネティックな不活化(Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma)

    曽我部 陽平, 鈴木 拓, 豊田 実, 今井 崇, 野島 正寛, 佐々木 泰史, 時野 隆至, 平塚 博義

    日本癌学会総会記事   67回   174 - 174   2008.9

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  • p53ファミリー(p73,p63)の標的遺伝子apolipoprotein Dの同定(p53 family members regulate the expression of the apolipoprotein D gene)

    佐々木 泰史, 安保 直樹, 根岸 秀明, 井戸川 雅史, 見田 裕章, 豊田 実, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   67回   60 - 60   2008.9

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  • 大腸癌におけるmicroRNA-34b/cおよびBTG4のCpGアイランドメチル化によるエピジェネティックな不活化(Epigenetic silencing of microRNA-34b/c and BTG4 is associated with CpG island hypermethylation in colorectal cancer)

    鈴木 拓, 豊田 実, 野島 正寛, 佐々木 泰史, 時野 隆至, 今井 浩三, 篠村 恭久

    日本癌学会総会記事   67回   71 - 71   2008.9

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  • 胃癌におけるKRAS遺伝子増幅と細胞内シグナルの活性化(Gene amplification of KRAS and activation of intracellular signaling pathways in gastric cancer)

    見田 裕章, 豊田 実, 青木 文夫, 明石 浩史, 丸山 玲緒, 佐々木 泰史, 鈴木 拓, 井戸川 雅史, 鹿島 理沙, サバウ・ソリン, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   67回   163 - 163   2008.9

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  • miRNAによるp21誘導抑制能をもつp53発現アデノウイルスベクターによる抗腫瘍効果の増強(Enhancement of antitumor effect by single adenovirus vector expressing p53 and suppressing p21 induction by miRNA)

    井戸川 雅史, 佐々木 泰史, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   67回   237 - 237   2008.9

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  • CHFRはNF-kappaBを抑制する(CHFR, a potential tumor suppressor, inhibits the transcriptional activity of NF-kappaB)

    鹿島 理沙, 見田 裕章, 豊田 実, 佐々木 泰史, 鈴木 拓, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   67回   410 - 410   2008.9

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  • DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. Reviewed International journal

    Yuki I Kawamura, Minoru Toyota, Rei Kawashima, Teruki Hagiwara, Hiromu Suzuki, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino, Reiji Kannagi, Taeko Dohi

    Gastroenterology   135 ( 1 )   142 - 151   2008.7

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    BACKGROUND & AIMS: It has long been known that malignant transformation is associated with abnormal expression of carbohydrate determinants. The aim of this study was to clarify the cause of cancer-associated abnormal glycosylation in gastrointestinal (GI) cancers. METHODS: We compared the expression levels of "glyco-genes," including glycosyltransferases and glycosidases, in normal GI mucosa and in gastric and colorectal cancer cells. To examine the possibility that DNA hypermethylation contributed to the down-regulation of these genes, we treated GI cancer cells with 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferase. RESULTS: The silencing of some of these glyco-genes, but not up-regulation of certain molecules, was observed. The Sd(a) carbohydrate was abundantly expressed in the normal GI mucosa, but its expression was significantly decreased in cancer tissues. When human colon and gastric cancer cells were treated with 5-aza-dC, cell surface expression of Sd(a) and the transcription of B4GALNT2, which catalyzes the synthesis of the Sd(a), were induced. The promoter region of the human B4GALNT2 gene was heavily hypermethylated in many of the GI cancer cell lines examined as well as in gastric cancer tissues (39 out of 78 cases). In addition, aberrant methylation of the B4GALNT2 gene was strongly correlated with Epstein-Barr virus-associated gastric carcinomas and occurred coincidentally with hypermethylation of the ST3GAL6 gene. CONCLUSIONS: Epigenetic changes in a group of glycosyltransferases including B4GALNT2 and ST3GAL6 represent a malignant phenotype of gastric cancer caused by silencing of the activity of these enzymes, which action may eventually induce aberrant glycosylation and expression of cancer-associated carbohydrate antigens.

    DOI: 10.1053/j.gastro.2008.03.031

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  • Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer. Reviewed International journal

    Reo Maruyama, Kimishige Akino, Minoru Toyota, Hiromu Suzuki, Takashi Imai, Mutsumi Ohe-Toyota, Eiichiro Yamamoto, Masanori Nojima, Tomoko Fujikane, Yasushi Sasaki, Toshiharu Yamashita, Yoshiyuki Watanabe, Hiroyoshi Hiratsuka, Koichi Hirata, Fumio Itoh, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    Carcinogenesis   29 ( 7 )   1312 - 8   2008.7

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    Gastric cancer cells often show altered Ras signaling, though the underlying molecular mechanism is not fully understood. We examined the expression profile of eight ras-association domain family (RASSF) genes plus MST1/2 and found that RASSF2A is the most frequently downregulated in gastric cancer. RASSF2A was completely silenced in 6 of 10 gastric cancer cell lines as a result of promoter methylation, and expression was restored by treating the cells with 5-aza-2'-deoxycytidine. Introduction of RASSF2A into non-expressing cell lines suppressed colony formation and induced apoptosis. These effects were associated with the cytoplasmic localization of RASSF2A and morphological changes to the cells. Complementary DNA microarray analysis revealed that RASSF2A suppresses the expression of inflammatory cytokines, which may in turn suppress angiogenesis and invasion. In primary gastric cancers, aberrant methylation of RASSF2A was detected in 23 of 78 (29.5%) cases, and methylation correlated significantly with an absence of the lymphatic invasion, absence of venous invasion, absence of lymph node metastasis, less advanced stages, Epstein-Barr virus, absence of p53 mutations and the presence of the CpG island methylator phenotype-high. These results suggest that epigenetic inactivation of RASSF2A is required for tumorigenesis in a subset of gastric cancers.

    DOI: 10.1093/carcin/bgn060

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  • Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Reviewed International journal

    Minoru Toyota, Hiromu Suzuki, Yasushi Sasaki, Reo Maruyama, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    Cancer research   68 ( 11 )   4123 - 32   2008.6

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    Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that, in cancer, expression of some miRNAs cells is silenced in association with CpG island hypermethylation. To identify epigenetically silenced miRNAs in colorectal cancer (CRC), we screened for miRNAs induced in CRC cells by 5-aza-2'-deoxycytidine (DAC) treatment or DNA methyltransferase knockout. We found that miRNA-34b (miR-34b) and miR-34c, two components of the p53 network, are epigenetically silenced in CRC; that this down-regulation of miR-34b/c is associated with hypermethylation of the neighboring CpG island; and that DAC treatment rapidly restores miR-34b/c expression. Methylation of the miR-34b/c CpG island was frequently observed in CRC cell lines (nine of nine, 100%) and in primary CRC tumors (101 of 111, 90%), but not in normal colonic mucosa. Transfection of precursor miR-34b or miR-34c into CRC cells induced dramatic changes in the gene expression profile, and there was significant overlap between the genes down-regulated by miR-34b/c and those down-regulated by DAC. We also found that the miR-34b/c CpG island is a bidirectional promoter which drives expression of both miR-34b/c and B-cell translocation gene 4 (BTG4); that methylation of the CpG island is also associated with transcriptional silencing of BTG4; and that ectopic expression of BTG4 suppresses colony formation by CRC cells. Our results suggest that miR-34b/c and BTG4 are novel tumor suppressors in CRC and that the miR-34b/c CpG island, which bidirectionally regulates miR-34b/c and BTG4, is a frequent target of epigenetic silencing in CRC.

    DOI: 10.1158/0008-5472.CAN-08-0325

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  • Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma. Reviewed International journal

    Yohei Sogabe, Hiromu Suzuki, Minoru Toyota, Kazuhiro Ogi, Takashi Imai, Masanori Nojima, Yasushi Sasaki, Hiroyoshi Hiratsuka, Takashi Tokino

    International journal of oncology   32 ( 6 )   1253 - 61   2008.6

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    Although mutations of APC, CTNNB1 (beta-catenin) and AXIN1 are rare in oral squamous cell carcinoma (OSCC), activation of the Wnt signaling pathway is thought to play an important role in oral carcinogenesis. In the present study, we examined the relationship between Wnt signaling and epigenetic alteration of the secreted frizzled-related protein (SFRP) genes in OSCC. We frequently detected loss of membrane localization of beta-catenin and its cytoplasmic or nuclear accumulation in OSCC cell lines, although these cell lines showed no APC or CTNNB1 (beta-catenin) mutations and no methylation of CDH1 (E-cadherin). By contrast, we frequently detected methylation of SFRP1 (7/17, 41%) SFRP2 (16/17, 94%) and SFRP5 (14/17, 82%) in a panel of OSCC cell lines, as well as in specimens of primary tumors collected from 44 OSCC patients (SFRP1, 10/42, 24%; SFRP2, 16/44, 36%; SFRP5, 7/43, 16%). We also observed that OSCC cell lines express various Wnt ligands, and that ectopic expression of SFRPs inhibited cancer cell proliferation. Our results confirm the frequent methylation and silencing of SFRP genes in OSCC, and suggest that their loss of function contributes to activation of Wnt signaling that leads to cell proliferation during oral carcinogenesis.

    DOI: 10.3892/ijo_32_6_1253

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  • Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma. Reviewed International journal

    Takashi Imai, Minoru Toyota, Hiromu Suzuki, Kimishige Akino, Kazuhiro Ogi, Yohei Sogabe, Lisa Kashima, Reo Maruyama, Masanori Nojima, Hiroaki Mita, Yasushi Sasaki, Fumio Itoh, Kohzoh Imai, Yasuhisa Shinomura, Hiroyoshi Hiratsuka, Takashi Tokino

    Cancer science   99 ( 5 )   958 - 66   2008.5

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    Genetic and epigenetic alterations in tumor-suppressor genes play important roles in human neoplasia. Ras signaling is often activated in oral squamous cell carcinoma (OSCC), although Ras mutations are rarely detected in Japanese OSCC patients, and the mechanisms underlying the gene's activation remain unclear. Here, we examined the expression of Ras association family (RASSF) genes in a panel of OSCC cell lines and found that RASSF2 is often downregulated by DNA methylation in OSCC cells. In addition, aberrant methylation of RASSF2 was detected in 12 of 46 (26%) primary OSCC, and 18 (39%) of those OSCC showed methylation of at least one RASSF gene. Ectopic expression of RASSF2 in OSCC cells suppressed cell growth and induced apoptosis. A RASSF2 deletion mutant lacking the Ras-association domain, which was therefore unable to interact with Ras, exhibited less pro-apoptotic activity than the full-length protein, indicating that the pro-apoptotic activity of RASSF2 is related to its association with Ras. Genomic screening of genes regulated by RASSF2 showed that genes involved in immune responses, angiogenesis, and metastasis are suppressed by RASSF2. Our results suggest that epigenetic inactivation of RASSF2 plays an important role in OSCC tumorigenesis, and that RASSF2 may be a useful molecular target for the diagnosis and treatment of OSCC.

    DOI: 10.1111/j.1349-7006.2008.00769.x

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  • A requirement for DICER to maintain full promoter CpG island hypermethylation in human cancer cells. Reviewed International journal

    Angela H Ting, Hiromu Suzuki, Leslie Cope, Kornel E Schuebel, Byron H Lee, Minoru Toyota, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino, Stephen B Baylin

    Cancer research   68 ( 8 )   2570 - 5   2008.4

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    Promoter hypermethylation is a prevalent phenomenon, found in virtually all cancer types studied thus far, and accounts for tumor suppressor gene silencing in the absence of genetic mutations. The mechanism behind the establishment and maintenance of such aberrant hypermethylation has been under intense study. Here, we have uncovered a link between aberrant gene silencing associated with promoter CpG island DNA methylation and the siRNA/miRNA processing enzyme, DICER, in human cancer cells. By comparing demethylated HCT116 colon cancer cells with HCT116 cells genetically rendered hypomorphic for DICER, we identified a group of epigenetically silenced genes that became reactivated in the absence of functional DICER. This reactivation is associated with a dramatic loss of localized promoter DNA hypermethylation. Thus, intact DICER is required to maintain full promoter DNA hypermethylation of select epigenetically silenced loci in human cancer cells.

    DOI: 10.1158/0008-5472.CAN-07-6405

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  • Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models. Reviewed International journal

    Yasushi Sasaki, Hideaki Negishi, Masashi Idogawa, Hiromu Suzuki, Hiroaki Mita, Minoru Toyota, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino

    Molecular cancer therapeutics   7 ( 4 )   779 - 87   2008.4

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    Therapeutic replacement of the wild-type p53 gene has been pursued as a potential gene therapy strategy in a variety of cancer types; however, some cancer models are resistant to p53 in vivo and in vitro. Therefore, to improve p53 gene therapy, it is important to overcome the resistance to p53-mediated apoptosis. Histone deacetylase inhibitors are a novel class of chemotherapeutic agents that are able to reverse the malignant phenotype of transformed cells. A natural histone deacetylase inhibitor, FK228, is reported to enhance adenovirus infection due in part to the up-regulation of coxsackievirus adenovirus receptor expression. In this study, preclinical experiments were done to establish a mechanistic rationale for the combination of adenovirus-mediated p53 family gene transfer and FK228 pretreatment in future clinical trials. Pretreatment with FK228 enhanced apoptosis in human cancer cells through enhanced transduction of Ad-p53. FK228 also induced hyperacetylation of the p53 protein and specifically enhanced p53-mediated Noxa expression. Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria. The double knockdown of Bax and Noxa expression by small interfering RNA antagonized the synergistic effect of Ad-p53 and FK228 on apoptosis induction. In human cancer xenograft models, FK228 significantly increased the therapeutic effectiveness of p53 as well as p63 gene therapy. These results provide a strong rationale for combining p53 gene therapy and FK228 pretreatment in cancer therapy.

    DOI: 10.1158/1535-7163.MCT-07-0395

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  • Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members. Reviewed International journal

    Yasushi Sasaki, Yuichiro Oshima, Ryota Koyama, Reo Maruyama, Hirofumi Akashi, Hiroaki Mita, Minoru Toyota, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino

    Molecular cancer research : MCR   6 ( 3 )   395 - 406   2008.3

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    p73 and p63 are members of the p53 gene family and have been shown to play an important role in development and homeostasis mainly by regulating the transcription of a variety of genes. A subset of these genes encodes secreted proteins and receptors that may be involved in the communication between adjacent cells. We report here that flotillin-2, a major hydrophobic protein on biomembrane microdomain lipid rafts, is a direct transcriptional target of the p53 family member genes. It has been suggested that such rafts could play an important role in many cellular processes including signal transduction, membrane trafficking, cytoskeletal organization, and pathogen entry. We found that the expression of flotillin-2 was specifically up-regulated by either TAp73beta or TAp63gamma, but not significantly by p53. In addition, flotillin-2 transcription is activated in response to cisplatin in a manner dependent on endogenous p73. By using small interference RNA designed to target p73, we showed that silencing endogenous p73 abolishes the induction of flotillin-2 transcription following cisplatin treatment. Furthermore, we identified a p73/p63-binding site located upstream of the flotillin-2 gene that is responsive to the p53 family members. This response element is highly conserved between humans and rodents. We also found that ectopic expression of TAp73 as well as TAp63 enhances signal transduction by assessing the interleukin-6-mediated phosphorylation of signal transducers and activators of transcription 3. Thus, in addition to direct transactivation, p53 family member genes enhance a set of cellular processes via lipid rafts.

    DOI: 10.1158/1541-7786.MCR-07-0108

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  • Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer Reviewed

    H. Suzuki, M. Toyota, H. Caraway, E. Gabrielson, T. Ohmura, T. Fujikane, N. Nishikawa, Y. Sogabe, M. Nojima, T. Sonoda, M. Mori, K. Hirata, K. Imai, Y. Shinomura, S. B. Baylin, T. Tokino

    BRITISH JOURNAL OF CANCER   98 ( 6 )   1147 - 1156   2008.3

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    DOI: 10.1038/sj.bjc.6604259

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  • 口腔扁平上皮癌におけるRAS関連遺伝子のジェネティックおよびエピジェネティックな異常の解析

    今井 崇, 秋野 公臣, 豊田 実, 鈴木 拓, 佐々木 泰史, 見田 裕章, 井戸川 雅史, 鹿島 理沙, 荻 和弘, 曽我部 陽平, 今井 浩三, 平塚 博義, 時野 隆至

    日本口腔科学会雑誌   57 ( 1 )   160 - 160   2008.1

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  • p53 Expression with p21 Suppression by Single Vector Enhances Antitumor Effect Reviewed

    Masashi Idogawa, Yasushi Sasaki, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    TUMOR BIOLOGY   29   73 - 73   2008

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  • Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. Reviewed

    Hideyasu Takagi, Shigeru Sasaki, Hiromu Suzuki, Minoru Toyota, Reo Maruyama, Masanori Nojima, Hiroyuki Yamamoto, Masao Omata, Takashi Tokino, Kohzoh Imai, Yasuhisa Shinomura

    Journal of gastroenterology   43 ( 5 )   378 - 89   2008

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    BACKGROUND: Activation of the Wnt signaling pathway is frequently observed in hepatocellular carcinoma (HCC), though mutation of three of its components, CTNNB1, AXIN1, and AXIN2, is observed substantially less often. METHODS: We examined the relationship between Wnt signaling and epigenetic alteration of secreted frizzled-related protein (SFRP) genes in HCC. RESULTS: We frequently detected the active form of beta-catenin and accumulation of nuclear beta-catenin in liver cancer cell lines. We detected methylation of SFRP family genes in liver cancer cell lines (SFRP1, 9/12, 75%; SFRP2, 7/12, 58%; SFRP4, 3/12, 25%; SFRP5, 7/12, 58%) and primary HCCs (SFRP1, 9/19, 47%; SFRP2, 12/19, 63%; SFRP5, 8/19, 42%), though methylation of SFRP4 was not found in primary HCCs. SFRP methylation also was detected in hepatitis B or C virus-associated chronic hepatitis (SFRP1, 6/37, 16%; SFRP2, 14/37, 38%; SFRP5, 5/37, 14%) and liver cirrhosis (SFRP1, 10/28, 36%; SFRP2, 9/28, 32%; SFRP5, 3/28, 11%), suggesting that methylation of these genes is an early event in liver carcinogenesis. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor (TCF/LEF) transcriptional activity in liver cancer cells, while overexpression of a beta-catenin mutant and depletion of SFRP1 using siRNA synergistically upregulated TCF/LEF transcriptional activity. CONCLUSIONS: Our results confirm the frequent methylation and silencing of Wnt antagonist genes in HCC, and suggest that their loss of function contributes to activation of Wnt signaling during hepatocarcinogenesis.

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  • Histone Deacetylase Inhibitor FK228 Enhances Adenovirus-mediated p53 Family Gene Therapy in Cancer Models Reviewed

    Yasushi Sasaki, Masashi Idogawa, Hiromu Suzuki, Hiroaki Mita, Minoru Toyota, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino

    TUMOR BIOLOGY   29 ( 4 )   24 - 24   2008

  • Genomic Mapping of 12p Amplifications in Gastric Cancer Reveal a 0.5-Mb Target Region Including KRAS Locus Reviewed

    Hiroaki Mita, Fumio Aoki, Hirofumi Akashi, Reo Maruyama, Yasushi Sasaki, Hiromu Suzuki, Masashi Idogawa, Lisa Kashima, Minoru Toyota, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    TUMOR BIOLOGY   29   83 - 83   2008

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  • In vitro transformation of adult rat hepatic progenitor cells into pancreatic endocrine hormone-producing cells. Reviewed

    Hiroyuki Kawasaki, Toru Mizuguchi, Yamato Kikkawa, Hideki Oshima, Yasushi Sasaki, Takashi Tokino, Yasuo Kokai, Jun-Ichi Miyazaki, Tadashi Katsuramaki, Toshihiro Mitaka, Koichi Hirata

    Journal of hepato-biliary-pancreatic surgery   15 ( 3 )   310 - 7   2008

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    BACKGROUND/PURPOSE: Pancreatic and duodenal homeobox factor 1 (Pdx-1) plays an important role in initiating differentiation toward pancreatic endocrine cells. The transdifferentiation or transformation of hepatocytes into pancreatic endocrine cells could be feasible, due to their similar cellular origins. Our goal in this study was to see if small hepatocytes (SHs) could give rise to pancreatic endocrine cells via exogenous Pdx-1 gene expression. METHODS: SHs were cultured for 10 days before adenovirus (Adt)-mediated Pdx-1 gene transfection. We performed western blot analysis for pancreatic transcription factors in the nuclei and reverse-transcription polymerase chain reaction (RT-PCR) for the gene expression of pancreatic endocrine hormones. Confocal laser microscanning analysis was used to observe the transformation of SHs. RESULTS: Pancreatic transcription factors such as Pdx-1, Ngn3, NeuroD, Nkx2.2, and Pax6 were induced after Adt-Pdx-1 gene transfection. The mRNA expression of pancreatic endocrine hormones (insulin, glucagon, and somatostatin) was induced after the gene transfection. Pdx-1 was expressed in the nucleus, where the cells were positive for one or more of the hormones and cytokeratin (CK) 8. Some cells were positive for multiple hormones. The insulin level increased while the glucagon level decreased after the glucose loading test, depending on the glucose concentration. CONCLUSIONS: SHs are transformed into functional pancreatic endocrine cells after Pdx-1 gene transfection.

    DOI: 10.1007/s00534-007-1252-3

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  • Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Reviewed International journal

    Hironobu Sato, Hiromu Suzuki, Minoru Toyota, Masanori Nojima, Reo Maruyama, Shigeru Sasaki, Hideyasu Takagi, Yohei Sogabe, Yasushi Sasaki, Masashi Idogawa, Tomoko Sonoda, Mitsuru Mori, Kohzoh Imai, Takashi Tokino, Yasuhisa Shinomura

    Carcinogenesis   28 ( 12 )   2459 - 66   2007.12

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    Activation of Wnt signaling has been implicated in tumorigenesis, and epigenetic silencing of Wnt antagonist genes has been detected in various cancers. In the present study, we examined the expression and methylation of DICKKOPF (DKK) family genes in gastrointestinal cancer cell lines. We found that all known DKK genes were frequently silenced in colorectal cancer (CRC) cells (DKK1, 3/9, 33%; DKK2, 8/9, 89%; DKK3, 5/9, 56% and DKK4, 5/9, 56%), but not in normal colon mucosa. DKK1, -2 and -3 have 5' CpG islands, and show an inverse relation between expression and methylation. DKK methylation also was frequently observed in gastric cancer (GC) cell lines (DKK1, 6/16, 38%; DKK2, 15/16, 94% and DKK3, 10/16, 63%), but was seen less frequently in hepatocellular carcinoma and pancreatic cancer cell lines. DKKs also were frequently methylated in primary CRCs (DKK1, 7/58, 12%; DKK2, 45/58, 78% and DKK3, 12/58, 21%) and GCs (DKK1, 15/31, 48%; DKK2, 26/31, 84% and DKK3, 12/31, 39%). Against a background of CTNNB1 or APC mutations, Dickkopfs (Dkks) were less effective inhibitors of Wnt signaling than secreted frizzled-related proteins, though over-expression of Dkks suppressed colony formation of CRC cells with such mutations. Our results demonstrate that DKKs are frequent targets of epigenetic silencing in gastrointestinal tumors, and that loss of DKKs may facilitate tumorigenesis through beta-catenin/T-cell factor-independent mechanisms.

    DOI: 10.1093/carcin/bgm178

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  • Gene amplification and overexpression of PRDM14 in breast cancers. Reviewed International journal

    Noriko Nishikawa, Minoru Toyota, Hiromu Suzuki, Toshio Honma, Tomoko Fujikane, Tousei Ohmura, Toshihiko Nishidate, Mutsumi Ohe-Toyota, Reo Maruyama, Tomoko Sonoda, Yasushi Sasaki, Takeshi Urano, Kohzoh Imai, Koichi Hirata, Takashi Tokino

    Cancer research   67 ( 20 )   9649 - 57   2007.10

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    Several genes that encode PR (PRDI-BF1 and RIZ) domain proteins (PRDM) have been linked to human cancers. To explore the role of the PR domain family genes in breast carcinogenesis, we examined the expression profiles of 16 members of the PRDM gene family in a panel of breast cancer cell lines and primary breast cancer specimens using semiquantitative real-time PCR. We found that PRDM14 mRNA is overexpressed in about two thirds of breast cancers; moreover, immunohistochemical analysis showed that expression of PRDM14 protein is also up-regulated. Analysis of the gene copy number revealed that PRDM14 is a target of gene amplification on chromosome 8q13, which is a region where gene amplification has frequently been detected in various human tumors. Introduction of PRDM14 into cancer cells enhanced cell growth and reduced their sensitivity to chemotherapeutic drugs. Conversely, knockdown of PRDM14 by siRNA induced apoptosis in breast cancer cells and increased their sensitivity to chemotherapeutic drugs, suggesting that up-regulated expression of PRDM14 may play an important role in the proliferation of breast cancer cells. That little or no expression of PRDM14 is seen in noncancerous tissues suggests that PRDM14 could be an ideal therapeutic target for the treatment of breast cancer.

    DOI: 10.1158/0008-5472.CAN-06-4111

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  • PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer. Reviewed International journal

    Yoshiyuki Watanabe, Minoru Toyota, Yutaka Kondo, Hiromu Suzuki, Takashi Imai, Mutsumi Ohe-Toyota, Reo Maruyama, Masanori Nojima, Yasushi Sasaki, Yoshitaka Sekido, Hiroyoshi Hiratsuka, Yasuhisa Shinomura, Kohzoh Imai, Fumio Itoh, Takashi Tokino

    Clinical cancer research : an official journal of the American Association for Cancer Research   13 ( 16 )   4786 - 94   2007.8

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    PURPOSE: PR (PRDI-BF1 and RIZ) domain proteins (PRDM) are a subfamily of the kruppel-like zinc finger gene products that play key roles during cell differentiation and malignant transformation. The aim of the present study was to begin to examine the involvement of epigenetic alteration of PRDM expression in gastric and colorectal cancer. EXPERIMENTAL DESIGN: We used real-time PCR to assess expression of PRDM1-17. In addition, we used bisulfite PCR to assess DNA methylation and chromatin immunoprecipitation to assess histone modification in colorectal and gastric cancer cell lines lacking PRDM5 expression. RESULTS: Among the 17 PRDM family genes tested, we found that PRDM5 is the most frequently silenced in colorectal and gastric cancer cell lines. Silencing of PRDM5 was mediated by either DNA methylation or trimethylation of Lys(27) of histone H3. Introduction of PRDM5 into cancer cells suppressed cell growth, suggesting that it acts as a tumor suppressor in gastrointestinal cancers. Methylation of PRDM5 was detected in 6.6% (4 of 61) of primary colorectal and 50.0% (39 of 78) of primary gastric cancers but not in noncancerous tissue samples collected from areas adjacent to the tumors. CONCLUSIONS: Our data suggest that epigenetic alteration of PRDM5 (e.g., methylation of its 5'-CpG island or trimethylation of Lys(27) of histone H3) likely plays a key role in the progression of gastrointestinal cancers and may be a useful molecular marker.

    DOI: 10.1158/1078-0432.CCR-07-0305

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  • CHFR有糸分裂チェックポイントタンパク質はNFκBの転写活性を抑制する(CHFR mitotic checkpoint protein inhibits the transcriptional activity of NF-κB)

    鹿島 理沙, 見田 裕章, 豊田 実, 佐々木 泰史, 鈴木 拓, 井戸川 雅史, 時野 隆至

    日本癌学会総会記事   66回   482 - 482   2007.8

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  • 多発性骨髄腫においてDNAメチル化により不活化される遺伝子の網羅的解析(Genomic Screening for Genes Silenced by DNA Methylation in Multiple Myeloma)

    丸山 玲緒, 豊田 実, 鈴木 拓, 安井 寛, 林 敏昭, 酒井 基, 石田 禎夫, 今井 浩三, 時野 隆至, 篠村 恭久

    日本癌学会総会記事   66回   458 - 458   2007.8

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  • アデノウイルス介在性p53ファミリー遺伝子療法効果のヒストンデアセチラーゼ阻害剤FK228による増大(The Histone Deacetylase Inhibitor FK228 Increases the Efficacy of Adenovirus-mediated p53 Family Gene Therapy)

    佐々木 泰史, 根岸 秀明, 井戸川 雅史, 鈴木 拓, 見田 裕章, 豊田 実, 丸山 玲緒, 明石 浩史, 篠村 恭久, 今井 浩三, 時野 隆至

    日本癌学会総会記事   66回   129 - 129   2007.8

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  • デジタルゲノムスキャンにより同定された胃癌におけるK-rasゲノム増幅(Genomic amplification of K-ras in gastric cancer identified by digital genome scanning)

    見田 裕章, 豊田 実, 青木 文夫, 明石 浩史, 丸山 玲緒, 佐々木 泰史, 鈴木 拓, 井戸川 雅史, 鹿島 理沙, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   66回   231 - 231   2007.8

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  • 口腔癌におけるRAS関連遺伝子の異常について(Alterations of RAS signaling pathway in oral squamous cell carcinoma)

    今井 崇, 秋野 公臣, 豊田 実, 鈴木 拓, 佐々木 泰史, 見田 裕章, 井戸川 雅史, 鹿島 理沙, 曽我部 陽平, 渡邊 嘉行, 今井 浩三, 平塚 博義, 時野 隆至

    日本癌学会総会記事   66回   314 - 314   2007.8

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  • Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer Reviewed

    M. Nojima, H. Suzuki, M. Toyota, Y. Watanabe, R. Maruyama, S. Sasaki, Y. Sasaki, H. Mita, N. Nishikawa, K. Yamaguchi, K. Hirata, F. Itoh, T. Tokino, M. Mori, K. Imai, Y. Shinomura

    ONCOGENE   26 ( 32 )   4699 - 4713   2007.7

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    DOI: 10.1038/sj.onc.1210259

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  • Antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines. Reviewed International journal

    Yuichiro Oshima, Yasushi Sasaki, Hideaki Negishi, Masashi Idogawa, Minoru Toyota, Toshiharu Yamashita, Takuro Wada, Satoshi Nagoya, Satoshi Kawaguchi, Toshihiko Yamashita, Takashi Tokino

    Cancer biology & therapy   6 ( 7 )   1058 - 66   2007.7

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    Osteosarcoma (OS) is one of the most common malignancies of the bone. Although prognosis of OS has improved significantly during the past several years due to more intensive chemotherapy and radiotherapy regimens, new therapeutic approaches are needed for recurrent and inoperable cases, p73 and p63, like their homologue, the tumor suppressor p53, are able to induce apoptosis in several cell types. Here, we evaluated the antitumor effects of p73 and p63 on eleven different human OS cell lines. In vitro, adenovirus-mediated transduction of p63gamma induced apoptosis in OS cells that are resistant to p53-mediated apoptosis, while less effect was observed following transduction of p73alpha or p63alpha. Interestingly, the apoptotic effects of p63gamma were greater than those of wild-type p53 in OS cells carrying MDM2-amplification. We then determined the in vivo therapeutic effect of intratumoral injection of adenovirus-vector expressing p53 family members on xenografts derived from Saos-2 cells implanted in nude mice, and showed that infection with p63y significantly suppressed tumor growth compared with p53. In addition, exogenous p73beta and p63gamma significantly increased the chemosensitivity of OS cells to doxorubicin and cisplatin, chemotherapeutic agents commonly used in the treatment of OS. Our results suggest that adenovirus-mediated transduction of p53 family members may have utility in gene therapy for OS, particularly in combination with chemotherapeutic agents.

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  • Ku70 and poly(ADP-ribose) polymerase-1 competitively regulate beta-catenin and T-cell factor-4-mediated gene transactivation: possible linkage of DNA damage recognition and Wnt signaling. Reviewed International journal

    Masashi Idogawa, Mitsuko Masutani, Miki Shitashige, Kazufumi Honda, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Setsuo Hirohashi, Tesshi Yamada

    Cancer research   67 ( 3 )   911 - 8   2007.2

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    Formation of the T-cell factor-4 (TCF-4) and beta-catenin nuclear complex is considered crucial to embryonic development and colorectal carcinogenesis. We previously reported that poly(ADP-ribose) polymerase-1 (PARP-1) interacts with the TCF-4 and beta-catenin complex and enhances its transcriptional activity. However, its biological significance remains unexplained. Using immunoprecipitation and mass spectrometry, we found that two Ku proteins, Ku70 and Ku80, were also associated with the complex. Knockdown of Ku70 by RNA interference increased the amount of beta-catenin associated with TCF-4 and enhanced the transcriptional activity. PARP-1 competed with Ku70 for binding to TCF-4. Treatment with bleomycin, a DNA-damaging alkylating agent, induced polyADP-ribosylation of PARP-1 protein and inhibited its interaction with TCF-4. Bleomycin conversely increased the amounts of Ku70 coimmunoprecipitated with TCF-4 and removed beta-catenin from TCF-4. We propose a working model in which the transcriptional activity of TCF-4 is regulated by the relative amount of Ku70, PARP-1, and beta-catenin proteins binding to TCF-4. Identification of the functional interaction of Ku70 as well as PARP-1 with the TCF-4 and beta-catenin transcriptional complex may provide insights into a novel linkage between DNA damage recognition/repair and Wnt signaling.

    DOI: 10.1158/0008-5472.CAN-06-2360

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  • Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Reviewed International journal

    Kimishige Akino, Minoru Toyota, Hiromu Suzuki, Takashi Imai, Reo Maruyama, Masanobu Kusano, Noriko Nishikawa, Yoshiyuki Watanabe, Yasushi Sasaki, Tamaki Abe, Eiichiro Yamamoto, Isao Tarasawa, Tomoko Sonoda, Mitsuru Mori, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    Cancer science   98 ( 1 )   88 - 95   2007.1

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    Epigenetic gene inactivation plays a key role in the development of various types of cancer. Using methylated CpG island amplification coupled with representational difference analysis to identify genes inactivated by DNA methylation in gastric cancer, we identified seven DNA fragments corresponding to the 5' CpG islands of the affected genes. One of the clones recovered was identical to the 5' flanking region of DFNA5, a gene previously shown to be associated with deafness and induced by DNA damage. Further analysis revealed that DFNA5 is expressed in normal tissues but is down-regulated in gastric cancer cell lines due to methylation of the region around its transcription start site. Treating gastric cancer cells that lacked DFNA5 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Methylation of DFNA5 was detected in 50% of primary gastric tumors, and was correlated with positivity for Epstein-Barr virus and the absence of metastasis. Moreover, introduction of exogenous DFNA5 into silenced cells suppressed colony formation. Taken together, these data suggest that the silencing of DFNA5 occurs frequently in gastric cancer and may play a key role in development and progression of the disease.

    DOI: 10.1111/j.1349-7006.2006.00351.x

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  • Genomic screening for genes silenced by DNA methylation in multiple myeloma Reviewed

    Yasui, Hiroshi, Toyota, Minoru, Maruyama, Reo, Tarasawa, Isao, Suzuki, Hiromu, Hayashi, Toshiaki, Sakai, Hajime, Ishida, Tadao, Asaoku, Hideki, Tokino, Takashi, Imai, Kohzoh, Shinomura, Yasuhisa

    TUMOR BIOLOGY   28   78 - 78   2007

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  • Proteins interacting with CHFR, mitotic-checkpoint ubiquitin ligase Reviewed

    Mita H, Toyota M, Sasaki Y, Suzuki H, Idogawa M, Kashima L, Tokino T

    Tumor Research   41   23 - 41   2006.12

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    Other Link: http://orcid.org/0000-0002-8507-1726

    DOI: 10.15114/tr.41.23

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  • Sequence motif discovery with computational genome-wide analysis Reviewed

    Akashi H, Aoki F, Toyota M, Maruyama R, Sasaki Y, Mita H, Tokura H, Imai K, Tatsumi H, Tokino T

    Tumor Research   41   59 - 69   2006.12

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    DOI: 10.15114/tr.41.59

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  • 口腔扁平上皮癌におけるRAS関連遺伝子のジェネティックおよびエピジェネティックな異常の解析

    今井 崇, 秋野 公臣, 豊田 実, 鈴木 拓, 佐々木 泰史, 見田 裕章, 井戸川 雅史, 荻 和弘, 鹿島 理沙, 曽我部 陽平, 今井 浩三, 平塚 博義, 時野 隆至

    日本癌学会総会記事   65回   199 - 199   2006.9

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  • 短いDNA断片の塩基配列情報を用いた定量的ゲノム解析法の開発と癌研究への応用

    見田 裕章, 豊田 実, 丸山 玲緒, 明石 浩史, 青木 文夫, 佐々木 泰史, 鹿島 理沙, 鈴木 拓, 井戸川 雅史, 苗代 康可, 今井 浩三, 篠村 恭久, 時野 隆至

    日本癌学会総会記事   65回   182 - 182   2006.9

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  • 大腸癌におけるエピジェネティックな変化を指標とした診断への比較検討

    渡邊 嘉行, 豊田 実, 鈴木 拓, 岡本 賢, 時野 隆至, 伊東 文生

    日本癌学会総会記事   65回   52 - 52   2006.9

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  • インシリコ解析による新規p53標的遺伝子群の網羅的な同定

    丸山 玲緒, 豊田 実, 明石 浩史, 佐々木 泰史, 青木 文夫, 鈴木 拓, 見田 裕章, 井戸川 雅史, 今井 浩三, 篠村 泰久, 時野 隆至

    日本癌学会総会記事   65回   79 - 79   2006.9

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  • CHFR(checkpoint with FHA and RING domain)によるNF-kBシグナリング制御

    鹿島 理沙, 見田 裕章, 豊田 実, 佐々木 泰史, 井戸川 雅史, 鈴木 拓, 時野 隆至

    日本癌学会総会記事   65回   162 - 162   2006.9

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  • p73によるIL-4シグナルの活性化と抗腫瘍活性

    佐々木 泰史, 見田 裕章, 豊田 実, 篠村 恭久, 今井 浩三, 時野 隆至

    日本臨床分子医学会学術総会プログラム・抄録集   43回   85 - 85   2006.7

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  • DNA断片の塩基配列情報に基づいたゲノムコピー数解析法の開発

    見田 裕章, 豊田 実, 丸山 玲緒, 青木 文夫, 明石 浩史, 鹿島 理沙, 佐々木 泰史, 鈴木 拓, 井戸川 雅史, 藤井 恭子, 篠村 恭久, 今井 浩三, 時野 隆至

    日本臨床分子医学会学術総会プログラム・抄録集   43回   63 - 63   2006.7

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  • Activation of the ribosomal protein L13 gene in human gastrointestinal cancer. Reviewed International journal

    Toshihisa Kobayashi, Yasushi Sasaki, Yuichiro Oshima, Hiroyuki Yamamoto, Hiroaki Mita, Hiromu Suzuki, Minoru Toyota, Takashi Tokino, Fumio Itoh, Kohzoh Imai, Yasuhisa Shinomura

    International journal of molecular medicine   18 ( 1 )   161 - 70   2006.7

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    Although ribosomal proteins are major components of ribosomes, recent data have shown them to have extraribosomal functions apart from ribosome and protein biosynthesis. In our earlier study, we showed that ribosomal protein L13 mRNA was up-regulated in response to DNA damage in hamster cells. We report here that L13 expression is up-regulated in human gastrointestinal cancers. We also examined the biological role of L13 on human cancer cells. Knocking down L13 expression using small interfering RNA (siRNA) resulted in drastic attenuation of cancer cell growth with significant G1 and G2/M arrest of the cell cycle. Moreover, L13 siRNA significantly enhanced the cellular sensitivity to certain DNA damaging agents and, concordantly, L13-overexpressing cells demonstrated greater chemoresistance compared to parent cells, suggesting an inverse correlation between L13 expression and chemosensitivity. By using semiquantitative RT-PCR, we analyzed expression of L13 in freshly resected cancer tissue of the stomach, colorectum and liver. Up-regulation of L13 mRNA expression was observed in 10 (28%) of 36 gastric, 19 (41%) of 46 colorectal and 5 (20%) of 25 liver cancer tissue samples compared to adjacent normal tissue samples. We also found that increased expression of the L13 gene correlated with clinical staging in gastric cancers. The results of this study suggest that L13 plays an essential role in the progression of some gastrointestinal malignancies.

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  • がん抑制遺伝子p53により誘導される新規分子の網羅的同定

    丸山 玲緒, 豊田 実, 青木 文夫, 佐々木 泰史, 明石 浩史, 鈴木 拓, 見田 裕章, 時野 隆至, 今井 浩三, 篠村 恭久

    日本臨床分子医学会学術総会プログラム・抄録集   43回   64 - 64   2006.7

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  • Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. Reviewed International journal

    Reo Maruyama, Fumio Aoki, Minoru Toyota, Yasushi Sasaki, Hirofumi Akashi, Hiroaki Mita, Hiromu Suzuki, Kimishige Akino, Mutsumi Ohe-Toyota, Yumiko Maruyama, Haruyuki Tatsumi, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

    Cancer research   66 ( 9 )   4574 - 83   2006.5

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    p53 is the most frequently mutated tumor suppressor gene in human neoplasia and encodes a transcriptional coactivator. Identification of p53 target genes is therefore key to understanding the role of p53 in tumorigenesis. To identify novel p53 target genes, we first used a comparative genomics approach to identify p53 binding sequences conserved in the human and mouse genome. We hypothesized that potential p53 binding sequences that are conserved are more likely to be functional. Using stringent filtering procedures, 32 genes were newly identified as putative p53 targets, and their responsiveness to p53 in human cancer cells was confirmed by reverse transcription-PCR and real-time PCR. Among them, we focused on the vitamin D receptor (VDR) gene because vitamin D3 has recently been used for chemoprevention of human tumors. VDR is induced by p53 as well as several other p53 family members, and analysis of chromatin immunoprecipitation showed that p53 protein binds to conserved intronic sequences of the VDR gene in vivo. Introduction of VDR into cells resulted in induction of several genes known to be p53 targets and suppression of colorectal cancer cell growth. In addition, p53 induced VDR target genes in a vitamin D3-dependent manner. Our in silico approach is a powerful method for identification of functional p53 binding sites and p53 target genes that are conserved among humans and other organisms and for further understanding the function of p53 in tumorigenesis.

    DOI: 10.1158/0008-5472.CAN-05-2562

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  • Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus. Reviewed International journal

    Masanobu Kusano, Minoru Toyota, Hiromu Suzuki, Kimishige Akino, Fumio Aoki, Masahiro Fujita, Masao Hosokawa, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino

    Cancer   106 ( 7 )   1467 - 79   2006.4

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    BACKGROUND: The CpG island methylator phenotype (CIMP), which is characterized by simultaneous methylation of the CpG islands of multiple genes, has been recognized as one of the important mechanisms in gastrointestinal carcinogenesis. METHODS: Methylation of the 5 methylated-in-tumors (MINT) loci and 12 tumor-related genes in 78 primary gastric carcinomas was examined using combined bisulfite-restriction analysis. Epstein-Barr virus (EBV)-associated gastric tumors were detected using real-time polymerase chain reaction analysis followed by an evaluation of the correlations between CIMP status, EBV-association, and genetic alteration of p53 and K-ras. The authors compared the clinicopathologic features of gastric carcinomas that had high CIMP methylation (CIMP-H) with tumors that had low CIMP methylation (CIMP-L) or negative CIMP methylation (CIMP-N). RESULTS: The methylation profiles of 12 genes showed nonrandom methylation, supporting the presence of CIMP in gastric carcinoma. No p53 mutations were detected among CIMP-H tumors, and no EBV association was detected in tumors that showed mutation of p53 and K-ras. In a multiple logistic regression model with CIMP-H as the dependent variable, proximal location (P = .011), diffuse type (P = .019), and less advanced pathologic TNM status (P = .043) contributed significantly to CIMP-H. Patients who had CIMP-N gastric tumors had a significantly worse survival than patients who had CIMP-H tumors (P = .004) or CIMP-L tumors (P = .012). EBV-associated tumors were associated strongly with CIMP-H, hypermethylation of tumor-related genes, and no p53 or K-ras mutation. CONCLUSIONS: CIMP status appeared to be associated with distinct genetic, epigenetic, and clinicopathologic features in gastric carcinomas. The finding that gastric carcinomas arose through different molecular pathways may affect not only tumor characteristics but also patient prognosis.

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  • Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma Reviewed

    H. Okuda, M. Toyota, W. Ishida, M. Furihata, M. Tsuchiya, M. Kamada, T. Tokino, T. Shuin

    Oncogene   25 ( 12 )   1733 - 1742   2006.3

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    DOI: 10.1038/sj.onc.1209200

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  • Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines Reviewed

    K Terasawa, M Toyota, S Sagae, K Ogi, H Suzuki, T Sonoda, K Akino, R Maruyama, N Nishikawa, K Imai, Y Shinomura, T Saito, T Tokino

    BRITISH JOURNAL OF CANCER   94 ( 6 )   914 - 921   2006.3

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    DOI: 10.1038/sj.bjc.6602984

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  • Unique domain functions of p63 isotypes that differentially regulate distinct aspects of epidermal homeostasis Reviewed

    KE King, RM Ponnamperuma, MJ Gerdes, T Tokino, T Yamashita, CC Baker, WC Weinberg

    CARCINOGENESIS   27 ( 1 )   53 - 63   2006.1

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    DOI: 10.1093/carcin/bgi200

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  • Application of methylation changes in a novel colon tumor suppressor gene, RASSF2, to tumor marker

    Toyota Minoru, Akino Kimishige, Suzuki Hiromu, Tokino akashi, Shinomura Y, Imai Kohzoh

    Japan Journal of Molecular Tumor Marker Research   21   5 - 6   2006

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    DOI: 10.11241/jsmtmr.21.5

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  • The role of T-fimbrin in the response to DNA damage: silencing of T-fimbrin by small interfering RNA sensitizes human liver cancer cells to DNA-damaging agents. Reviewed International journal

    Hiroshi Ikeda, Yasushi Sasaki, Toshihisa Kobayashi, Hiromu Suzuki, Hiroaki Mita, Minoru Toyota, Fumio Itoh, Yasuhisa Shinomura, Takashi Tokino, Kohzoh Imai

    International journal of oncology   27 ( 4 )   933 - 40   2005.10

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    Fimbrins (also known as plastins) are actin-binding proteins of the cortical cytoskeleton present in all cells and conserved from yeast to mammals. We previously reported that the up-regulation of T-fimbrin, a fimbrin isoform, in association with G2 arrest following DNA damage and that a lack of T-fimbrin expression shortens the radiation-induced G2 arrest in Chinese hamster ovarian cells. In this study, we further investigated the role of T-fimbrin in DNA-damage response using a panel of human liver cancer cell lines and small interfering RNA technology. T-fimbrin was differentially expressed in human liver cancer cell lines. Colony formation assays revealed that cell lines lacking T-fimbrin expression were highly sensitive to DNA damage compared to cell lines that express T-fimbrin. Using siRNA designed to target T-fimbrin, we demonstrated that silencing endogenous T-fimbrin causes a marked increase in the cellular sensitivity to VP-16 and UV irradiation. Moreover, T-fimbrin deletion abrogated UV-mediated cell cycle checkpoint, and consequently led to increased apoptotic cell death in resistant cells. These findings suggest that the status of T-fimbrin expression may be a useful molecular marker for predicting the responsiveness of cancer cells to treatment with chemotherapeutic drugs.

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  • 分裂期チェックポイント分子CHFRの結合分子探索と機能解析

    見田 裕章, 豊田 実, 鹿島 理沙, 佐々木 泰史, 秋野 公臣, 鈴木 拓, 井戸川 雅史, 下重 美紀, 山田 哲司, 篠村 恭久, 今井 浩三, 時野 隆至

    日本癌学会総会記事   64回   327 - 327   2005.9

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  • DNAの異常メチル化を指標とした大腸癌アベレージリスク群の設定と検診への応用

    渡邊 嘉行, 豊田 実, 秋野 公臣, 鈴木 拓, 前畑 忠照, 岡本 賢, 奥瀬 千晃, 今井 浩三, 篠村 恭久, 伊東 文生, 時野 隆至

    日本癌学会総会記事   64回   540 - 540   2005.9

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  • RASエフェクター,RASSF2遺伝子は大腸がんにおける新規がん抑制遺伝子である(The Ras Effector RASSF2 is a Novel Tumor Suppressor Gene in Human Colorectal Cancer)

    秋野 公臣, 豊田 実, 鈴木 拓, 見田 裕章, 佐々木 泰史, 篠村 恭久, 今井 浩三, 時野 隆至

    日本癌学会総会記事   64回   136 - 137   2005.9

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  • Id2 protein is selectively upregulated by UVB in primary, but not in immortalized human keratinocytes and inhibits differentiation. Reviewed International journal

    Cynthia M Simbulan-Rosenthal, Valerie Trabosh, Ana Velarde, Feng-Pai Chou, Ahmad Daher, Fnu Tenzin, Takashi Tokino, Dean S Rosenthal

    Oncogene   24 ( 35 )   5443 - 58   2005.8

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    Solar ultraviolet B (UVB) acts as both an initiator and promoter in models of multistage skin carcinogenesis. We found that, whereas UVB induces apoptosis in human papillomavirus-16 E6/7-immortalized keratinocytes, it inhibits markers of differentiation in human foreskin keratinocytes (HFK). Potential mechanisms for this differential response were examined by DNA microarray, which revealed that UVB alters the expression of three of the four human inhibitor of differentiation/DNA binding (Id) proteins that comprise a class of helix-loop-helix family of transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. These results were verified by RT-PCR and immunoblot analysis of control and UVB-irradiated primary and immortalized keratinocytes. Whereas Id1 was downregulated in both cell types, Id2 expression was upregulated in primary HFK, but not immortalized cells. In contrast, Id3 expression was significantly increased only in immortalized cells. The differential expression pattern of Id2 in response to UVB was recapitulated in reporter constructs containing the 5' regulatory regions of this gene. Id2 promoter activity increased in response to UVB in HFK, but not in immortalized cells. To identify the regulatory elements in the Id2 promoter that mediate transcriptional activation by UVB in HFK, promoter deletion/mutation analysis was performed. Deletion analysis revealed that transactivation involves a 166 bp region immediately upstream to the Id2 transcriptional start site and is independent of c-Myc. The consensus E twenty-six (ETS) binding site at -120 appears to mediate UVB transcriptional activation of Id2 because point mutations at this site completely abrogated this response. Chromatin immunoprecipitation and electrophoretic mobility-shift assays verified that the Id2 promoter interacts with known Id2 promoter (ETS) binding factors Erg1/2 and Fli1, but not with c-Myc; and this interaction is enhanced after UVB exposure. Similar to the effects of UVB exposure, ectopic expression of Id2 protein in primary HFK resulted in inhibition of differentiation, as shown by decreased levels of the terminal differentiation marker keratin K1 and inhibition of involucrin crosslinking. Reduction of Id2 expression by small interfering RNAs attenuated the UVB-induced inhibition of differentiation in these cells. These results suggest that UVB-induced inhibition of differentiation of primary HFK is at least, in part, due to the upregulation of Id2, and that upregulation of Id2 by UVB might predispose keratinocytes to carcinogenesis by preventing their normal differentiation program.

    DOI: 10.1038/sj.onc.1208709

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  • Identification of pigment epithelium-derived factor as a direct target of the p53 family member genes. Reviewed International journal

    Yasushi Sasaki, Yasuyoshi Naishiro, Yuichiro Oshima, Kohzoh Imai, Yusuke Nakamura, Takashi Tokino

    Oncogene   24 ( 32 )   5131 - 6   2005.7

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    p63 and p73 show a high degree of structural homology to p53 and are members of a family of transcriptional factors that can activate transcription of p53-responsive genes. p53 is mutated in more than 50% of human cancers, whereas p63 and p73 are rarely mutated. Studies of knockout mice also revealed an unexpected functional diversity among the p53 family. To determine how p63 and p73 are involved in tumorigenesis and normal development, we used cDNA microarray to examine 9216 genes in human colorectal cancer cells. We discovered that the expression of pigment epithelium-derived factor (PEDF) was specifically induced by either p63 or p73, but not by p53. We also report here that the PEDF gene contains a response element specific for p63 and p73 in its promoter region and is a direct target of p63 and p73. Collectively, p63 and p73 may be involved in cell fate by inducing PEDF expression.

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  • Small interfering RNA-induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors. Reviewed International journal

    Kazuhiro Ogi, Minoru Toyota, Hiroaki Mita, Ayumi Satoh, Lisa Kashima, Yasushi Sasaki, Hiromu Suzuki, Kimishige Akino, Noriko Nishikawa, Makoto Noguchi, Yasuhisa Shinomura, Kohzoh Imai, Hiroyoshi Hiratsuka, Takashi Tokino

    Cancer biology & therapy   4 ( 7 )   773 - 80   2005.7

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    Alterations in the function of cell cycle checkpoints are frequently detected in oral squamous cell carcinomas (OSCCs), and are often associated with the sensitivity of the cancer cells to chemotherapeutic drugs. Recently, a mitotic checkpoint gene, Chfr, was shown to be inactivated by promoter methylation and point mutations in various human tumors. Here we show that the absence of its product, CHFR, is associated with mitotic checkpoint dysfunction, and that cancer cells lacking CHFR are sensitive to microtubule inhibitors. Checkpoint impairment appears to be caused by a prophase defect in this case, as OSCC cells lacking CHFR showed phosphorylation of histone H3 on Ser10 and translocation of cyclin B1 to the nucleus. When CHFR-deficient OSCC cells were treated with a microtubule inhibitor (docetaxel or paclitaxel), significant numbers of apoptotic cells were observed. Moreover, disruption of CHFR using small interfering RNA (siRNA) impaired the mitotic checkpoint, thereby reducing the ability of OSCC cells to arrest at G2/M phase and making them more sensitive to microtubule inhibitors. Our results suggest that CHFR could be a useful molecular target for chemotherapy.

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  • p53によるビタミンD受容体の発現誘導と癌治療への応用

    丸山 玲緒, 豊田 実, 青木 文夫, 佐々木 泰史, 明石 浩史, 見田 裕章, 鈴木 拓, 時野 隆至, 今井 浩三, 篠村 恭久

    日本臨床分子医学会学術総会プログラム・抄録集   42回   112 - 112   2005.7

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  • The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Reviewed International journal

    Kimishige Akino, Minoru Toyota, Hiromu Suzuki, Hiroaki Mita, Yasushi Sasaki, Mutsumi Ohe-Toyota, Jean-Pierre J Issa, Yuji Hinoda, Kohzoh Imai, Takashi Tokino

    Gastroenterology   129 ( 1 )   156 - 69   2005.7

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    BACKGROUND & AIMS: Activation of Ras signaling is a hallmark of colorectal cancer (CRC), but the roles of negative regulators of Ras are not fully understood. Our aim was to address that question by surveying genetic and epigenetic alterations of Ras-Ras effector genes in CRC cells. METHODS: The expression and methylation status of 6 RASSF family genes were examined using RT-PCR and bisulfite PCR in CRC cell lines and in primary CRCs and colorectal adenomas. Colony formation assays and flow cytometry were used to assess the tumor suppressor activities of RASSF1 and RASSF2. Immunofluorescence microscopy was used to determine the effect of altered RASSF2 expression on cell morphology. Mutations of K- ras , BRAF, and p53 were identified using single-strand conformation analysis and direct sequencing. RESULTS: Aberrant methylation and histone deacetylation of RASSF2 was associated with the gene's silencing in CRC. The activities of RASSF2, which were distinct from those of RASSF1, included induction of morphologic changes and apoptosis; moreover, its ability to prevent cell transformation suggests that RASSF2 acts as a tumor suppressor in CRC. Primary CRCs that showed K- ras /BRAF mutations also frequently showed RASSF2 methylation, and inactivation of RASSF2 enhanced K- ras -induced oncogenic transformation. RASSF2 methylation was also frequently identified in colorectal adenomas. CONCLUSIONS: RASSF2 is a novel tumor suppressor gene that regulates Ras signaling and plays a pivotal role in the early stages of colorectal tumorigenesis.

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  • Upregulation of BNIP3 by 5-aza-2'-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death. Reviewed

    Tamaki Abe, Minoru Toyota, Hiromu Suzuki, Masafumi Murai, Kimishige Akino, Masako Ueno, Masanori Nojima, Atsushi Yawata, Hiroyuki Miyakawa, Toshihiro Suga, Hideto Ito, Takao Endo, Takashi Tokino, Yuji Hinoda, Kohzoh Imai

    Journal of gastroenterology   40 ( 5 )   504 - 10   2005.5

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    BACKGROUND: Pancreatic cancer cells often show resistance to hypoxia-mediated apoptosis, but the molecular mechanism underlying that resistance remains unknown. The purpose of the present study, therefore, was to examine the role of epigenetic gene alteration in the resistance to hypoxia-mediated apoptosis among pancreatic cancer cells. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of five genes associated with hypoxia-mediated apoptosis (PUMA, Caspase-8 [CASP8], APAF-1, BNIP3, and BNIP3L) in a panel of pancreatic cancer cell lines. Protein expression was examined by Western blot analysis, using lysates from cells incubated under normoxic or hypoxic conditions. The methylation status of the genes was determined using bisulfite-PCR and sequencing. The percentages of cells that were apoptotic were determined using flow cytometry. RESULTS: Under normoxic conditions, the expression of the BNIP3 gene varied among the 12 pancreatic cancer cell lines tested, with 50% of them showing no BNIP3 expression at all, whereas expression of the other four genes was readily detected in all 12 cell lines. DNA methylation of BNIP3's CpG island in the region around the transcription start site of the gene was closely associated with its silencing. The expression of BNIP3 was restored by the methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-dC), as was the hypoxia-mediated pancreatic cancer cell death. CONCLUSIONS: BNIP3 expression is silenced in some pancreatic cancer cells by the methylation of its CpG island. Demethylation of BNIP3, using a methyltransferase inhibitor, restores the gene's expression and induces hypoxia-mediated cell death. BNIP3 may thus be a useful target for new therapies aimed at treating pancreatic cancer.

    DOI: 10.1007/s00535-005-1576-1

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  • Aberrant laminin beta3 isoforms downstream of EWS-ETS fusion genes in Ewing family tumors. Reviewed International journal

    Hideto Irifune, Hiroyuki Nishimori, Goichi Watanabe, Kouichi Yoshida, Tatsuru Ikeda, Chihiro Matsui, Masaaki Morohashi, Satoshi Kawaguchi, Satoshi Nagoya, Takuro Wada, Toshihiko Yamashita, Yusuke Nakamura, Takashi Tokino

    Cancer biology & therapy   4 ( 4 )   449 - 55   2005.4

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    Ewing family tumors (EFTs) are associated with a chromosomal translocation resulting in a fusion of the amino-terminus of EWS with the DNA-binding domain of an ETS transcription factor. Although previous reports suggested that these chimeric proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line, HT-1080, by retroviral transduction. Here we report that the LAMB3 gene encoding the beta3 chain of basement membrane protein laminin-5 is induced to a significantly higher level in cells expressing EWS-ETSs than in cells expressing normal ETSs. Additionally through use of an antisense oligonucleotide for EWS-ERG in the W-ES EFT cell line, laminin beta3 protein was reduced coordinately with EWS-ERG fusion protein expression. Furthermore, we found small mRNAs were preferentially transcribed from the LAMB3 gene in EFT cell lines. Molecular cloning of the entire coding region shows that the alternative transcripts from different promoter(s) located within the intron 14, which encode small proteins, likely are major products of the LAMB3 gene in EFT cells. We show that the small isoforms conferred increased anchorage-independent proliferation to NIH3T3 cells. Together with previous studies showing that laminin-5 is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by upregulation of LAMB3 expression.

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  • Abnormal beta-catenin expression in oral cancer with no gene mutation: correlation with expression of cyclin D1 and epidermal growth factor receptor, Ki-67 labeling index, and clinicopathological features. Reviewed International journal

    Tetsuyo Odajima, Yasushi Sasaki, Nobuyuki Tanaka, Yuko Kato-Mori, Hiroko Asanuma, Tatsuru Ikeda, Masaaki Satoh, Hiroyoshi Hiratsuka, Takashi Tokino, Norimasa Sawada

    Human pathology   36 ( 3 )   234 - 41   2005.3

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    Beta-Catenin not only acts as a regulator of E-cadherin-mediated cell-cell adhesion but also plays an important role in Wnt signaling. To assess the prevalence of Wnt signaling, we examined beta-catenin mutation and its immunohistochemical protein expression in oral cancers. The results were linked with expression of cyclin D1, one of the target genes of Wnt signaling, expression of epidermal growth factor receptor (EGFR) relevant to beta-catenin tyrosine phosphorylation, Ki-67 labeling index, clinicopathological features, and survival. In the analysis based on membranous expression of beta-catenin, 75 (68.2%) of 110 cases showed a reduced membranous pattern, and the remaining 35 (31.8%) had a preserved membranous pattern similar to that in oral epithelium. In the analysis of another category of beta-catenin expression, a cytoplasmic/nuclear pattern was observed in 21 (19.1%) of the 110 tumors. Most (19/21, 90.5%) of these tumors had a concomitant reduction of membranous expression of beta-catenin. The reduced membranous or cytoplasmic/nuclear pattern of beta-catenin was significantly associated with an invasive growth pattern, EGFR expression, an increased Ki-67 labeling index, and shorter survival but not with cyclin D1 expression. Mutational analyses of beta-catenin were performed for 39 cases, including the 21 tumors with a cytoplasmic/nuclear pattern, but no mutations in the beta-catenin gene exon 3 were detected in these samples. Our data indicate that altered expression of beta-catenin may play an important role in tumor progression through increased proliferation and invasiveness under EGFR activation. However, mutations of beta-catenin do not appear to be responsible for tumor development and abnormal expression of beta-catenin in oral cancers.

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  • Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

    M Murai, M Toyota, A Satoh, H Suzuki, K Akino, H Mita, Y Sasaki, T Ishida, L Shen, G Garcia-Manero, JPJ Issa, Y Hinoda, T Tokino, K Imai

    BRITISH JOURNAL OF CANCER   92 ( 6 )   1165 - 1172   2005.3

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    DOI: 10.1038/sj.bjc.6602422

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  • Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. Reviewed International journal

    Masafumi Murai, Minoru Toyota, Hiromu Suzuki, Ayumi Satoh, Yasushi Sasaki, Kimishige Akino, Masako Ueno, Fumihiko Takahashi, Masanobu Kusano, Hiroaki Mita, Kazuyoshi Yanagihara, Takao Endo, Yuji Hinoda, Takashi Tokino, Kohzoh Imai

    Clinical cancer research : an official journal of the American Association for Cancer Research   11 ( 3 )   1021 - 7   2005.2

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    BNIP3 protein is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested, and its absence was not caused by gene mutation or by altered expression of hypoxia inducible factor-1, a key transcription factor that regulates BNIP3 expression. On the other hand, methylation of the 5' CpG island of BNIP3 was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Apparently, epigenetic alteration of BNIP3 is a frequent and cancer-specific event, which suggests that inactivation of BNIP3 likely plays a key role in the progression of some gastrointestinal cancers and that it may be a useful molecular target for therapy.

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  • Tight junction protein MAGI-1 is up-regulated by transfection with connexin 32 in an immortalized mouse hepatic cell line: cDNA microarray analysis. Reviewed International journal

    Masaki Murata, Takashi Kojima, Toshinobu Yamamoto, Mitsuru Go, Ken-ichi Takano, Hideki Chiba, Takashi Tokino, Norimasa Sawada

    Cell and tissue research   319 ( 2 )   341 - 7   2005.2

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    Gap junctions are considered to play a crucial role in differentiation of epithelial cells, including hepatocytes. Recently, we found that Cx32 but not Cx26 was closely related to tight junctional proteins in primary cultured rat hepatocytes (Kojima et al., Exp Cell Res 263:193-201, 2001) and that Cx32 formation and/or Cx32-mediated intercellular communication could induce expression and function of tight junctions in a mouse hepatic cell line (Kojima et al., Exp Cell Res 276:40-51, 2002). In this study, to investigate the mechanisms of induction of tight junctions by transfection with Cx32, we performed cDNA microarray analysis of Cx32 transfectants, compared with parental cells derived from Cx32-deficient hepatocytes. In cDNA microarray analysis, a 2.5-fold increase in expression of membrane-associated guanylate kinase with inverted orientation-1 (MAGI-1), which is known to be localized at adherens and tight junction regions, was observed. High expression of MAGI-1 in Cx32 transfectants was confirmed by Western blotting and RT-PCR. MAGI-1 was colocalized with occludin, claudin-2, ZO-1, and F-actin, but not with E-cadherin in the apical-most regions at cell borders of Cx32 transfectants, similar to junctional adhesion molecule-1 (JAM-1), which may play a crucial role in formation and assembly of tight junctions. Treatment with the gap junction blocker 18beta-glycyrrhetinic acid did not affect expression of MAGI-1 and JAM-1 in Cx32 transfectants. These results suggest that Cx32 expression is in part related to induction of tight junctions through modulation of MAGI-1 expression in an immortalized mouse hepatic cell line.

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  • Enhanced Bax in oral SCC in relation to antitumor effects of chemotherapy. Reviewed International journal

    Kanako Takemura, Makoto Noguchi, Kazuhiro Ogi, Takashi Tokino, Hiromi Kubota, Akihiro Miyazaki, Geniku Kohama, Hiroyoshi Hiratsuka

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   34 ( 2 )   93 - 9   2005.2

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    BACKGROUND: Antitumor effects of chemotherapeutic agents are commonly associated with the induction of apoptosis. Bax belongs to the Bcl-2 family and induces apoptosis. The present study was conducted to investigate the relationship between enhanced Bax expression in oral squamous cell carcinoma (SCC; cell lines and clinical cases) and the antitumor effects of chemotherapy. METHODS: In three oral SCC cell lines, Bax expression before and after treatment with chemotherapeutic agents [docetaxel (TXT), cisplatin and 5-fluorouracil] was examined by reverse transcriptase-polymerase chain reaction and immunoblotting. The effects of treatment were assessed by counting the number of viable cells and determining sub-G1 cells. Tissue samples (both biopsy specimens before chemotherapy and surgically excised specimens after chemotherapy) from nine patients with oral SCC who underwent neoadjuvant chemotherapy were immunostained for Bax. The relationship between enhancement of Bax expression and chemotherapeutic effects was established. RESULTS: Two of three cell lines did not express Bax mRNA or protein before treatment. After treatment, Bax expression was enhanced only by TXT in one cell line, but by all chemotherapeutic agents in the other two cell lines. In three of nine patients, Bax expression was not found before chemotherapy. Two of these three patients showed enhanced Bax expression after chemotherapy including TXT, but one still failed to express Bax. Both in cell lines and clinical cases, enhancement of Bax after chemotherapy was associated with antitumor effects. CONCLUSION: Certain chemotherapeutic agents enhance Bax expression in oral SCC, and it is suggested that this contributes to the antitumor effects of chemotherapy.

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  • Identification of a specific target sequence for p53 family in the Jagged2 gene Reviewed

    Yuichiro Oshima, Setsuko Ishida, Reo Maruyama, Minoru Toyota, Toshihiko Yamashita, Takashi Tokino, Yasushi Sasaki

    Tumor Research   40   13 - 24   2005

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  • Epigenetic inactivation of SFRP's complements genetic alterations to allow constitutive Wnt pathway signaling in human colorectal cancer

    S. H., T. M., T. T., M. M., I. K.

    Japan Journal of Molecular Tumor Marker Research   20   73 - 74   2005

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    Other Link: http://search.jamas.or.jp/link/ui/2007193403

    DOI: 10.11241/jsmtmr.20.73

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  • Dual role of p53 in DNA binding. Reviewed International journal

    Takashi Tokino

    Cancer biology & therapy   3 ( 12 )   1322 - 3   2004.12

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  • Erratum: Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-γ in haematopoietic tumour cells (British Journal of Cancer (2004) 90 (844-852) doi:10.1038/sj.bjc.6601602) Reviewed

    Y. Morimoto, M. Toyota, H. Ikeda, T. Tokino, K. Imai

    British Journal of Cancer   91 ( 11 )   1978   2004.11

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  • Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-gamma-induced HLA-DR expression in colorectal and gastric cancer cells. Reviewed International journal

    Ayumi Satoh, Minoru Toyota, Hideyuki Ikeda, Yoshikazu Morimoto, Kimishige Akino, Hiroaki Mita, Hiromu Suzuki, Yasushi Sasaki, Takayuki Kanaseki, Yukio Takamura, Hidenobu Soejima, Takeshi Urano, Kazuyoshi Yanagihara, Takao Endo, Yuji Hinoda, Masahiro Fujita, Masao Hosokawa, Noriyuki Sato, Takashi Tokino, Kohzoh Imai

    Oncogene   23 ( 55 )   8876 - 86   2004.11

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    Tightly regulated at the level of transcription, expression of MHC class II molecules varies significantly among gastrointestinal cancers. High levels of MHC class II expression are often associated with a better prognosis, which is indicative of the involvement of CD4+ lymphocytes in tumor suppression, but the molecular mechanism by which MHC class II expression is regulated remains unclear. In the present study, we investigated the expression of one inducible MHC class II molecule, HLA-DR, and its coactivators in a panel of colorectal and gastric cancer cell lines. Interferon-gamma induced expression of HLA-DR in 14 of 20 cell lines tested; the remaining six cell lines did not express HLA-DR. Analysis of the expression of transcription factors and coactivators associated with HLA-DR revealed that the loss of CIITA expression was closely associated with the absence of HLA-DR induction. Moreover, DNA methylation of the 5' CpG island of CIITA-PIV was detected in all cancer cells that lacked CIITA. The methylation and resultant silencing of CIITA-PIV depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3B, and their genetic inactivation restored CIITA-PIV expression. It thus appears that CIITA methylation is a key mechanism that enables some gastrointestinal cancer cells to escape immune surveillance.

    DOI: 10.1038/sj.onc.1208144

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  • Identification of SCN3B as a novel p53-inducible proapoptotic gene. Reviewed International journal

    Katsuya Adachi, Minoru Toyota, Yasushi Sasaki, Toshiharu Yamashita, Setsuko Ishida, Mutsumi Ohe-Toyota, Reo Maruyama, Yuji Hinoda, Tsuyoshi Saito, Kohzoh Imai, Ryuichi Kudo, Takashi Tokino

    Oncogene   23 ( 47 )   7791 - 8   2004.10

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    Tumor suppressor p53 is a transcription factor that induces growth arrest and/or apoptosis in response to cellular stress. To identify novel p53-inducible genes, we compared the expression of genes in normal mouse embryo fibroblasts (MEFs) to p53-null cells by cDNA representational difference analysis. We report here that expression of endogenous sodium channel subunit beta 3 (SCN3B) is upregulated in mouse embryonic fibroblasts by DNA damage in a p53-dependent manner. In addition, we found that SCN3B levels are upregulated in human cancer cell lines by DNA damaging agents, as well as by overexpression of p53, but not significantly by p63 or p73. Furthermore, we identified two putative p53-binding sites upstream of the first exon (RE1) and in the third intron (RE2). The p53 protein can directly interact with the putative p53-binding sites in vivo, as assessed by chromatin immunoprecipitation. A reporter gene assay revealed that these two p53-binding sites are functional response elements. The SCN3B protein appears to be localized to the endoplasmic reticulum (ER). Introduction of the SCN3B gene into T98G and Saos2 cells potently suppressed colony formation. Furthermore, we found that adenovirus-mediated transfer of SCN3B induced apoptosis when combined with anticancer agents. The results presented here suggest that SCN3B mediates a p53-dependent apoptotic pathway and may be a candidate for gene therapy combined with anticancer drugs.

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  • T-fimbrin遺伝子のG2/M期チェックポイントへの関与と抗がん剤感受性

    池田 博, 佐々木 泰史, 見田 裕章, 豊田 実, 時野 隆至, 今井 浩三

    日本癌学会総会記事   63回   471 - 471   2004.9

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  • Reply: CIITA methylation and decreased levels of HLA-DR in tumour progression

    Y Morimoto, M Toyota, H Ikeda, T Tokino, K Imai

    BRITISH JOURNAL OF CANCER   91 ( 4 )   814 - 815   2004.8

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  • Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Reviewed International journal

    Hiromu Suzuki, D Neil Watkins, Kam-Wing Jair, Kornel E Schuebel, Sanford D Markowitz, Wei Dong Chen, Theresa P Pretlow, Bin Yang, Yoshimitsu Akiyama, Manon Van Engeland, Minoru Toyota, Takashi Tokino, Yuji Hinoda, Kohzoh Imai, James G Herman, Stephen B Baylin

    Nature genetics   36 ( 4 )   417 - 22   2004.4

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    Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers. It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin) or AXIN2 (encoding axin-2, also known as conductin). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus. We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer. SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development. Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.

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  • Epigenetic inactivation of TMS1/ASC in ovarian cancer. Reviewed International journal

    Katsuhiko Terasawa, Satoru Sagae, Minoru Toyota, Kuniko Tsukada, Kazuhiro Ogi, Ayumi Satoh, Hiroaki Mita, Kohzoh Imai, Takashi Tokino, Ryuichi Kudo

    Clinical cancer research : an official journal of the American Association for Cancer Research   10 ( 6 )   2000 - 6   2004.3

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    PURPOSE: The purpose of this work was to explore the role of epigenetic inactivation of apoptotic pathways in ovarian cancer by examining the DNA methylation and expression status of four proapoptotic genes in primary ovarian cancers and cancer cell lines and to correlate those findings with the clinicopathological features of ovarian cancer patients. EXPERIMENTAL DESIGN: Genomic DNA was isolated from 15 ovarian cancer cell lines, 80 primary ovarian cancer specimens, and 4 normal ovary specimens using phenol-chloroform extraction. The methylation status of the DNA was evaluated using combined bisulfite restriction analysis, gene expression was evaluated using reverse transcription-PCR, and histone acetylation was evaluated using chromatin immunoprecipitation. RESULTS: Of the four proapoptotic genes studied, expression of TMS1/ASC was absent in six ovarian cancer cell lines. Dense methylation of the 5' region of TMS1/ASC was detected in cells not expressing TMS1/ASC. Treating methylated cells with 5-aza-deoxycytidine restored gene expression, confirming the role of methylation in silencing the gene. Chromatin immunoprecipitation revealed histone to be deacetylated in cells not expressing TMS1/ASC, indicating that histone deacetylation is also involved in silencing TMS1/ASC. Aberrant methylation of TMS1/ASC was detected in 15 of 80 ovarian cancer tissues (19%) but in none of the normal ovary specimens. Aberrant methylation of TMS1/ASC was observed significantly more often in clear cell-type ovarian cancers than in other tumor types (P < 0.0001). CONCLUSIONS: Methylation-mediated silencing of TMS1/ASC confers a survival advantage to tumor cells by enabling them to escape apoptosis. The role for aberrant methylation in human ovarian tumorigenesis may be particularly important for ovarian cancers with the clear cell phenotype.

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  • Regulation of MHC class II expression in glioma cells by class II transactivator (CIITA). Reviewed International journal

    Yukio Takamura, Hideyuki Ikeda, Takayuki Kanaseki, Minoru Toyota, Takashi Tokino, Kohzoh Imai, Kiyohiro Houkin, Noriyuki Sato

    Glia   45 ( 4 )   392 - 405   2004.3

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    We first classified 12 malignant glioma cell lines into three different groups (types 1-3) with respect to major histocompatibility complex (MHC) class II expression and analyzed each group based on the different expression status of the class II transactivator (CIITA) gene. Glioma type 1 (2 of 12) showed constitutive expression of all class II molecules that might be mediated by activation of B cell-specific CIITA promoter III. Glioma type 2 represented the major phenotype (66.7 %) of malignant glioma cell lines, and MHC class II expression was induced by interferon-gamma (IFN-gamma) in this phenotype. Analysis of glioma tissue samples revealed that CIITA promoter IV was detected in 9 of 11 patients (81.8%); however, promoter III was only in two (18.2%). Moreover, cultured glioma cells obtained from a fresh tumor sample upregulated expression of CIITA and class II molecules in the presence of IFN-gamma, strongly suggesting that glioma type 2 might be predominant in glioma tissues. Glioma type 3 (2 of 12) showed CIITA transcripts but loss of MHC class II expression even in the presence of IFN-gamma. In addition, we determined that the constitutive MHC class II expression in the glioma cell lines (type 1) was the result of transcriptional activation of the CIITA gene. This phenomenon was mediated by global histone acetylation over 6 kb upstream from the transcriptional start site of CIITA promoter III. Moreover, stable transfection of CIITA promoter IV as well as promoter III into MHC class II inducible cell lines restored the constitutive expression of all class II molecules. These studies lay the foundation to understand the molecular basis for the expression of class II molecules in gliomas.

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  • Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-gamma in haematopoietic tumour cells

    Y Morimoto, M Toyota, A Satoh, M Murai, H Mita, H Suzuki, Y Takamura, H Ikeda, T Ishida, N Sato, T Tokino, K Imai

    BRITISH JOURNAL OF CANCER   90 ( 4 )   844 - 852   2004.2

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    DOI: 10.1038/sj.bjc.6601602

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  • Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer

    M Ueno, M Toyota, K Akino, H Suzuki, M Kusano, A Satoh, H Mita, Y Sasaki, M Nojima, K Yanagihara, Y Hinoda, T Tokino, K Imai

    TUMOR BIOLOGY   25 ( 3 )   134 - 140   2004

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    DOI: 10.1159/000079145

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  • Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer. Reviewed International journal

    Toshiro Obata, Minoru Toyota, Ayumi Satoh, Yasushi Sasaki, Kazuhiro Ogi, Kimishige Akino, Hiromu Suzuki, Masafumi Murai, Takefumi Kikuchi, Hiroaki Mita, Fumio Itoh, Jean-Pierre J Issa, Takashi Tokino, Kohzoh Imai

    Clinical cancer research : an official journal of the American Association for Cancer Research   9 ( 17 )   6410 - 8   2003.12

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    PURPOSE: Aberrant methylation of CpG islands can be a good molecular marker for identifying genes inactivated in cancer. We found the proapoptotic gene HRK to be a target for hypermethylation in human cancers and examined the role of such methylation in silencing the gene's expression. EXPERIMENTAL DESIGN: Methylation of HRK was evaluated by bisulfite-PCR and bisulfite sequencing in a group of colorectal and gastric cancer cell lines and primary cancers. Gene expression and histone acetylation were examined by reverse transcription-PCR and chromatin immunoprecipitation analyses, respectively. Apoptosis of cancer cells after treatment with a DNA methyltransferase inhibitor and/or histone deacetylase inhibitor was examined with fluorescence-activated cell-sorting analysis. RESULTS: The region around the HRK transcription start site was methylated in 36% of colorectal and 32% of gastric cancer cell lines and was closely associated with loss of expression in those cell types. HRK expression was restored by treatment with a methyltransferase inhibitor, 5-aza-deoxycytidine, and enhanced further by addition of histone deacetylase inhibitor trichostatin A or depsipeptide. Such restoration of HRK expression was well correlated with induction of apoptosis and enhancement of Adriamycin-induced apoptosis. Expression of other proapoptotic genes, including BAX, BAD, BID, and PUMA, was unaffected by treatment with 5-aza-deoxycytidine. Aberrant methylation of HRK was also frequently detected in primary colorectal cancers that showed methylation of multiple genes, including p16INK4A and hMLH1, and was associated with wild-type p53. CONCLUSION: HRK methylation can be a useful molecular target for cancer therapy in a subset of colorectal and gastric cancers.

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  • Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer. Reviewed International journal

    Ayumi Satoh, Minoru Toyota, Fumio Itoh, Yasushi Sasaki, Hiromu Suzuki, Kazuhiro Ogi, Takefumi Kikuchi, Hiroaki Mita, Toshiharu Yamashita, Takashi Kojima, Masanobu Kusano, Masahiro Fujita, Masao Hosokawa, Takao Endo, Takashi Tokino, Kohzoh Imai

    Cancer research   63 ( 24 )   8606 - 13   2003.12

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    Mitotic checkpoints prevent errors in chromosome segregation that can lead to neoplasia. Therefore, it is notable that gastric cancers often show impaired checkpoint function. In the present study, we examined the functional consequences of epigenetic inactivation of the mitotic checkpoint gene CHFR in gastric cancers. CHFR expression was silenced by DNA methylation of the 5' region of the gene in 20% of the gastric cancer cell lines tested and in 39% of primary gastric cancers; expression could be restored by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, histones H3 and H4 were found to be deacetylated in cell lines showing aberrant methylation, indicating a role for histone deacetylation in the methylation-dependent gene silencing. Cells not expressing CHFR showed impaired checkpoint function, which led to nuclear localization of cyclin B1 after treatment with docetaxel or paclitaxel, two microtubule inhibitors. Apparently, the absence of CHFR is associated with sensitivity of cells to mitotic stress caused by microtubule inhibition, and restoration of CHFR expression by 5-aza-2'-deoxycytidine or adenoviral gene transfer restored the checkpoint. By affecting mitotic checkpoint function, CHFR inactivation likely plays a key role in tumorigenesis in gastric cancer. Moreover, the aberrant methylation of CHFR appears to be a good molecular marker with which to predict the sensitivity of gastric cancers to microtubule inhibitors.

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  • Identification of the interleukin 4 receptor alpha gene as a direct target for p73. Reviewed International journal

    Yasushi Sasaki, Hiroaki Mita, Minoru Toyota, Setsuko Ishida, Ichiro Morimoto, Toshiharu Yamashita, Toshihiro Tanaka, Kohzoh Imai, Yusuke Nakamura, Takashi Tokino

    Cancer research   63 ( 23 )   8145 - 52   2003.12

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    p73 has a high degree of structural homology to p53 and can activate transcription of p53-responsive genes. However, analysis of p73-deficient mice revealed a marked divergence in the physiological activities of p53 family genes and distinguishes p73 from p53. Mice deficient for p73 exhibit profound defects, including hippocampal dysgenesis, chronic infection, and inflammation, as well as abnormalities in pheromone sensory pathways. p73 plays important roles in neurogenesis, sensory pathways, and homeostatic regulation. Here, we found that the interleukin 4 receptor alpha (IL-4Ralpha) gene is up-regulated by p73 but not significantly by p53 in several human cancer cell lines. IL-4Ralphatranscription is also activated in response to cisplatin, a DNA-damaging agent known to induce p73. By using small interference RNA designed to target p73, we demonstrated that silencing endogenous p73 abrogates the induction of the IL-4Ralpha gene after cisplatin treatment. Furthermore, we identified a p73-binding site in the first intron of the IL-4Ralpha gene that can directly interact with the p73 protein in vivo. This p73-binding site consists of eight copies of a 10-bp consensus p53-binding motif and is a functional response element that is relatively specific for p73 among the p53 family. p73beta promoted localized nucleosomal acetylation through recruitment of coactivator p300, indicating that p73 regulates transcription of IL-4Ralpha through the unique p73-binding site. We also found that p73beta-transfected tumor cells are sensitive to IL-4-mediated apoptosis. Our data suggest that IL-4Ralpha could mediate, in part, certain immune responses and p73-dependent cell death.

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  • MCA-RDA法を用いた消化器癌における新規メチル化標的遺伝子の同定

    秋野 公臣, 豊田 実, 荻 和弘, 小畑 俊郎, 石井 卓, 佐藤 亜由美, 村井 政史, 丸山 玲緒, 見田 裕章, 佐々木 泰史, 遠藤 高夫, 今井 浩三, 時野 隆至

    日本癌学会総会記事   62回   286 - 286   2003.8

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  • 口腔扁平上皮癌におけるM期チェックポイント遺伝子の発現異常とmicrotubule inhibitor感受性

    荻 和弘, 豊田 実, 田中 信幸, 野口 誠, 佐藤 亜由美, 佐々木 泰史, 見田 裕章, 鈴木 拓, 今井 浩三, 時野 隆至

    日本癌学会総会記事   62回   222 - 222   2003.8

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  • Epigenetic inactivation of CHFR in human tumors. Reviewed International journal

    Minoru Toyota, Yasushi Sasaki, Ayumi Satoh, Kazuhiro Ogi, Takefumi Kikuchi, Hiromu Suzuki, Hiroaki Mita, Nobuyuki Tanaka, Fumio Itoh, Jean-Pierre J Issa, Kam-Wing Jair, Kornel E Schuebel, Kohzoh Imai, Takashi Tokino

    Proceedings of the National Academy of Sciences of the United States of America   100 ( 13 )   7818 - 23   2003.6

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    Cell-cycle checkpoints controlling the orderly progression through mitosis are frequently disrupted in human cancers. One such checkpoint, entry into metaphase, is regulated by the CHFR gene encoding a protein possessing forkhead-associated and RING finger domains as well as ubiquitin-ligase activity. Although defects in this checkpoint have been described, the molecular basis and prevalence of CHFR inactivation in human tumors are still not fully understood. To address this question, we analyzed the pattern of CHFR expression in a number of human cancer cell lines and primary tumors. We found CpG methylation-dependent silencing of CHFR expression in 45% of cancer cell lines, 40% of primary colorectal cancers, 53% of colorectal adenomas, and 30% of primary head and neck cancers. Expression of CHFR was precisely correlated with both CpG methylation and deacetylation of histones H3 and H4 in the CpG-rich regulatory region. Moreover, CpG methylation and thus silencing of CHFR depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3b, as their genetic inactivation restored CHFR expression. Finally, cells with CHFR methylation had an intrinsically high mitotic index when treated with microtubule inhibitor. This means that cells in which CHFR was epigenetically inactivated constitute loss-of-function alleles for mitotic checkpoint control. Taken together, these findings shed light on a pathway by which mitotic checkpoint is bypassed in cancer cells and suggest that inactivation of checkpoint genes is much more widespread than previously suspected.

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  • deltaNp63alpha functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes. Reviewed International journal

    Kathryn E King, Roshini M Ponnamperuma, Toshiharu Yamashita, Takashi Tokino, Lela A Lee, Marian F Young, Wendy C Weinberg

    Oncogene   22 ( 23 )   3635 - 44   2003.6

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    deltaNp63 is overexpressed in squamous carcinomas where it is associated with proliferation and is believed to enhance cell growth by blocking p53-mediated transactivation. In normal epithelium, deltaNp63alpha protein expression is abundant in basal cells and decreases with differentiation. To explore the biological consequences of deltaNp63alpha overexpression in relation to squamous carcinogenesis, we evaluated its effect on normal squamous differentiation and p53 transactivation function in keratinocytes. Forced overexpression of deltaNp63alpha in primary murine keratinocytes in vitro inhibits morphological differentiation induced by elevated extracellular [Ca(2+)], abrogates Ca(2)(+)-induced growth arrest, and blocks expression of maturation-specific proteins keratin 10 and filaggrin. This suggests that deltaNp63 overexpression in squamous carcinomas may serve to maintain the basal cell phenotype and promote cell survival. deltaNp63alpha blocks transactivation of p53 responsive reporter constructs mediated by endogenous or exogenous p53 at 17 h postinfection, as expected. However, at 41 h, when p53-mediated transactivation is diminished, deltaNp63alpha enhances transactivation of these reporter constructs by 2.2-12-fold over control. Maximal deltaNp63alpha-induced transactivation requires intact p53 responsive elements, but is independent of cellular p53 status. This positive transcriptional function of deltaNp63alpha appears to be cell-type specific, as it is not observed in primary dermal fibroblasts or Saos-2 cells. These findings support deltaNp63alpha as a master regulator of keratinocyte differentiation, and suggest a novel function of this protein in the maintenance of epithelial homeostasis.

    DOI: 10.1038/sj.onc.1206536

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  • ヒト腫瘍におけるM期チェックポイント遺伝子CHFRの異常メチル化と発現抑制

    佐藤 亜由美, 豊田 実, 佐々木 泰史, 荻 和弘, 小畑 俊郎, 菊地 剛, 鈴木 拓, 伊東 文生, 時野 隆至, 今井 浩三

    日本癌学会総会記事   61回   88 - 88   2002.10

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  • 紫外線(UVB)によって転写誘導又は抑制されるヒトメラノサイト遺伝子の解析

    金 海英, 山下 利春, 佐々木 泰史, 時野 隆至, 神保 孝一

    日本研究皮膚科学会年次学術大会・総会プログラム   27回   189 - 189   2002.8

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  • p53ファミリー遺伝子の機能解析 遺伝子治療をめざして Reviewed

    佐々木 泰史, 時野 隆至

    札幌医学雑誌   71 ( 1〜2 )   1 - 6   2002.4

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    Other Link: http://ir.cc.sapmed.ac.jp/dspace/handle/123456789/225

    DOI: 10.15114/smj.71.1

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  • Methylated CpG Island Amplification of Representational Difference Analysis for Oral Cancer <Review>

    Ogi Kazuhiro, Toyota Minoru, Kohama Geniku, Tokino Takashi

    Tumor research : experimental and clinical   37   9 - 15   2002

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    Other Link: http://ir.cc.sapmed.ac.jp/dspace/handle/123456789/200

    DOI: 10.15114/tr.37.9

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  • EWS-ETS family融合遺伝子の標的遺伝子の発現解析

    渡邊 吾一, 西森 博幸, 入船 秀仁, 佐々木 泰史, 前仏 均, 田中 敏博, 吉田 幸一, 石井 清一, 中村 祐輔, 時野 隆至

    日本癌学会総会記事   60回   334 - 334   2001.9

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  • Dried Feces Spots as an Alternative DNA Source: Detection of K-ras Mutations in Colorectal Cancer Screening

    Yamaguchi Akihiro, Hashimoto Naoko, Tsutae Wataru, Seino Kuniyoshi, Osanai Hiroyuki, Yamamoto Naoya, Tokino Takashi, Sato Noriyuki, Kikuchi Kokichi

    Tumor research : experimental and clinical   36   7 - 13   2001

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    Other Link: http://ir.cc.sapmed.ac.jp/dspace/handle/123456789/193

    DOI: 10.15114/tr.36.7

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  • p53類似遺伝子p73,p51の抗腫瘍効果についての検討

    佐々木 泰史, 森本 一郎, 中谷 宇一郎, 石田 勢津子, 山下 利春, 今井 浩三, 鬼原 史, 田中 敏博, 中村 祐輔, 時野 隆至

    日本癌学会総会記事   59回   55 - 55   2000.9

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  • ヒト大腸癌由来細胞株におけるp53類似遺伝子p73,p51によるアポトーシス誘導と抗癌剤との併用効果

    石田 勢津子, 佐々木 泰史, 森本 一郎, 中谷 宇一郎, 山下 利春, 今井 浩三, 時野 隆至

    日本癌学会総会記事   59回   324 - 324   2000.9

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  • Ewing肉腫特異的なEWS-ETS融合転写因子の標的遺伝子

    吉田 幸一, 佐々木 泰史, 梅沢 明弘, 秦 順一, 鬼原 史, 田中 敏博, 中村 祐輔, 時野 隆至

    日本癌学会総会記事   59回   53 - 53   2000.9

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  • 頭頸部癌におけるβ-catenin遺伝子の蛋白発現とmutation,増殖因子受容体の発現

    小田島 哲世, 佐々木 泰史, 山口 晃, 田中 信幸, 池田 健, 佐藤 昌明, 時野 隆至

    日本癌学会総会記事   59回   162 - 162   2000.9

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  • 子宮頸部,内膜細胞診,組織診とヒトパピローマウイルス(HPV)型,K-rasとの関係

    梶野 由里, 山口 昭弘, 新家 瑠奈, 清野 邦義, 日野 順子, 沓澤 武, 時野 隆至, 佐藤 昇志, 小野江 和則, 菊地 浩吉

    日本病理学会会誌   89 ( 1 )   238 - 238   2000.3

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  • Apoptotic signaling cascade is regulated by p53 status in X-ray- irradiated cells

    D. Kobayashi, T. Tokino, N. Watanabe

    Biotherapy   14 ( 5 )   482 - 484   2000

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  • Nineteenth International Symposium on Cancer, Sapporo, 7-9 July 1999: Cancer genomics and molecular diagnosis - The Nineteenth International Symposium of Sapporo Cancer Seminar Reviewed

    M. Perucho, T. Tokino, Y. Nakamura

    Japanese Journal of Cancer Research   90 ( 11 )   1273 - 1276   1999

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  • Extranodal non-Hodgkin's lymphoma associated with systemic bone metastasis and secondary myelofibrosis

    Kasahara, K., Takahashi, T., Oka, T., Yamamoto, M., Sirata, T., Idogawa, M., Naeshiro, M., Hayashi, T., Adachi, M., Hinoda, Y., Imai, K.

    [Rinshō ketsueki] The Japanese journal of clinical hematology   39 ( 12 )   1180 - 1184   1998.12

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    DOI: 10.11406/rinketsu.39.1180

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  • GML遺伝子導入によってもたらされる細胞増殖抑制機構の解析 Reviewed

    上田 和毅, 三好 康雄, 木村 康利, 時野 隆至, 綿谷 正弘, 安富 正幸, 中村 祐輔

    日本癌学会総会記事   57回   160 - 160   1998.8

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  • p53により発現が誘導される新規遺伝子の単離

    井阪 茂之, 三好 康雄, 時野 隆至, 東 千尋, 村田 雄二, 中村 祐輔

    日本癌学会総会記事   57回   440 - 440   1998.8

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  • Cloning, expression and mapping of a novel human zinc-finger gene TCF17 homologous to rodent Kid1

    Y. Omori, H. Kyushiki, S. Takeda, M. Suzuki, A. Kawai, T. Fujiwara, E. Takahashi, Y. Nakamura

    Cytogenetic and Genome Research   78 ( 3-4 )   285 - 288   1997.1

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    DOI: 10.1159/000134673

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  • Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1) Reviewed

    T. Shiratsuchi, H. Nishimori, H. Ichise, Y. Nakamura, T. Tokino

    Cytogenetic and Genome Research   79 ( 1-2 )   103 - 108   1997.1

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    DOI: 10.1159/000134693

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  • Cloning, expression and chromosome mapping of adducin-like 70 (ADDL), a human cDNA highly homologous to human erythrocyte adducin Reviewed

    T. Katagiri, K. Ozaki, T. Fujiwara, F. Shimizu, A. Kawai, S. Okuno, M. Suzuki, Y. Nakamura, E. Takahashi, Y. Hirai

    Cytogenetic and Genome Research   74 ( 1-2 )   90 - 95   1996.1

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    DOI: 10.1159/000134389

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  • Isolation, characterization and chromosomal assignment of the human WNT7A gene

    S. Ikegawa, Y. Kumano, K. Okui, T. Fujiwara, E. Takahashi, Y. Nakamura

    Cytogenetic and Genome Research   74 ( 1-2 )   149 - 152   1996

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    DOI: 10.1159/000134404

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  • Fifty novel sequence-tagged sites (STSs) on human chromosome 11q13.4→q25 identified from microclones generated by microdissection Reviewed

    H. Soejima, K. Yoshiura, T. Tamura, T. Tokino, Y. Nakamura, N. Niikawa, Y. Jinno

    Cytogenetic and Genome Research   70 ( 1-2 )   108 - 111   1995

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    DOI: 10.1159/000134003

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  • Identification and characterization of a cdna, which is highly homologous to the ribonucleoprotein gene, from a locus (D10s102) closely linked to men2 (multiple endocrine neoplasia type 2) Reviewed

    S. Takiguchi, T. Tokino, T. Imai, A. Tanigami, K. Koyama, Y. Nakamura

    Cytogenetic and Genome Research   64 ( 2 )   128 - 130   1993

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    DOI: 10.1159/000133568

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  • A 14-MB PHYSICAL MAP OF THE REGION AT CHROMOSOME-11Q13 HARBORING THE MEN1 LOCUS AND THE TUMOR AMPLICON REGION Reviewed

    A TANIGAMI, T TOKINO, K TAKITA, S TAKIGUCHI, Y NAKAMURA

    GENOMICS   13 ( 1 )   16 - 20   1992.5

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  • Different type of hepatitis B virus (HBV) DNA integrants that may reflect the integration process Reviewed

    Kousaku Okubo, Takaaki Nakamura, Takashi Tokino, Kenichi Matsubara

    Gastroenterologia Japonica   25 ( 2 )   23 - 30   1990.9

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    DOI: 10.1007/BF02779924

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  • Regional localization of the LCA oncogene to human chromosome region 2q14→q21 Reviewed

    T. Tokino, H. Satoh, M. C. Yoshida, T. Ochiya, K. Matsubara

    Cytogenetic and Genome Research   48 ( 1 )   63 - 64   1988

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    DOI: 10.1159/000132589

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  • CARRIER DETECTION IN JAPANESE HEMOPHILIA A FAMILIES USING FACTOR-VIII GENE PROBE (F8A) AND THE GENE-LINKED ST 14-1 PROBE Reviewed

    M NISHINO, T NISHIMURA, H NAKA, S MIKAMI, T TOKINO, T MUROTSU

    JAPANESE JOURNAL OF HUMAN GENETICS   32 ( 3 )   237 - 245   1987.9

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  • Carrier detection in Japanese haemophilia a families using factor VIII gene probe (F8A) and the gene-linked ST 14-1 probe Reviewed

    Masato Nishino, Takuya Nishimura, Hiroyuki Naka, Sadaaki Mikami, Takashi Tokino, Tomoaki Murotsu

    The Japanese Journal of Human Genetics   32 ( 3 )   237 - 245   1987.9

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    DOI: 10.1007/BF01876878

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  • Replication of mini-F plasmid in vitro promoted by purified E protein Reviewed

    Kanae Muraiso, Takashi Tokino, Tomoaki Murotsu, Kenichi Matsubara

    MGG Molecular &amp; General Genetics   206 ( 3 )   519 - 521   1987.3

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    DOI: 10.1007/BF00428895

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  • RAS野生型進行大腸癌に対する抗EGFR抗体治療におけるDroplet Digital PCRを用いた血中循環腫瘍DNAのモニタリング前向き観察研究

    高橋直樹, 中村慶史, 木藤陽介, 久保田英嗣, 朝山雅子, 粂川陽祐, 原浩樹, 松島知広, 辻国広, 片岡洋望, 津矢田明泰, 佐々木泰史, 井戸川雅史, 時野隆至, 澤田武

    大腸癌研究会プログラム・抄録集   101st   2024

  • Molecular mechanisms of suppression of Claudin-1 expression in oral cancer cell lines

    丹下正一朗, 井戸川雅史, 川島秀器, 佐々木泰史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   46th   2023

  • Identification of novel prognosticator gene in malignant pancreatic cancer

    Shoichiro Tange, Tomomi Hirano, Masashi Idogawa, Eishu Hirata, Issei Imoto, Takashi Tokino

    CANCER SCIENCE   113   2022.2

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  • RAS野生型転移性大腸癌患者における循環腫瘍DNA中のRAS、BRAF、PIK3CA変異の同定と腫瘍組織の変異との比較

    澤田 武, 久保田 英嗣, 中村 慶史, 高橋 直樹, 太田 亮介, 井戸川 雅史, 佐々木 泰史, 時野 隆至, 源 利成, 片岡 洋望

    日本癌学会総会記事   80回   [P15 - 6]   2021.9

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  • 症例特異的変異を用いた頭頸部扁平上皮癌におけるctDNAモニタリング

    古後 龍之介, 真子 知美, 岩谷 岳, 西塚 哲, 佐々木 泰史, 井戸川 雅史, 時野 隆至, 中川 尚志

    日本癌学会総会記事   80回   [J14 - 6]   2021.9

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  • 膵臓がんにおける新規予後予測遺伝子の機能解析

    丹下 正一朗, 平野 朋美, 井戸川 雅史, 平田 英周, 井本 逸勢, 時野 隆至

    日本癌学会総会記事   80回   [J15 - 6]   2021.9

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  • 長鎖非コードRNA lncAC1は大腸癌の進行を促進する

    小泉 昌代, 井戸川 雅史, 丹下 正一朗, 時野 隆至

    日本癌学会総会記事   80回   [P14 - 5]   2021.9

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  • カスタムパネルシーケンスを用いた日本人メラノーマのドライバー遺伝子の検出

    肥田 時征, 井戸川 雅史, 堀本 浩平, 加藤 潤史, 佐藤 さゆり, 藤岡 茉生, 丹下 正一朗, 時野 隆至, 宇原 久

    日本皮膚科学会雑誌   131 ( 5 )   1363 - 1363   2021.5

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  • 日本人口腔扁平上皮癌における全exome解析

    佐々木泰史, 中垣貴文, 中垣貴文, 荻和弘, 丹下正一朗, 井戸川雅史, 宮崎晃亘, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   42nd   2019

  • 食道癌肉腫の遺伝子変異解析(Exome sequence analysis of carcinomatous and sarcomatous elements of an esophageal carcinosarcoma)

    佐々木 教之, 岩谷 岳, 遠藤 史隆, 鴻巣 正史, 秋山 有史, 佐々木 泰史, 時野 隆至, 西塚 哲

    日本癌学会総会記事   77回   326 - 326   2018.9

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  • Digital PCRを用いた食道癌患者における症例特異的血漿中遊離DNAモニタリング(Patient-specific circulating tumor DNA monitoring using digital PCR in esophageal squamous cell cancer patients)

    岩谷 岳, 遠藤 史隆, 佐々木 泰史, 八重樫 瑞典, 佐藤 慧, 佐々木 教之, 秋山 有史, 佐々木 章, 増田 万里, 時野 隆至, 西塚 哲

    日本癌学会総会記事   77回   930 - 930   2018.9

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  • 新規p53標的遺伝子として同定されたp120カテニンファミリー蛋白の癌における役割

    鈴木菜摘, 井戸川雅史, 大箸智子, 佐々木泰史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   41st   2018

  • 胃がん発生に関与する長鎖non-coding RNAの同定

    北嶋 洋志, 丸山 玲緒, 山本 英一郎, 新沼 猛, 甲斐 正広, 時野 隆至, 仲瀬 裕志, 鈴木 拓

    生命科学系学会合同年次大会   2017年度   [2P - 0828]   2017.12

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  • 慢性B型肝炎の核酸アナログ製剤治療後発がんに関与するmicroRNAの探索

    若杉 英樹, 鈴木 拓, 佐々木 基, 新沼 猛, 山本 英一郎, 甲斐 正広, 高橋 秀明, 伊東 文生, 時野 隆至, 仲瀬 裕志

    日本癌学会総会記事   76回   P - 3310   2017.9

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  • 新規大腸がん線維芽細胞関連遺伝子の同定

    沼田 有斗, 萬 顕, 山本 英一郎, 新沼 猛, 北嶋 洋志, 甲斐 正広, 青木 敬則, 若杉 英樹, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事   76回   P - 2219   2017.9

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  • 大腸がんにおける腫瘍血管内皮関連遺伝子の同定

    萬 顕, 山本 英一郎, 沼田 有斗, 新沼 猛, 北嶋 洋志, 甲斐 正広, 青木 敬則, 若杉 英樹, 時野 隆至, 中瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事   76回   P - 2224   2017.9

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  • 大腸腫瘍の表面構造が反映する腫瘍内不均一性

    山本 英一郎, 山野 泰穂, 青木 敬則, 新沼 猛, 甲斐 正広, 佐々木 泰史, 時野 隆至, 菅井 有, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   76回   P - 2228   2017.9

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  • 消化管間質腫瘍においてエピジェネティックに制御される長鎖noncoding RNAの探索

    新沼 猛, 北嶋 洋志, 山本 英一郎, 甲斐 正広, 仲瀬 裕志, 時野 隆至, 今井 浩三, 鈴木 拓

    日本癌学会総会記事   76回   P - 2257   2017.9

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  • 食道癌患者におけるCirculating tumor DNAを用いたLiquid biopsy systemの開発

    岩谷 岳, 遠藤 史隆, 佐々木 泰史, 八重樫 瑞典, 千葉 丈広, 秋山 有史, 増田 万里, 山田 哲司, 時野 隆至, 西塚 哲

    日本癌学会総会記事   76回   J - 3064   2017.9

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  • 慢性胃炎および胃癌に関する長鎖noncoding RNAの同定と機能解析

    北嶋 洋志, 丸山 玲緒, 山本 英一郎, 新沼 猛, 青木 敬則, 甲斐 正広, 時野 隆至, 今井 浩三, 仲瀬 裕志, 鈴木 拓

    日本癌学会総会記事   76回   P - 3231   2017.9

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  • DOWNREGULATION OF MIR-200B IS ASSOCIATED WITH CISPLATIN-RESISTANCE IN BLADDER CANCER CELLS

    Tetsuya Shindo, Naotaka Nishiyama, Takeshi Niinuma, Hiroshi Kitajima, Masahiro Kai, Takashi Tokino, Nobuo Shinkai, Hiromu Suzuki, Naoya Masumori

    JOURNAL OF UROLOGY   197 ( 4 )   E568 - E569   2017.4

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  • 多発性骨髄腫に対するDot1L阻害剤の抗腫瘍効果解明を目指したエピゲノム解析

    石黒一也, 北嶋洋志, 新沼猛, 丸山玲緒, 甲斐正広, 池田博, 石田禎夫, 佐々木泰史, 時野隆至, 仲瀬裕志, 鈴木拓

    エピゲノムはどこまで操れるようになったか 第11回日本エピジェネティクス研究会年会プログラム集 理研シンポジウム 平成29年   2017

  • 慢性胃炎および胃癌に関連する長鎖noncoding RNAの同定

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    日本癌学会総会記事   75回   P - 1225   2016.10

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  • 大腸癌における腫瘍血管内皮関連遺伝子の同定

    萬 顕, 山本 英一郎, 津矢田 明泰, 沼田 有斗, 甲斐 正広, 新沼 猛, 北嶋 洋志, 青木 敬則, 若杉 秀樹, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

    日本癌学会総会記事   75回   P - 1282   2016.10

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  • Targeted semiconductor sequencing of 409 cancer-related genes for somatic mutations and copy number variations in multiple myeloma

    Hiroshi Ikeda, Yasushi Sasaki, Kazuya Ishiguro, Tadao Ishida, Yuka Aoki, Takashi Tokino

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-3188

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  • LIMA1は新規p53標的遺伝子であり癌細胞浸潤を抑制する

    大箸智子, 井戸川雅史, 佐々木泰史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   39th   2016

  • 長鎖非コードRNAのフロンティア 生化学、分子生物学、医学からのアプローチ 慢性胃炎から胃癌への発癌過程に関与しうる長鎖非コードRNAの網羅的探索と病的意義の解明

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    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2W15 - p   2015.12

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  • 大腸癌においてDNAメチル化により抑制されている長鎖非コードRNAの網羅的同定

    石黒 一也, 粂川 昂平, 丸山 玲緒, 山本 英一郎, 津矢田 明泰, 進藤 哲哉, 新沼 猛, 甲斐 正広, 山野 泰穂, 菅井 有, 時野 隆至, 篠村 恭久, 鈴木 拓

    日本癌学会総会記事   74回   E - 1165   2015.10

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  • 慢性胃炎から胃癌への発癌過程に関与する長鎖非コードRNAの同定と機能解析の試み

    佐藤 由梨, 丸山 玲緒, 北嶋 洋志, 山本 英一郎, 新沼 猛, 粂川 昂平, 甲斐 正広, 能正 勝彦, 井戸川 雅史, 佐々木 泰史, 篠村 恭久, 時野 隆至, 鈴木 拓

    日本癌学会総会記事   74回   E - 1172   2015.10

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  • The effect of forced expression of k-ras mutation on gastrointestinal cancer cells and IGF-IR targeting therapy

    Yasushi Adachi, Yasutaka Matsunaga, Yasushi Sasaki, Katsuhiko Nosho, Hiroyuki Yamamoto, Yoshiaki Arimura, Takao Endo, Yasuo Kato, Takashi Tokino, David P. Carbone, Yasuhisa Shinomura

    CANCER RESEARCH   75   2015.8

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  • Molecular diagnostics of drug resistant multiple myeloma cases using targeted next generation sequencing

    Hiroshi Ikeda, Yasushi Sasaki, Tetsuyuki Igarashi, Yuka Aoki, Toshiaki Hayashi, Tadao Ishida, Takashi Tokino, Yasuhisa Sinomura

    CANCER RESEARCH   75   2015.8

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  • Interaction between monocytes and bone marrow microenvironment in pathogenesis of multiple myeloma

    Hiroshi Ikeda, Yuka Aoki, Toshiaki Hyayashi, Yumiko Maruyama, Tadao Ishida, Takashi Tokino, Yasuhisa Shinomura, Yasushi Sasaki

    CANCER RESEARCH   74 ( 19 )   2014.10

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    DOI: 10.1158/1538-7445.AM2014-139

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  • 慢性胃炎から胃癌への発癌過程に関与する長鎖ncRNAの網羅的探索と機能解析の試み(Systematic identification of long non-coding RNAs involved in gastritis and gastric tumorigenesis)

    丸山 玲緒, 北嶋 洋志, 山本 英一郎, 新沼 猛, 萬 顕, 粂川 昂平, 津矢田 明泰, 鈴木 亮, 甲斐 正広, 能正 勝彦, 時野 隆至, 篠村 恭久, 鈴木 拓

    日本癌学会総会記事   73回   E - 2096   2014.9

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  • 大腸癌においてDNAメチル化により抑制されているlincRNAの網羅的同定(Genome-wide identification of lincRNAs epigenetically silenced by DNA methylation in colon cancer)

    五十嵐 哲祥, 粂川 昂平, 丸山 玲緒, 山本 英一郎, 津矢田 明泰, 鈴木 亮, 新沼 猛, 甲斐 正広, 山野 泰穂, 菅井 有, 時野 隆至, 篠村 恭久, 鈴木 拓

    日本癌学会総会記事   73回   P - 1126   2014.9

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  • Close Up実験法 Series252 Clinical Genomicsを目指した半導体NGSによるがんゲノム解析

    丸喜明, 佐々木泰史, 中村友紀, 横井左奈, 大平美紀, 時野隆至, 永瀬浩喜

    実験医学   32 ( 11 )   1781 - 1788   2014.7

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  • p53の直接転写標的AKR1B10は大腸癌で発現抑制されp53誘導アポトーシスを制御する

    大箸 智子, 井戸川 雅史, 佐々木 泰史, 時野 隆至

    Personalized Medicine Universe. Japanese Edition   3 ( Suppl.1 )   50 - 50   2014.6

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  • 次世代半導体シーケンサーを用いた口腔扁平上皮癌におけるがん関連遺伝子の変異解析

    中垣 貴文, 佐々木 泰史, 井戸川 雅史, 竹田 康佑, 田村 みゆき, 大箸 智子, 荻 和弘, 平塚 博義, 時野 隆至

    Personalized Medicine Universe. Japanese Edition   3 ( Suppl.1 )   51 - 51   2014.6

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  • 消化器癌の発生や進展に関与する長鎖ncRNAの量的・質的異常の探索と臨床応用への試み

    丸山 玲緒, 山本 英一郎, 粂川 昂平, 津矢田 明泰, 鈴木 亮, 芦田 仁己, 甲斐 正広, 佐藤 亜紀子, 新沼 猛, 山野 泰穂, 菅井 有, 篠村 恭久, 時野 隆至, 鈴木 拓

    日本分子腫瘍マーカー研究会誌   29   71 - 72   2014.4

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    Other Link:: http://search.jamas.or.jp/link/ui/2015388708

    DOI: 10.11241/jsmtmr.29.71

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  • p53標的遺伝子AKR1B10はp53誘導性アポトーシスを増強することで大腸発癌を抑制する

    大箸智子, 井戸川雅史, 佐々木泰史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   37th   2014

  • Ion PGMシーケンサーを用いたがん関連遺伝子の網羅的変異解析

    小橋建太, 佐々木泰史, 中垣貴文, 竹田康佑, 田村みゆき, 大箸智子, 井戸川雅史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   37th   2014

  • ゲノム網羅的p53結合領域解析とマイクロアレイを組み合わせたp53標的長鎖非コードRNA(lincRNA)の同定と解析

    井戸川雅史, 大箸智子, 佐々木泰史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   37th   2014

  • 消化器癌において重要な役割を果たす長鎖ncRNAの網羅的同定の試み(Global identification of novel long non-coding RNAs potentially involved in gastrointestinal cancer)

    丸山 玲緒, 山本 英一郎, 粂川 昂平, 津矢田 明泰, 鈴木 亮, 芦田 仁己, 佐藤 亜紀子, 甲斐 正広, 山野 泰穂, 菅井 有, 篠村 恭久, 時野 隆至, 鈴木 拓

    日本癌学会総会記事   72回   124 - 124   2013.10

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  • Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma (vol 4, 101, 2012)

    Yuka Aoki, Masanori Nojima, Hiromu Suzuki, Hiroshi Yasui, Reo Maruyama, Eiichiro Yamamoto, Masami Ashida, Mitsuhiro Itagaki, Hideki Asaoku, Hiroshi Ikeda, Toshiaki Hayashi, Kohzoh Imai, Mitsuru Mori, Takashi Tokino, Tadao Ishida, Minoru Toyota, Yasuhisa Shinomura

    GENOME MEDICINE   5 ( 10 )   2013.10

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    DOI: 10.1186/gm491

    ORCID Put Code : 73058177

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  • 多発性骨髄腫におけるLINE-1異常低メチル化と臨床遺伝子学的特徴の相関(LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma)

    野島 正寛, 青木 由佳, 安井 寛, 丸山 玲緒, 山本 英一郎, 麻奥 英毅, 時野 隆至, 長村 文孝, 石田 禎夫, 今井 浩三, 篠村 恭久, 鈴木 拓

    日本癌学会総会記事   72回   305 - 305   2013.10

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  • 消化器癌の発生や進展に関与する長鎖ncRNAの量的・質的異常の探索と臨床応用への試み

    丸山 玲緒, 山本 英一郎, 粂川 昂平, 津矢田 明泰, 鈴木 亮, 芦田 仁己, 甲斐 正広, 佐藤 亜紀子, 新沼 猛, 山野 泰穂, 菅井 有, 篠村 恭久, 時野 隆至, 鈴木 拓

    日本分子腫瘍マーカー研究会プログラム・講演抄録   33回   100 - 101   2013.9

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  • 消化管内視鏡の生検検体におけるヒストン修飾の網羅的な解析と新規分子マーカー同定の試み

    丸山 玲緒, 山本 英一郎, 粂川 昂平, 井戸川 雅史, 野島 正寛, 甲斐 正広, 佐藤 亜紀子, 佐々木 泰史, 山野 泰穂, 菅井 有, 篠村 恭久, 時野 隆至, 鈴木 拓

    日本分子腫瘍マーカー研究会誌   28   16 - 17   2013.3

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  • ゲノム網羅的p53結合領域解析によるp53ファミリーの転写標的となる大型遺伝子介在性非コードRNA(lincRNA)の同定と機能解析

    井戸川雅史, 大箸智子, 佐々木泰史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   36th   2013

  • p53によるXPO1の抑制機構とその意義

    佐々木泰史, 佐々木泰史, 小橋健太, 鈴木信太郎, 田村みゆき, 竹田康祐, 井戸川雅史, 井戸川雅史, 篠村恭久, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   36th   2013

  • 腫瘍マーカーとしてのエピジェネティクス研究の展望 消化管内視鏡の生検検体におけるヒストン修飾の網羅的な解析と新規分子マーカー同定の試み

    丸山 玲緒, 山本 英一郎, 粂川 昂平, 井戸川 雅史, 野島 正寛, 甲斐 正広, 佐藤 亜紀子, 佐々木 泰史, 山野 泰穂, 菅井 有, 篠村 恭久, 時野 隆至, 鈴木 拓

    日本分子腫瘍マーカー研究会プログラム・講演抄録   32回   33 - 34   2012.9

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  • microRNA-196aとHOTAIRの過剰発現は消化管間質腫瘍の悪性度と相関する(Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors)

    鈴木 拓, 新沼 猛, 野島 正寛, 丸山 玲緒, 山本 英一郎, 甲斐 正広, 能正 勝彦, 山本 博幸, 時野 隆至, 今井 浩三, 篠村 恭久

    日本癌学会総会記事   71回   419 - 419   2012.8

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  • 大腸癌においてエピジェネティックに抑制されている長鎖ncRNAの網羅的同定の試み(Global identification of novel long non-coding RNAs silenced by epigenetic mechanism in colon cancer)

    丸山 玲緒, 粂川 昂平, 山本 英一郎, 井戸川 雅史, 野島 正寛, 甲斐 正広, 能正 勝彦, 佐々木 泰史, 山野 泰穂, 菅井 有, 篠村 恭久, 時野 隆至, 鈴木 拓

    日本癌学会総会記事   71回   381 - 381   2012.8

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  • 大腸腫瘍におけるニューロテンシン受容体1型遺伝子のメチル化と臨床的意義(Epigenetic silencing of neurotensin receptor type 1 (NTSR1) in colorectal tumor and its clinical implications)

    山本 英一郎, 鈴木 拓, 神前 正幸, 丸山 玲緒, 山野 泰穂, 澤田 武, 能正 勝彦, 山本 博幸, 甲斐 正広, 時野 隆至, 菅井 有, 今井 浩三, 篠村 恭久

    日本癌学会総会記事   71回   302 - 303   2012.8

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  • p53ファミリーを用いた人工ハイブリッド遺伝子の作成とアポトーシス誘導活性

    佐々木泰史, 佐々木泰史, 大島雄一郎, 小山良太, 田村みゆき, 井戸川雅史, 井戸川雅史, 篠村恭久, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   35th   2012

  • ゲノム網羅的shRNAスクリーニングによるp53変異癌細胞でのアポトーシス誘導

    大箸智子, 井戸川雅史, 杉坂淳, 田村みゆき, 佐々木泰史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   35th   2012

  • がんの浸潤・遊走能に関わるp53ファミリーの新規標的FOXF1の同定と機能解析

    田村みゆき, 佐々木泰史, 大箸智子, 井戸川雅史, 時野隆至

    日本分子生物学会年会プログラム・要旨集(Web)   35th   2012

  • Overexpression of Aurora A by loss of CHFR gene expression increases the growth and survival of HTLV-1-infected T cells through enhanced NF-kappaB activity (Retraction of vol 124, pg 2607, 2009)

    M. Tomita, M. Toyota, C. Ishikawa, T. Nakazato, T. Okudaira, T. Matsuda, J. N. Uchihara, N. Taira, K. Ohshiro, M. Senba, Y. Tanaka, K. Ohshima, H. Saya, T. Tokino, N. Mori

    INTERNATIONAL JOURNAL OF CANCER   129 ( 11 )   2763 - 2763   2011.12

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  • がんのエピジェネティクス 基礎研究と臨床応用の進歩 エピゲノム解析による造血器腫瘍の新たな分子標的の同定(Exploration of novel molecular targets for the therapy against hematological malignancies through epigenome analysis)

    豊田 実, 野島 正寛, 鈴木 拓, 丸山 玲緒, 山本 英一郎, 甲斐 正広, 時野 隆至, 篠村 恭久, 今井 浩三

    日本癌学会総会記事   70回   254 - 255   2011.9

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  • 大腸洗浄液を用いた新しい大腸癌の診断方法(Epigenetic alteration of DNA in mucosal wash fluid predicts invasiveness of colorectal tumors)

    神前 正幸, 山本 英一郎, 鈴木 拓, 山野 泰穂, 甲斐 正広, 菅井 有, 時野 隆至, 今井 浩三, 篠村 恭久, 豊田 実

    日本癌学会総会記事   70回   135 - 135   2011.9

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  • 異なる前癌病変に由来したCIMP大腸癌の亜型(Different subgroups of colorectal cancer with CIMP arise from genetically and epigenetically distinct early lesions)

    山本 英一郎, 鈴木 拓, 山野 泰穂, 神前 正幸, 澤田 武, 丸山 玲緒, 甲斐 正広, 菅井 有, 時野 隆至, 今井 浩三, 篠村 恭久, 豊田 実

    日本癌学会総会記事   70回   46 - 46   2011.9

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  • 大腸癌のエピゲノム解析からアプローチする癌関連miRNAの探索(Genome-wide profiling of chromatin signatures reveals epigenetic regulation of microRNA genes in colorectal cancer)

    鈴木 拓, 山本 英一郎, 野島 正寛, 丸山 玲緒, 高丸 博之, 甲斐 正広, 時野 隆至, 今井 浩三, 豊田 実, 篠村 恭久

    日本癌学会総会記事   70回   88 - 89   2011.9

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  • 乳癌においてDNAメチル化により不活化される遺伝子のゲノム網羅的解析

    西川 紀子, 豊田 実, 鈴木 拓, 藤兼 智子, 九冨 五郎, 亀嶋 秀和, 鈴木 やすよ, 大村 東生, 時野 隆至, 平田 公一

    日本外科学会雑誌   112 ( 臨増1-2 )   393 - 393   2011.5

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  • A comprehensive analysis to screen for epigenetically silenced miRNA genes in colorectal cancer

    Hiromu Suzuki, Eiichiro Yamamoto, Masanori Nojima, Takashi Shimizu, Takashi Tokino, Yasuhisa Shinomura, Minoru Toyota

    CANCER RESEARCH   71   2011.4

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    DOI: 10.1158/1538-7445.AM2011-90

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  • Molecular mechanisms of anti-tumor activity of RAS association domain protein, RASSF2

    61 ( 6 )   590 - 593   2010.11

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  • 染色体不安定性に関連した大腸腺腫内の異常メチル化(Epigenetic field defect in colorectal adenoma associated with chromosomal instability)

    澤田 武, 山本 英一郎, 鈴木 拓, 山野 泰穂, 神前 正幸, 甲斐 正広, 菅井 有, 時野 隆至, 今井 浩三, 篠村 恭久, 伊東 文生, 豊田 実

    日本癌学会総会記事   69回   44 - 44   2010.8

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  • 拡大内視鏡によるCIMP陽性大腸癌の前がん病変の診断(Identification of precursor lesions of colorectal cancers with CIMP by molecular-magnifying colonoscopy)

    神前 正幸, 山本 英一郎, 鈴木 拓, 山野 泰穂, 甲斐 正広, 菅井 有, 時野 隆至, 今井 浩三, 篠村 恭久, 豊田 実

    日本癌学会総会記事   69回   340 - 340   2010.8

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  • GISTにおけるLINE-1低メチル化と悪性度との相関(A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors)

    新沼 猛, 鈴木 拓, 野島 正寛, 五十嵐 伸一, 山本 英一郎, 高丸 博之, 田沼 徳真, 山本 博幸, 時野 隆至, 今井 浩三, 豊田 実, 篠村 恭久

    日本癌学会総会記事   69回   341 - 341   2010.8

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  • CIMP大腸癌の起源(The origin of colorectal cancer with CpG island methylator phenotype)

    山本 英一郎, 鈴木 拓, 山野 泰穂, 神前 正幸, 甲斐 正広, 菅井 有, 時野 隆至, 今井 浩三, 篠村 恭久, 豊田 実

    日本癌学会総会記事   69回   43 - 43   2010.8

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  • NEGATIVE REGULATION OF HEPATOMA-DERIVED GROWTH FACTOR BY P53

    Y. Sasaki, H. Negishi, R. Koyama, M. Kusano, H. Suzuki, M. Fujita, M. Toyota, T. Tokino

    TUMOR BIOLOGY   31   S74 - S75   2010.8

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  • 乳癌においてDNAメチル化により不活化される遺伝子のゲノム網羅的解析

    西川 紀子, 豊田 実, 鈴木 拓, 里見 蕗乃, 藤兼 智子, 九冨 五郎, 亀島 秀和, 鈴木 やすよ, 大村 東生, 時野 隆至, 平田 公一

    日本乳癌学会総会プログラム抄録集   18回   354 - 354   2010.5

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  • Epigenetic silencing of microRNA-34b/c in human gastric cancer

    Hiromu Suzuki, Eiichiro Yamamoto, Masanori Nojima, Takashi Tokino, Kohzoh Lnnai, Minoru Toyota, Yasuhisa Shinomura

    CANCER RESEARCH   70   2010.4

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    DOI: 10.1158/1538-7445.AM10-4945

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  • CHFR, a potential tumor suppressor, downregulates interleukin-8 via inhibition of NF-kappa B

    Takashi Tokino, Lisa Kashima, Minoru Toyota, Yasushi Sasaki

    CANCER RESEARCH   70   2010.4

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    DOI: 10.1158/1538-7445.AM10-3070

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  • DNA障害におけるPARP-1とKu70によるWnt/β-cateninシグナルの拮抗的制御

    井戸川 雅史, 山田 哲司, 篠村 恭久, 広橋 説雄, 今井 浩三, 時野 隆至

    日本分子腫瘍マーカー研究会誌   25   44 - 46   2010.2

  • DNA障害におけるPARP-1とKu70によるWnt/β-cateninシグナルの拮抗的制御

    井戸川 雅史, 山田 哲司, 篠村 恭久, 広橋 説雄, 今井 浩三, 時野 隆至

    日本分子腫瘍マーカー研究会プログラム・講演抄録   29回   61 - 63   2009.9

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  • 胃癌、大腸癌におけるIRFファミリーのエピジェネティックな不活化(Epigenetic inactivation of interferon regulatory factors (IRFs) in colorectal and gastric cancer)

    山下 真幸, 豊田 実, 鈴木 拓, 野島 正寛, 渡邊 嘉行, 明石 浩史, 山本 英一郎, 佐々木 泰史, 菅井 有, 篠村 恭久, 今井 浩三, 時野 隆至, 伊東 文生

    日本癌学会総会記事   68回   174 - 174   2009.8

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  • 大腸癌の多段階腫瘍形成における異常DNAメチル化の役割(The role of aberrant DNA methylation in multistep carcinogenesis of colorectal cancer)

    山本 英一郎, 山野 泰穂, 鈴木 拓, 野島 正寛, 丸山 怜緒, 時野 隆至, 今井 浩三, 篠村 恭久, 豊田 実

    日本癌学会総会記事   68回   94 - 94   2009.8

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  • IGFBP7はCpGアイランドメチル化因子表現型をもつ大腸癌において特異的にサイレンシングされるp53応答性遺伝子である(IGFBP7 is a p53 responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype)

    丸山 玲緒, 鈴木 拓, 野島 正寛, 山本 英一郎, 五十嵐 伸一, 高丸 博之, 甲斐 正広, 山本 博幸, 伊東 文生, 時野 隆至, 今井 浩三, 豊田 実, 篠村 恭久

    日本癌学会総会記事   68回   172 - 173   2009.8

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  • 脱メチル化による遺伝子上方制御の全ゲノムスクリーニングによる乳癌の後成的サイレンシング標的の同定(Genomic Screening for Genes Upregulated by Demethylation Identified Targets of Epigenetic Silencing in Breast Cancer)

    西川 紀子, 豊田 実, 鈴木 拓, 藤兼 智子, 野島 正寛, 豊田 睦美, 西舘 敏彦, 佐々木 泰, 平田 公一, 時野 隆至

    日本癌学会総会記事   68回   178 - 179   2009.8

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  • Cancer epigenomics: Implications of DNA methylation in personalized cancer therapy

    Minoru Toyota, Hiromu Suzuki, Toshiharu Yamashita, Koichi Hirata, Kohzoh Imai, Takashi Tokino, Yasuhisa Shinomura

    CANCER SCIENCE   100 ( 5 )   787 - 791   2009.5

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    DOI: 10.1111/j.1349-7006.2009.01095.x

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  • 多発性骨髄腫におけるDNA異常メチル化の網羅的解析と,新規メチル化標的遺伝子RASD1

    安井寛, 豊田実, 多羅澤功, 丸山玲緒, 野島正寛, 野島正寛, 池田博, 鈴木拓, 林敏昭, 酒井基, 石田禎夫, 麻奥英毅, 時野隆至, 今井浩三, 篠村恭久

    臨床血液   49 ( 9 )   879   2008.9

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  • 皺襞肥大型胃炎におけるゲノムワイドな低メチル化とCpGアイランド高メチル化の関連(Genome-wide hypomethylation and regional hypermethylation in H. pylori-related enlarged fold gastritis)

    山本 英一郎, 豊田 実, 鈴木 拓, 野島 正寛, 丸山 玲緒, 五十嵐 伸一, 時野 隆至, 今井 浩三, 篠村 恭久

    日本癌学会総会記事   67回   70 - 70   2008.9

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  • 乳癌においてDNAメチル化により不活化される遺伝子のゲノム網羅的解析(Genome-wide Analysis for the Genes Silenced by DNA Methylation in Breast Cancer)

    藤兼 智子, 豊田 実, 鈴木 拓, 西川 紀子, 大村 東生, 西舘 敏彦, 佐々木 泰史, 平田 公一, 時野 隆至

    日本癌学会総会記事   67回   171 - 171   2008.9

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  • miRNA abriormalities in gastrointestinal cancers

    井戸川 雅史, 時野 隆至, 篠村 恭久

    最新医学   63 ( 0 )   1849 - 1859   2008.9

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  • Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer (vol 98, pg 1147, 2008)

    H. Suzuki, M. Toyota, H. Carraway, E. Gabrielson, T. Ohmura, T. Fujikane, N. Nishikawa, Y. Sogabe, M. Nojima, T. Sonoda, M. Mori, K. Hirata, K. Imai, Y. Shinomura, S. B. Baylin, T. Tokino

    BRITISH JOURNAL OF CANCER   99 ( 2 )   384 - 384   2008.7

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  • DNA異常メチル化により引き起こされる消化管の癌性糖鎖不全現象

    河村 由紀, 豊田 実, 川島 麗, 萩原 輝記, 鈴木 拓, 篠村 恭久, 時野 隆至, 今井 浩三, 土肥 多惠子

    日本臨床分子医学会学術総会プログラム・抄録集   45回   79 - 79   2008.7

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  • 乳癌におけるヒストンメチル化酵素PRDM 14遺伝子の診断・治療への応用の可能性

    西川 紀子, 豊田 実, 本間 敏男, 藤兼 智子, 西舘 俊彦, 大村 東生, 今井 浩三, 時野 隆至, 平田 公一

    日本外科学会雑誌   109 ( 臨増2 )   202 - 202   2008.4

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  • Epigenetic Gene Silencing and microRNA in Human Colon Cancer

    Minoru Toyota, Hiromu Suzuki, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai

    TUMOR BIOLOGY   29   17 - 17   2008

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  • LINE-1 Hypomethylation is Associated with Increased CpG Island Methylation in H-pylori-related Enlarged Fold Gastritis

    Masanori Nojima, Eiichiro Yamamoto, Minoru Toyota, Hiromu Suzuki, Yutaka Kondo, Tamana Sanomura, Yoko Murayama, Mutsumi Ohe-Toyota, Reo Maruyama, Masami Ashida, Kyoko Fujii, Yasushi Sasaki, Norio Hayashi, Mitsuru Mori, Kohzoh Imai, Takashi Tokino, Yasuhisa Shinomura

    TUMOR BIOLOGY   29   84 - 84   2008

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  • Epigenetic Silencing of Interferon Regulatory Factor(IRF) Family Genes in Colorectal and Gastric Cancer

    Masaki Yamashita, Hiromu Suzuki, Masanori Nojima, Shinichi Igarashi, Yasuhisa Shinomura, Kohzoh Imai, Takashi Tokino, Fumio Itoh, Minoru Toyota

    TUMOR BIOLOGY   29   43 - 43   2008

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  • What's New in SURGERY FRONTIER 蛋白キナーゼに関連した分子標的治療薬 EGFR阻害剤

    藤兼 智子, 豊田 実, 時野 隆至, 平田 公一

    Surgery Frontier   14 ( 4 )   430 - 432   2007.12

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  • 【遺伝子・蛋白の網羅的解析から消化器疾患に迫る】 DNAメチル化のゲノムワイドな解析

    豊田 実, 今井 崇, 曽我部 陽平, 藤兼 智子, 時野 隆至, 篠村 恭久

    分子消化器病   4 ( 3 )   196 - 200   2007.9

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  • H.pylori感染胃炎のCDH1遺伝子メチル化解析による未分化型胃癌ハイリスク群の推定(CDH1 gene methylation profile in H. pylori-related gastritis identified high-risk group of diffuse-type gastric cancer)

    山本 英一郎, 豊田 実, 鈴木 拓, 丸山 玲緒, 見田 裕章, 佐々木 泰史, 時野 隆至, 今井 浩三, 篠村 恭久

    日本癌学会総会記事   66回   294 - 294   2007.8

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  • 大腸癌・胃癌におけるPRDM5のエピジェネティックな不活化(Epigenetic inactivation of PRDM5 in colorectal and gastric cancer)

    山下 真幸, 渡邊 嘉行, 豊田 実, 近藤 豊, 鈴木 拓, 今井 崇, 丸山 玲緒, 佐々木 泰史, 関戸 好孝, 篠村 恭久, 今井 浩三, 伊東 文生, 時野 隆至

    日本癌学会総会記事   66回   315 - 315   2007.8

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  • 大腸癌におけるDFNA5のエピジェネテッィクな不活性化(Epigenetic inactivation of DFNA5 in colorectal cancers)

    藤兼 智子, 豊田 実, 鈴木 拓, 丸山 玲緒, 今井 浩三, 平田 公一, 時野 隆至

    日本癌学会総会記事   66回   315 - 315   2007.8

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  • 乳癌におけるヒストンメチル化酵素PRDM14遺伝子の発現上昇および遺伝子増幅(Gene Amplification and Overexpression of PRDM14 in Breast Cancers)

    西川 紀子, 豊田 実, 鈴木 拓, 本間 敏男, 藤兼 智子, 大村 東生, 豊田 睦美, 佐々木 泰史, 園田 智子, 今井 浩三, 時野 隆至, 平田 公一

    日本癌学会総会記事   66回   477 - 477   2007.8

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  • Ku70とPARP-1によるbeta-catenin/TCF-4転写の制御(Regulation of the beta-catenin/TCF-4-mediated gene transactivation by Ku70 and poly(ADP-ribose) polymerase-1 (PARP-1))

    井戸川 雅史, 益谷 美都子, 今井 浩三, 広橋 説雄, 篠村 恭久, 時野 隆至, 山田 哲司

    日本癌学会総会記事   66回   235 - 235   2007.8

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  • Dysregulation of mitotic checkpoint proteins chfr and aurora a in HTLV-i-infected T cells

    Mariko Tomita, Chie Ishikawa, Tetsuro Nakazato, Minoru Toyota, Takashi Tokino, Naoki Mori

    AIDS RESEARCH AND HUMAN RETROVIRUSES   23 ( 4 )   588 - 589   2007.4

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  • 胃癌におけるRASSF2の異常メチル化と細胞内機能の解析

    山本 英一郎, 豊田 実, 鈴木 拓, 丸山 玲緒, 見田 裕章, 阿部 環, 佐々木 泰史, 時野 隆至, 今井 浩三, 篠村 恭久

    日本消化器病学会雑誌   104 ( 臨増総会 )   A160 - A160   2007.3

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  • 癌関連機能性RNAの網羅的解析とエピジェネティックな異常

    豊田実, 豊田実, 丸山玲緒, 丸山玲緒, 鈴木拓, 野島正寛, 鹿島理沙, 佐々木泰史, 今井浩三, 篠村恭久, 時野隆至

    生化学   2007

  • 胃癌におけるK-ras遺伝子増幅の解析

    見田裕章, 豊田実, 青木文夫, 明石浩史, 丸山玲緒, 佐々木泰史, 鈴木拓, 井戸川雅史, 鹿島理沙, SABAU Sorin, 今井浩三, 篠村恭久, 時野隆至

    生化学   2007

  • The positive transcription elongation factor B mediates myocyte enhancer factor 2-dependent transcription

    Masanori Nojima, Hiromu Suzuki, Minoru Toyota, Takashi Tokino, Mitsuru Mori, Koh Fujinaga, Kohzoh Imai, Yasuhisa Shinomura

    TUMOR BIOLOGY   28   82 - 82   2007

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  • CHFR mitotic checkpoint protein inhibits the transcriptional activity of NF-kappa B

    KASHIMA Lisa, MITA Hiroaki, TOYOTA Minoru, SASAKI Yasushi, SUZUKI Hiromu, IDOGAWA Masashi, TOKINO Takashi

    生化学   2007

  • Identification of HDGF as a transcriptional target downregulated by p53

    NEGISHI Hideaki, SASAKI Yasushi, SUZUKI Hiromu, MARUYAMA Reo, TOYOTA Minoru, SAITO Tsuyoshi, TOKINO Takashi

    日本癌学会学術総会記事   66th   2007

  • p53遺伝子治療におけるヒストン脱アセチル化酵素阻害剤FK228の併用効果

    佐々木泰史, 佐々木泰史, 時野隆至, 今井浩三, 篠村恭久

    日本癌治療学会誌   42 ( 2 )   2007

  • 胃癌における高頻度なWntシグナル活性化とSFRP遺伝子のエピジェネティックな不活化

    鈴木 拓, 豊田 実, 野島 正寛, 丸山 玲緒, 時野 隆至, 篠村 恭久, 森 満, 今井 浩三

    生物物理化学 = Journal of Electrophoresis   50 ( 3 )   128 - 128   2006.9

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  • 大腸発癌におけるPoly(ADP-ribose)Polymerase-1(PARP-1)によるTCF/β-cateninの転写制御

    井戸川 雅史, 時野 隆至, 篠村 恭久, 今井 浩三, 広橋 説雄, 山田 哲司

    日本消化器病学会雑誌   103 ( 臨増大会 )   A880 - A880   2006.9

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  • β-cateninのFUS/TLSとの結合によるスプライシング制御

    井戸川 雅史, 佐藤 智, 時野 隆至, 篠村 恭久, 今井 浩三, 広橋 説雄, 山田 哲司

    日本癌学会総会記事   65回   38 - 39   2006.9

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  • 胃癌におけるRasシグナル関連分子のジェネティック・エピジェネティックな異常の解析

    山本 英一郎, 豊田 実, 鈴木 拓, 見田 裕章, 丸山 玲緒, 阿部 環, 佐藤 裕信, 多羅澤 功, 西川 紀子, 佐々木 泰史, 時野 隆至, 今井 浩三, 篠村 恭久

    日本癌学会総会記事   65回   133 - 133   2006.9

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  • 悪性リンパ腫におけるTIMP-2遺伝子のメチル化と発現抑制

    多羅澤 功, 鈴木 拓, 豊田 実, 丸山 玲緒, 阿部 環, 佐藤 裕信, 山本 英一郎, 佐々木 泰史, 石田 禎夫, 時野 隆至, 今井 浩三, 篠村 恭久

    日本癌学会総会記事   65回   361 - 361   2006.9

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  • 悪性胸膜中皮腫においてDNAメチル化により制御されるがん抑制遺伝子の網羅的解析

    後藤 康洋, 近藤 豊, 横山 俊彦, 谷口 哲郎, 長田 啓隆, 鈴木 拓, 時野 隆至, 豊田 実, 今井 浩三, 長谷川 好規, 下方 薫, 関戸 好孝

    日本癌学会総会記事   65回   200 - 200   2006.9

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  • 胃癌におけるRasシグナル関連分子のジェネティック・エピジェネティックな異常の解析

    山本 英一郎, 豊田 実, 鈴木 拓, 見田 裕章, 丸山 玲緒, 阿部 環, 佐藤 裕信, 多羅澤 功, 西川 紀子, 佐々木 泰史, 時野 隆至, 今井 浩三, 篠村 恭久

    日本臨床分子医学会学術総会プログラム・抄録集   43回   71 - 71   2006.7

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  • PARP-1とKu70の協調によるβ-catenin/TCF-4の転写制御

    井戸川 雅史, 時野 隆至, 篠村 恭久, 今井 浩三, 広橋 説雄, 山田 哲司

    日本臨床分子医学会学術総会プログラム・抄録集   43回   61 - 61   2006.7

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  • DNAメチル化のp53経路への関与と消化器癌における分子診断

    豊田 実, 丸山 玲緒, 鈴木 拓, 佐々木 泰史, 阿部 環, 佐藤 裕信, 山本 英一郎, 伊東 文生, 時野 隆至, 今井 浩三, 篠村 恭久

    日本臨床分子医学会学術総会プログラム・抄録集   43回   65 - 65   2006.7

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  • DNAメチル化によるp53標的遺伝子のサイレンシングとがん化における意義

    豊田実, 鈴木拓, 丸山玲緒, 佐々木泰史, 渡邊嘉行, 西川紀子, 阿部環, 佐藤裕信, 見田裕章, 伊東文生, 時野隆至, 今井浩三, 篠村恭久

    日本癌学会学術総会記事   65th   2006

  • Activation of the ribosomal protein L13 gene in human gastrointestinal cancer.

    KASHIMA Lisa, SASAKI Yasushi, KOBAYASHI Toshihisa, OSHIMA Yuichiro, SUZUKI Hiromu, MITA Hiroaki, TOYOTA Minoru, IMAI Kohzoh, SHINOMURA Yasuhisa, TOKINO Takashi

    生化学   2006

  • p53ファミリー(p73,p63)の標的遺伝子flotillin-2の同定

    佐々木泰史, 佐々木泰史, 大島雄一郎, 苗代康可, 苗代康可, 見田裕章, 見田裕章, 豊田実, 豊田実, 丸山玲緒, 明石浩史, 明石浩史, 篠村恭久, 今井浩三, 中村祐輔, 時野隆至

    日本癌学会学術総会記事   65th   2006

  • Comparative analysis of human and mouse genomes identified vitamin D receptor as a direct target of p53-mediated transcriptional activation

    Maruyama Reo, M. Toyota, Y. Shinomura, T. Tokino, K. Imai

    TUMOR BIOLOGY   27   84 - 84   2006

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  • The Ras effector RASSF2 is a novel tumor suppressor gene in human colorectal cancer

    Minoru Toyota, A. Kimishige, T. Takashi, S. Yasuhisa, K. Imai

    TUMOR BIOLOGY   27   5 - 5   2006

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  • p53およびvitamin D受容体(VDR)を標的とした大腸癌治療法の開発

    丸山玲緒, 豊田実, 豊田実, 佐々木泰史, 明石浩史, 見田裕章, 鈴木拓, 鈴木拓, 時野隆至, 今井浩三, 篠村恭久

    日本消化器病学会雑誌   103   2006

  • 消化器癌におけるリボソーム蛋白質L13の活性化と抗癌剤感受性

    佐々木泰史, 小林寿久, 伊東文生, 山本博幸, 見田裕章, 豊田実, 時野隆至, 今井浩三, 篠村恭久

    日本癌治療学会誌   41 ( 2 )   2006

  • p53ファミリーを用いた骨肉腫細胞に対するアポトーシスの誘導

    大島雄一郎, 大島雄一郎, 川口哲, 加谷光規, 名越智, 和田卓郎, 山下敏彦, 佐々木泰史, 豊田実, 時野隆至

    日本整形外科学会雑誌   80 ( 6 )   2006

  • 骨肉腫に対するp53ファミリーを用いた抗腫瘍活性の基礎的研究

    大島雄一郎, 佐々木泰史, 豊田実, 見田裕章, 和田卓郎, 名越智, 川口哲, 加谷光規, 山下敏彦, 時野隆至

    日本癌学会学術総会記事   65th   2006

  • The histone deacetylase inhibitor FK228 increases the efficacy of adenovirus-mediated p53 family gene therapy in in vitro and in vivo human cancer models

    Y Sasaki, Y Oshima, H Mita, Y Naishiro, M Toyota, K Imai, T Tokino

    JOURNAL OF CLINICAL ONCOLOGY   23 ( 16 )   231S - 231S   2005.6

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  • A full genome scan for gastric cancer

    M Aoki, Y Yamamura, H Noshiro, K Sakai, J Yokota, T Kohno, T Tokino, S Ishida, S Ohyama, Ninomiya, I, K Uesaka, M Kitajima, S Shimada, S Matsuno, M Yano, M Hiratsuka, H Sugimura, F Itoh, T Minamoto, Y Maehara, S Takenoshita, T Aikou, H Katai, K Yoshimura, T Takahashi, K Akagi, M Sairenji, K Yamamoto, T Sasazuki

    JOURNAL OF MEDICAL GENETICS   42 ( 1 )   83 - 87   2005.1

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  • RASシグナル伝達におけるRASSF2遺伝子の機能解析

    高橋文彦, 豊田実, 豊田実, 秋野公臣, 秋野公臣, 鈴木拓, 鈴木拓, 見田裕章, 佐々木泰史, 篠村恭久, 今井浩三, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • p53ファミリーを用いた骨肉腫に対する遺伝子治療の基礎的研究

    大島雄一郎, 大島雄一郎, 佐々木泰史, 豊田実, 見田裕章, 和田貞郎, 和田貞郎, 名越哲, 名越哲, 川口哲, 川口哲, 山下敏彦, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • 抗がん剤応答性ペプチドフィンガープリントの網羅的検出

    苗代康可, 土佐紀子, 豊田実, 見田裕章, 佐々木泰史, 今井浩三, 小海康夫, 時野隆至

    日本病理学会会誌   94 ( 1 )   2005

  • 胃癌において異常メチル化により不活化している新規遺伝子ACMG1

    佐藤裕信, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 佐々木泰史, 上野理子, 篠村恭久, 篠村恭久, 時野隆至, 今井浩三

    日本癌学会学術総会記事   64th   2005

  • p53によるVDR(vitamin D receptor)の発現誘導

    丸山玲緒, 豊田実, 豊田実, 明石浩史, 明石浩史, 佐々木泰史, 青木文夫, 見田裕章, 鈴木拓, 鈴木拓, 篠村恭久, 今井浩三, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • がん治療モデルマウスを用いた治療応答性Chemo-responsive fingerprintsの探索

    土佐紀子, 苗代康可, 豊田実, 見田裕章, 佐々木泰史, 時野隆至, 今井浩三, 小海康夫

    日本病理学会会誌   94 ( 1 )   2005

  • 5-aza-2’-deoxycytidineによるBNIP3遺伝子の発現回復はすい癌細胞における低酸素誘導性細胞死感受性を増強する

    阿部環, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 見田裕章, 佐々木泰史, 佐々木泰史, 遠藤高夫, 篠村恭久, 時野隆至, 今井浩三

    日本癌学会学術総会記事   64th   2005

  • 胃癌においてメチル化により不活化している新規癌抑制遺伝子の同定

    上野理子, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 見田裕章, 佐々木泰史, 佐々木泰史, 篠村恭久, 時野隆至, 今井浩三

    日本癌学会学術総会記事   64th   2005

  • CpG Island Methylator Phenotype胃癌の分子生物・臨床病理学的特徴とEBウイルス関連胃癌との関係

    草野真暢, 草野真暢, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 佐々木泰史, 垣内英樹, 伊東文生, 篠村恭久, 今井浩三, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • 分裂期チェックポイント分子CHFRの機能解析

    鹿島理沙, 見田裕章, 豊田実, 豊田実, 豊田実, 佐々木泰史, 井戸川雅史, 井戸川雅史, 鈴木拓, 秋野公臣, 秋野公臣, 時野隆至

    日本分子生物学会年会講演要旨集   28th   2005

  • 胃癌におけるメチル化標的新規癌関連遺伝子の検討

    渡辺嘉行, 渡辺嘉行, 豊田実, 豊田実, 秋野公臣, 秋野公臣, 鈴木拓, 鈴木拓, 井戸川雅史, 井戸川雅史, 鹿島里沙, 見田裕章, 佐々木泰史, 伊東文生, 時野隆至

    日本分子生物学会年会講演要旨集   28th   2005

  • p53ファミリーの抗腫よう活性と癌治療への応用:HDAC阻害剤FK228の併用効果も含めて

    石田勢津子, 石田勢津子, 佐々木泰史, 佐々木泰史, 大島雄一郎, 見田裕章, 見田裕章, 豊田実, 豊田実, 今井浩三, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • 塩基配列情報を基盤とした定量的ゲノム解析法の開発と癌研究への応用

    見田裕章, 豊田実, 豊田実, 丸山玲緒, 青木文夫, 明石浩史, 佐々木泰史, 鹿島理沙, 秋野公臣, 鈴木拓, 苗代康司, 井戸川雅史, 大西浩文, 大西浩文, 辰巳治之, 今井浩三, 篠村恭久, 時野隆至

    日本分子生物学会年会講演要旨集   28th   2005

  • 分裂期チェックポイントCHFRの機能解析

    鹿島理沙, 見田裕章, 豊田実, 豊田実, 豊田実, 佐々木泰史, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • Detection of Chemo-responsive Fingerprints in Serum Level using Model System

    土佐紀子, 土佐紀子, 苗代康可, 苗代康可, 豊田実, 豊田実, 見田裕章, 見田裕章, 佐々木泰史, 佐々木泰史, 時野隆至, 今井浩三, 小海康夫

    日本プロテオーム学会大会プログラム・抄録集   2005 (Web)   2005

  • p53ファミリーp73,p63/p51の標的遺伝子の検索

    佐々木泰史, 佐々木泰史, 苗代康可, 苗代康可, 見田裕章, 見田裕章, 豊田実, 豊田実, 石田勢津子, 大島雄一郎, 丸山玲緒, 明石浩史, 明石浩史, 篠村恭久, 中村祐輔, 今井浩三, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • p53ファミリー(p53,p73,p63)の抗腫よう活性

    佐々木泰史, 大島雄一郎, 見田裕章, 山下利春, 篠村恭久, 今井浩三, 時野隆至

    日本癌治療学会誌   40 ( 2 )   2005

  • p53によるビタミンD受容体の発現誘導と抗腫よう効果の増強作用

    丸山玲緒, 豊田実, 豊田実, 佐々木泰史, 青木文夫, 明石浩史, 明石浩史, 見田裕章, 鈴木拓, 鈴木拓, 今井浩三, 篠村恭久, 時野隆至

    日本分子生物学会年会講演要旨集   28th   2005

  • がん治療モデルマウスをもちいた治療応答性Chemo-responsive fingerprintsの探索

    苗代康可, 土佐紀子, 土佐紀子, 豊田実, 見田裕章, 佐々木泰史, 今井浩三, 時野隆至, 小海康夫

    日本癌学会学術総会記事   64th   2005

  • 口腔へん平上皮癌における分泌型Frizzled関連蛋白遺伝子のエピジェネティックな不活化

    曽我部陽平, 曽我部陽平, 鈴木拓, 鈴木拓, 鈴木拓, 豊田実, 豊田実, 豊田実, 秋野公臣, 秋野公臣, 佐々木泰史, 見田裕章, 草野真暢, 草野真暢, 今井崇, 時野隆至, 平塚博義

    日本癌学会学術総会記事   64th   2005

  • 消化器癌におけるribosomal protein L13遺伝子の活性化

    佐々木泰史, 佐々木泰史, 小林寿久, 山本博幸, 伊東文生, 豊田実, 豊田実, 見田裕章, 見田裕章, 時野隆至, 今井浩三, 篠村恭久

    日本分子生物学会年会講演要旨集   28th   2005

  • アクチン結合タンパクT-fimbrinとDNA損傷に対する応答性:T-fimbrinの発現抑制は肝癌細胞株のDNA損傷に対する感受性を高める。

    池田博, 佐々木泰史, 佐々木泰史, 見田裕章, 見田裕章, 豊田実, 豊田実, 篠村恭久, 時野隆至, 今井浩三

    日本癌学会学術総会記事   64th   2005

  • ゲノム比較とニューラルネットによるp53結合配列解析システムの開発

    明石浩史, 丸山玲緒, 丸山玲緒, 青木文夫, 豊田実, 豊田実, 佐々木泰史, 佐々木泰史, 見田裕章, 見田裕章, 大西浩文, 戸倉一, 苗代康司, 苗代康司, 辰巳浩之, 今井浩三, 今井浩三, 時野隆至

    日本癌学会学術総会記事   64th   2005

  • 統合的sequence motif解析システムの開発とその応用

    明石 浩史, 丸山 玲緒, 青木 文夫, 豊田 実, 佐々木 泰史, 戸倉 一, 西城 一翼, 山口 徳蔵, 見田 裕章, 苗代 康可, 辰巳 治之, 今井 浩三, 時野 隆至

    医療情報学連合大会論文集   24回   842 - 843   2004.11

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  • Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-gamma in haematopoietic tumour cells (vol 90, pg 844, 2004)

    Y Morimoto, M Toyota, H Ikeda, T Tokino, K Imai

    BRITISH JOURNAL OF CANCER   91 ( 11 )   1978 - 1978   2004.11

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  • Delta Np63 isotypes differentially regulate keratinocyte proliferation and differentiation

    WC Weinberg, T Yamashita, T Tokino, M Young, R Ponnamperuma, K King

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   122 ( 3 )   A23 - A23   2004.3

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  • p53結合配列解析のための統合的解析システムの開発

    明石浩史, 丸山玲緒, 青木文夫, 豊田実, 佐々木泰史, 見田裕章, 苗代康可, 辰巳治之, 時野隆至

    日本癌学会総会記事   63rd   2004

  • ヒトとマウスのゲノム比較解析による新規p53標的遺伝子同定の試み

    丸山玲緒, 豊田実, 明石浩史, 青木文夫, 佐々木泰史, 見田裕章, 垣内英樹, 辰巳治之, 時野隆至

    日本癌学会総会記事   63rd   2004

  • p53ファミリー遺伝子,p63,p73によるPigment Epithelium Derived Factorの発現誘導

    苗代康可, 佐々木泰史, 今井浩三, 中村祐輔, 時野隆至

    日本分子生物学会年会プログラム・講演要旨集   27th   2004

  • 造血器腫ようにおけるアポトーシス関連遺伝子のエピジェネティックな異常の解析

    高橋文彦, 豊田実, 村井政史, 鈴木拓, 見田裕章, 佐々木泰史, 石田禎夫, 時野隆至, 今井浩三

    日本癌学会総会記事   63rd   2004

  • ヒト胃癌におけるナトリウムトランスポーターファミリー遺伝子SLC5A8の異常メチル化と発現抑制

    上野理子, 豊田実, 秋野公臣, 見田裕章, 村井政史, 佐々木泰史, 鈴木拓, 遠藤高夫, 時野隆至

    日本癌学会総会記事   63rd   2004

  • 消化器癌におけるMHC class II発現消失とClass II transactivatorのエピジェネティックな異常

    佐藤亜由美, 豊田実, 池田英之, 鈴木拓, 見田裕章, 秋野公臣, 佐々木泰史, 時野隆至, 今井浩三

    日本癌学会総会記事   63rd   2004

  • 消化管癌におけるSEZ6L遺伝子のエピジェネティックな不活化

    野島正寛, 鈴木拓, 豊田実, 秋野公臣, 見田裕章, 佐々木泰史, 時野隆至, 今井浩三

    日本癌学会総会記事   63rd   2004

  • 新規p53標的遺伝子としてのSCN3B遺伝子の同定

    森本一郎, 足立賢哉, 豊田実, 佐々木泰史, 丸山玲緒, 日野田裕治, 工藤隆一, 今井浩三, 時野隆至

    日本癌学会総会記事   63rd   2004

  • p73転写制御因子によるIL-4シグナルの活性化

    佐々木泰史, 見田裕章, 豊田実, 石田勢津子, 山下利春, 田中敏博, 中村祐輔, 今井浩三, 時野隆至

    日本癌学会総会記事   63rd   2004

  • ヒトとマウスのゲノム比較解析による新規p53標的遺伝子の同定

    丸山玲緒, 豊田実, 明石浩史, 青木文夫, 佐々木泰史, 見田裕章, 垣内英樹, 辰巳治之, 時野隆至

    日本分子生物学会年会プログラム・講演要旨集   27th   2004

  • インシリコ解析による新規p53標的遺伝子同定の試み

    丸山玲緒, 豊田実, 明石浩史, 青木文夫, 佐々木泰史, 見田裕章, 垣内英樹, 時野隆至, 今井浩三

    情報計算化学生物学会大会予稿集   2004   2004

  • アクチン結合蛋白T-fimbrinによるG2/M期制御と抗癌剤感受性

    佐々木泰史, 池田博, 見田裕章, 豊田実, 時野隆至, 日野田裕治, 今井浩三

    日本分子生物学会年会プログラム・講演要旨集   27th   2004

  • 大腸癌における分泌型Frizzled関連蛋白遺伝子のエピジェネティックな不活化は大腸癌におけるWntシグナル経路活性化を補完する

    鈴木拓, 豊田実, 野島正寛, 秋野公臣, 見田裕章, 佐々木泰史, 苗代康可, 時野隆至, 森満

    日本癌学会総会記事   63rd   2004

  • RASシグナル伝達におけるGenetic/Epigenetic異常の解析

    秋野公臣, 豊田実, 鈴木拓, 草野真暢, 苗代康可, 見田裕章, 佐々木泰史, 今井浩三, 時野隆至

    日本癌学会総会記事   63rd   2004

  • 抗がん剤応答性ペプチドフィンガープリントの網羅的検出

    苗代康可, 土佐紀子, 豊田実, 見田裕章, 佐々木泰史, 小海康夫, 今井浩三, 時野隆至

    日本癌学会総会記事   63rd   2004

  • Berrant methylation and gene silencing of proapoptotic genes, hrk, in gastrointestinal tumors.

    F Itoh, M Toyota, T Obata, A Satoh, Y Sasaki, H Suzuki, T Tokino, JPJ Issa, K Imai

    CLINICAL CANCER RESEARCH   9 ( 16 )   6160S - 6160S   2003.12

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  • End User指向ネットワーク対応型ゲノム解析システムの開発とその応用によるp53 family gene標的遺伝子の同定

    明石 浩史, 豊田 実, 青木 文夫, 佐々木 泰史, 大西 浩文, 見田 裕章, 戸倉 一, 苗代 康可, 丸山 玲緒, 中村 正弘, 今井 浩三, 時野 隆至, 辰巳 治之, 秋野 豊明

    医療情報学連合大会論文集   23回   439 - 440   2003.11

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  • Bioinformaticsによるゲノム・遺伝子解析と臨床への応用

    明石 浩史, 豊田 実, 時野 隆至, 辰巳 治之, 今井 浩三

    Drug delivery system   18 ( 3 )   218 - 218   2003.5

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  • 新しいユビキチンリガーゼCHFRの不活化とM期チェックポイント制御における役割

    佐藤亜由美, 豊田実, 佐々木泰史, 見田裕章, 荻和弘, 鈴木拓, 遠藤高夫, 伊東文生, 時野隆至

    日本癌学会総会記事   62nd   2003

  • 口腔へん平上皮癌におけるM期チェックポイント遺伝子の発現異常とmicrotubule inhibitor感受性

    荻和弘, 豊田実, 佐々木泰史, 見田裕章, 佐藤亜由美, 今井浩三, 時野隆至

    日本癌治療学会誌   38 ( 2 )   2003

  • ヒト胃癌におけるナトリウムトランスポーターファミリー遺伝子SLC5A8の異常メチル化と発現抑制

    田賀理子, 豊田実, 秋野公臣, 佐藤亜由美, 見田裕章, 村井政史, 佐々木泰史, 鈴木拓, 時野隆至

    日本分子生物学会年会プログラム・講演要旨集   26th   2003

  • ヒト腫ようにおけるM期チェックポイント遺伝子CHFRの発現抑制と微小管阻害剤感受性

    佐藤亜由美, 豊田実, 見田裕章, 佐々木泰史, 秋野公臣, 田賀理子, 丸山玲緒, 遠藤高夫, 時野隆至

    日本分子生物学会年会プログラム・講演要旨集   26th   2003

  • アクチン結合タンパクT-fimbrinの遺伝子発現と抗癌剤感受性との関連性

    池田博, 佐々木泰史, 小林寿久, 長谷川公子, 見田裕章, 豊田実, 時野隆至, 今井浩三

    日本消化器病学会雑誌   100   2003

  • 全ゲノム配列を対象とするsequence motif解析システムの開発と臨床応用

    明石浩史, 豊田実, 青木文夫, 佐々木泰史, 見田裕章, 辰巳治之, 時野隆至, 今井浩三

    日本癌学会総会記事   62nd   2003

  • p53ファミリーの抗腫よう活性と癌治療への応用

    佐々木泰史, 石田勢津子, 苗代康可, 今井浩三, 時野隆至

    日本癌学会総会記事   62nd   2003

  • M期チェックポイント遺伝子CHFRの機能解析

    見田裕章, 豊田実, 佐藤亜由美, 荻和弘, 佐々木泰史, 苗代康可, 秋野公臣, 今井浩三, 時野隆至

    日本分子生物学会年会プログラム・講演要旨集   26th   2003

  • DNA損傷により発現誘導されるタンパクt-fimbrinのG2/Mcheckpointへの関与と抗癌剤感受性

    池田博, 佐々木泰史, 豊田実, 見田裕章, 時野隆至, 今井浩三

    日本癌治療学会誌   38 ( 2 )   2003

  • 消化器癌におけるTCF2遺伝子のエピジェネティックな異常

    丸山玲緒, 豊田実, 荻和弘, 鈴木拓, 秋野公臣, 佐々木泰史, 見田裕章, 佐藤亜由美, 時野隆至

    日本癌学会総会記事   62nd   2003

  • p53ファミリーの抗腫よう活性と癌治療への応用

    佐々木泰史, 苗代康可, 今井浩三, 山下利春, 時野隆至

    日本癌治療学会誌   38 ( 2 )   2003

  • p53ファミリーのアポトーシス誘導活性と癌治療への応用

    佐々木泰史, 時野隆至, 今井浩三

    日本内科学会雑誌   92   2003

  • インシリコゲノム解析を利用したp53標的遺伝子の同定と応用

    丸山玲緒, 豊田実, 佐々木泰史, 明石浩史, 見田裕章, 秋野公臣, 辰巳治之, 時野隆至, 今井浩三

    日本分子生物学会年会プログラム・講演要旨集   26th   2003

  • p53ファミリーの抗腫よう活性と癌治療への応用

    佐々木泰史, 苗代康可, 今井浩三, 時野隆至

    日本消化器病学会雑誌   100   2003

  • p53ファミリー遺伝子の抗腫よう活性

    時野隆至, 佐々木泰史

    日本癌治療学会誌   38 ( 2 )   2003

  • 【p53経路とRB経路 ここまでわかった細胞癌化のメカニズム】 p53ファミリーの新しい機能

    佐々木 泰史, 時野 隆至

    細胞工学   22 ( 1 )   34 - 38   2002.12

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  • 高速並列処理技術を用いたウェブベース全ゲノム解析システムの開発とその評価

    明石 浩史, 青木 文夫, 豊田 実, 佐々木 泰史, 中村 正弘, 大西 浩文, 戸倉 一, 西城 一翼, 伊東 文生, 今井 浩三, 時野 隆至, 辰巳 治之

    医療情報学連合大会論文集   22回   252 - 253   2002.11

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  • DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers

    A Satoh, M Toyota, F Itoh, T Kikuchi, T Obata, Y Sasaki, H Suzuki, A Yawata, M Kusano, M Fujita, M Hosokawa, K Yanagihara, T Tokino, K Imai

    BRITISH JOURNAL OF CANCER   86 ( 11 )   1817 - 1823   2002.6

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  • p53ファミリー遺伝子,p63とp73の個性

    佐々木 泰史, 時野 隆至

    最新医学   57 ( 4 )   947 - 951   2002.4

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  • p53ファミリー遺伝子,p63/p51,p73によるNotchシグナルの活性化

    佐々木泰史, 石田勢津子, 森本一郎, 田中敏博, 今井浩三, 中村祐輔, 時野隆至

    日本癌学会総会記事   61st   2002

  • DNAメチル化による遺伝子不活化の分子機構

    豊田実, 菊地剛史, 佐藤亜由美, 佐々木泰史, 小畑俊郎, 秋野公臣, 鈴木拓, 時野隆至, 今井浩三

    日本癌学会総会記事   61st   2002

  • 全ゲノムを対象とする高速並列処理によるp53結合部位解析システムの開発とその臨床応用

    明石浩史, 豊田実, 青木文夫, 佐々木泰史, 西森博幸, 今井浩三, 辰巳治之, 時野隆至

    日本癌学会総会記事   61st   2002

  • 消化器癌におけるアポトーシス関連遺伝子Hrkの異常メチル化

    小畑俊郎, 豊田実, 佐々木泰史, 佐藤亜由美, 菊地剛史, 鈴木拓, 伊東文生, 時野隆至, 今井浩三

    日本癌学会総会記事   61st   2002

  • p53ファミリーを用いた消化器癌に対する遺伝子治療の基礎的研究 HDAC阻害剤FK228の併用効果も含めて

    佐々木泰史, 今井浩三, 時野隆至

    日本癌治療学会誌   37 ( 2 )   2002

  • 新しいp53標的遺伝子SCBP1の同定と機能解析

    足立賢哉, 豊田実, 佐々木泰史, 石田勢津子, 斉藤豪, 工藤隆一, 時野隆至

    日本癌学会総会記事   61st   2002

  • ネットワーク・マルチパラレル・コンピューティングによる遺伝子解析システムの開発

    青木 文夫, 明石 浩史, 豊田 実, 宮司 正道, 佐々木 泰史, 西森 博幸, 時野 隆至, 辰巳 治之

    医療情報学連合大会論文集   21回   534 - 535   2001.11

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  • 【ゲノム医療と情報システム】 情報システムのポストゲノムプロジェクトへの応用

    辰巳 治之, 青木 文夫, 明石 浩史, 宮司 正道, 豊田 実, 佐々木 泰史, 西森 博幸, 時野 隆至, 伊東 文生, 今井 浩三

    新医療   28 ( 11 )   64 - 69   2001.11

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  • Induction of apoptosis in melanoma cell lines by p53 and its related proteins

    T Yamashita, T Tokino, H Tonoki, T Moriuchi, HY Jin, F Omori, K Jimbow

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   117 ( 4 )   914 - 919   2001.10

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  • 【ネットワーク最前線】 ポストゲノム・プロジェクトのアプリケーション p53遺伝子機能解析とマルチパラレルコンピューティング

    青木 文夫, 辰巳 治之, 明石 浩史, 宮司 正道, 豊田 実, 佐々木 泰史, 西森 博幸, 時野 隆至

    医療とコンピュータ   12 ( 9 )   31 - 40   2001.9

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  • アデノウイルスベクターを用いたp53ファミリー遺伝子導入は大腸癌由来細胞株に細胞周期停止とアポトーシスを誘導する 大腸癌の遺伝子治療への応用

    佐々木 泰史, 時野 隆至

    放射線生物研究   36 ( 3 )   279 - 290   2001.9

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  • Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer

    Y Sasaki, Morimoto, I, S Ishida, T Yamashita, K Imai, T Tokino

    GENE THERAPY   8 ( 18 )   1401 - 1408   2001.9

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  • Contribution of caspase-3 differs by p53 status in apoptosis induced by X-irradiation

    D Kobayashi, T Tokino, N Watanabe

    JAPANESE JOURNAL OF CANCER RESEARCH   92 ( 4 )   475 - 481   2001.4

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  • Mutational analysis of the beta-catenin gene in gastric carcinomas

    Y Sasaki, Morimoto, I, M Kusano, M Hosokawa, F Itoh, K Yanagihara, K Imai, T Tokino

    TUMOR BIOLOGY   22 ( 2 )   123 - 130   2001.3

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  • ネットワーク・マルチパラレル・コンピューティングによるp53結合配列解析システムの開発

    明石浩史, 豊田実, 青木文夫, 佐々木泰史, 宮司正道, 西森博幸, 今井浩三, 時野隆至, 辰巳治之

    日本癌学会総会記事   60th   2001

  • アデノウイルスベクターを用いたp53ファミリー遺伝子導入は大腸癌由来細胞株に細胞周期停止とアポトーシスを誘導する一大腸癌の遺伝子治療への応用

    佐々木泰史, 時野隆至

    放射線生物研究   36 ( 3 )   2001

  • p53ノックアウトマウスを用いたp53標的遺伝子の同定

    石田勢津子, 豊田実, 佐々木泰史, 森本一郎, 伊東文生, 今井浩三, 時野隆至

    日本癌学会総会記事   60th   2001

  • p53類似遺伝子p73,p63/p51の標的遺伝子の検索

    佐々木泰史, 森本一郎, 石田勢津子, 今井浩三, 鬼原史, 田中敏博, 中村祐輔, 時野隆至

    日本癌学会総会記事   60th   2001

  • 潰よう性大腸炎におけるメチル化の異常と発癌リスク予測への応用

    豊田実, 伊東文生, 菊地剛史, 鈴木拓, 小畑俊郎, 佐藤亜由美, 佐々木泰史, 時野隆至, 今井浩三

    日本癌学会総会記事   60th   2001

  • p53標的遺伝子としてのオステオポンチン遺伝子の同定

    森本一郎, 佐々木泰史, 石田勢津子, 伊東文生, 今井浩三, 時野隆至

    日本癌学会総会記事   60th   2001

  • p53類似遺伝子(p73,p51)を用いた大腸癌に対する遺伝子治療の基礎的研究

    佐々木泰史, 坂本裕史, 時野隆至

    日本消化器病学会雑誌   98   2001

  • p53AlP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53

    K Oda, H Arakawa, T Tanaka, K Matsuda, C Tanikawa, T Mori, H Nishimori, K Tamai, T Tokino, Y Nakamura, Y Taya

    CELL   102 ( 6 )   849 - 862   2000.9

  • 子宮内膜癌におけるSRCの変異

    小林 寛治, 寒河江 悟, 杉村 政樹, 西岡 善宏, 時野 隆至, 工藤 隆一

    日本癌学会総会記事   59回   565 - 566   2000.9

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  • A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter in endometrial carcinomas

    Y Nishioka, K Kobayashi, S Sagae, S Ishioka, A Nishikawa, M Matsushima, Y Kanamori, T Minaguchi, Y Nakamura, Takashi Tokino, R Kudo

    JAPANESE JOURNAL OF CANCER RESEARCH   91 ( 6 )   612 - 615   2000.6

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  • Nora, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis

    E Oda, R Ohki, H Murasawa, J Nemoto, T Shibue, T Yamashita, T Tokino, T Taniguchi, N Tanaka

    SCIENCE   288 ( 5468 )   1053 - 1058   2000.5

  • Induction of cellular genes is mediated by the Bel1 transactivator in foamy virus-infected human cells

    A Wagner, A Doerks, M Aboud, A Alonso, T Tokino, RM Flugel, M Lochelt

    JOURNAL OF VIROLOGY   74 ( 10 )   4441 - 4447   2000.5

  • Isolation and characterization of a novel TP53-inducible gene, TP53TG5, which suppresses growth and shows cell cycle-dependent transition of expression

    S Isaka, Y Takei, T Tokino, K Koyama, Y Miyoshi, M Suzuki, E Takahashi, C Azuma, Y Murata, Y Nakamura

    GENES CHROMOSOMES & CANCER   27 ( 4 )   345 - 352   2000.4

  • Mutation of the SRC gene in endometrial carcinoma

    M Sugimura, K Kobayashi, S Sagae, Y Nishioka, S Ishioka, K Terasawa, T Tokino, R Kudo

    JAPANESE JOURNAL OF CANCER RESEARCH   91 ( 4 )   395 - 398   2000.4

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  • AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1

    S Satoh, Y Daigo, Y Furukawa, T Kato, N Miwa, T Nishiwaki, T Kawasoe, H Ishiguro, M Fujita, T Tokino, Y Sasaki, S Imaoka, M Murata, T Shimano, Y Yamaoka, Y Nakamura

    NATURE GENETICS   24 ( 3 )   245 - 250   2000.3

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  • Adenovirus-mediated transfer of p53-related genes induces apoptosis of human cancer cells

    S Ishida, T Yamashita, U Nakaya, T Tokino

    JAPANESE JOURNAL OF CANCER RESEARCH   91 ( 2 )   174 - 180   2000.2

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  • The role of p53-target genes in human cancer

    Takashi Tokino, Y Nakamura

    CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY   33 ( 1 )   1 - 6   2000.1

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    DOI: 10.1016/S1040-8428(99)00051-7

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  • p53ノックアストマウスを用いたp53標的遺伝子の同定

    森本一郎, 佐々木泰史, 石田勢津子, 中谷宇一郎, 山下利春, 伊東文生, 今井浩三, 時野隆至

    Japanese Journal of Cancer Research   91 ( Supplement (Sept) )   2000

  • 頭頚部癌におけるβ-catenin遺伝子の蛋白発現とmutation,増殖因子受容体の発現

    小田島哲世, 佐々木泰史, 山口晃, 田中信幸, 池田健, 佐藤昌明, 時野隆至

    Japanese Journal of Cancer Research   91 ( Supplement (Sept) )   2000

  • Ewing肉腫特異的なEWS-ETS融合転写因子の標的遺伝子

    吉田幸一, 佐々木泰史, 梅沢明弘, 秦順一, 鬼原史, 田中敏博, 中村祐輔, 時野隆至

    Japanese Journal of Cancer Research   91 ( Supplement (Sept) )   2000

  • Ewing肉腫/PNETに特異的EWS-ETS融合転写因子の標的遺伝子

    吉田幸一, 佐々木泰史, 梅沢明弘, 秦順一, 鬼原史, 田中敏博, 中村祐輔, 時野隆至

    DNAチップ技術研究会プログラム・抄録集   1st   2000

  • p53類似遺伝子p73,p51の抗腫よう効果についての検討

    佐々木泰史, 森本一郎, 中谷宇一郎, 石田勢津子, 今井浩三, 鬼原史, 田中敏博, 中村祐輔, 時野隆至

    Japanese Journal of Cancer Research   91 ( Supplement (Sept) )   2000

  • ヒト大腸癌由来細胞株におけるp53類似遺伝子p73,p51によるアポトーシス誘導と抗癌剤との併用効果

    石田勢津子, 佐々木泰史, 森本一郎, 中谷宇一郎, 山下利春, 今井浩三, 時野隆至

    Japanese Journal of Cancer Research   91 ( Supplement (Sept) )   2000

  • Induction of transformation and p53-dependent apoptosis by adenovirus type 5 E4orf6/7 cDNA

    S Yamano, T Tokino, M Yasuda, M Kaneuchi, M Takahashi, Y Niitsu, K Fujinaga, T Yamashita

    JOURNAL OF VIROLOGY   73 ( 12 )   10095 - 10103   1999.12

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  • Localization of membrane-associated guanylate kinase (MAGI)-1/BAI-associated protein (BAP) 1 at tight junctions of epithelial cells

    N Ide, Y Hata, H Nishioka, K Hirao, Yao, I, M Deguchi, A Mizoguchi, H Nishimori, T Tokino, Y Nakamura, Y Takai

    ONCOGENE   18 ( 54 )   7810 - 7815   1999.12

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  • Retrovirus vectors designed for efficient transduction of cytotoxic or cytostatic genes

    M Ui, M Takada, T Arai, K Matsumoto, K Yamada, T Nakahata, T Nishiwaki, Y Furukawa, Takashi Tokino, Y Nakamura, H Iba

    GENE THERAPY   6 ( 10 )   1670 - 1678   1999.10

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  • 細胞傷害性や細胞増殖抑制活性を持つ遺伝子発現用レトロウイルスベクターの設計と開発

    宇井 基泰, 新井 徹, 中畑 龍俊, 西脇 忠, 古川 洋一, 時野 隆至, 中村 祐輔, 伊庭 英夫

    日本癌学会総会記事   58回   319 - 319   1999.8

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  • Mutational analysis of STK11 gene in ovarian carcinomas

    Y Nishioka, K Kobayashi, S Sagae, M Sugimura, S Ishioka, M Nagata, K Terasawa, T Tokino, R Kudo

    JAPANESE JOURNAL OF CANCER RESEARCH   90 ( 6 )   629 - 632   1999.6

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  • Mutational analysis of beta-catenin gene in Japanese ovarian carcinomas: Frequent mutations in endometrioid carcinomas

    S Sagae, K Kobayashi, Y Nishioka, M Sugimura, S Ishioka, M Nagata, K Terasawa, T Tokino, R Kudo

    JAPANESE JOURNAL OF CANCER RESEARCH   90 ( 5 )   510 - 515   1999.5

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  • Recombinant adenovirus expressing wild-type p53 is antiangiogenic: A proposed mechanism for bystander effect

    M Nishizaki, T Fujiwara, T Tanida, A Hizuta, H Nishimori, Takashi Tokino, Y Nakamura, M Bouvet, JA Roth, N Tanaka

    CLINICAL CANCER RESEARCH   5 ( 5 )   1015 - 1023   1999.5

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  • Mutations of the beta-catenin gene in endometrial carcinomas

    K Kobayashi, S Sagae, Y Nishioka, T Tokino, R Kudo

    JAPANESE JOURNAL OF CANCER RESEARCH   90 ( 1 )   55 - 59   1999.1

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  • Identification of BAIAP2 (BAI-associated protein 2), a novel human homologue of hamster IRSp53, whose SH3 domain interacts with the cytoplasmic domain of BAI1

    K Oda, T Shiratsuchi, H Nishimori, J Inazawa, H Yoshikawa, Y Taketani, Y Nakamura, T Tokino

    CYTOGENETICS AND CELL GENETICS   84 ( 1-2 )   75 - 82   1999

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  • Induction of apoptosis in T98G glioblastoma cells by transfection of GML, a p53 target gene

    K Ueda, Y Miyoshi, T Tokino, M Watatani, Y Nakamura

    ONCOLOGY RESEARCH   11 ( 3 )   125 - 132   1999

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  • P-2 子宮内膜癌におけるβ-catenin遺伝子の変異

    小林 寛治, 寒河江 悟, 西岡 嘉宏, 時野 隆至, 工藤 隆一

    日本産科婦人科學會雜誌   51   "S - 360"   1999

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  • Significant increase of adenovirus infectivity in glioma cell lines by extracellular domain of hCAR

    T Mori, H Arakawa, T Tokino, K Mineura, Y Nakamura

    ONCOLOGY RESEARCH   11 ( 11-12 )   513 - 521   1999

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  • 胃癌におけるβ-カテニンの発現性と遺伝子異常の検索

    佐々木泰史, 森本一郎, 伊東文生, 柳原五吉, 今井浩三, 時野隆至

    日本癌学会総会記事   58th   1999

  • Molecular cloning, mapping, and characterization of a novel human gene, MTA1-L1, showing homology to a metastasis-associated gene, MTA1

    M Futamura, H Nishimori, T Shiratsuchi, S Saji, Y Nakamura, T Tokino

    JOURNAL OF HUMAN GENETICS   44 ( 1 )   52 - 56   1999

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  • Cloning and characterization of BAP3 (BAI-associated protein 3), a C2 domain-containing protein that interacts with BAI1

    T Shiratsuchi, K Oda, H Nishimori, M Suzuki, E Takahashi, T Tokino, Y Nakamura

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   251 ( 1 )   158 - 165   1998.10

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  • Isolation of a novel TP53 target gene from a colon cancer cell line carrying a highly regulated wild-type TP53 expression system

    Y Takei, S Ishikawa, T Tokino, T Muto, Y Nakamura

    GENES CHROMOSOMES & CANCER   23 ( 1 )   1 - 9   1998.9

  • CSR, a scavenger receptor-like protein with a protective role against cellular damage caused by UV irradiation and oxidative stress

    HJ Han, Takashi Tokino, Y Nakamura

    HUMAN MOLECULAR GENETICS   7 ( 6 )   1039 - 1046   1998.6

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  • Cloning and characterization of BAI-associated protein 1: A PDZ domain-containing protein that interacts with BAI1

    T Shiratsuchi, M Futamura, K Oda, H Nishimori, Y Nakamura, Takashi Tokino

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   247 ( 3 )   597 - 604   1998.6

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  • Cloning and characterization of the murine P2XM receptor gene

    G Nawa, T Urano, T Tokino, T Ochi, Y Miyoshi

    JOURNAL OF HUMAN GENETICS   43 ( 4 )   262 - 267   1998

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  • Overexpression of GML promotes radiation-induced cell cycle arrest and apoptosis

    K Kagawa, T Inoue, T Tokino, Y Nakamura, T Akiyama

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   241 ( 2 )   481 - 485   1997.12

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  • A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis

    H Nishimori, T Shiratsuchi, T Urano, Y Kimura, K Kiyono, K Tatsumi, S Yoshida, M Ono, M Kuwano, Y Nakamura, T Tokino

    ONCOGENE   15 ( 18 )   2145 - 2150   1997.10

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  • A novel brain-specific p53-target gene, BAI1, containing thrombospondin type1 repeats inhibits experimental angiogenesis.

    T Tokino, H Nishimori, T Shiratsuchi, T Urano, Y Kimura, K Kiyono, K Tatsumi, S Yoshida, M Ono, M Kuwano, Y Nakamura

    AMERICAN JOURNAL OF HUMAN GENETICS   61 ( 4 )   A84 - A84   1997.10

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  • GML sensitizes cancer cells to Taxol by induction of apoptosis

    Y Kimura, T Furuhata, T Shiratsuchi, H Nishimori, K Hirata, Y Nakamura, T Tokino

    ONCOGENE   15 ( 11 )   1369 - 1374   1997.9

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  • Cloning of P2XM a novel human P2X receptor gene regulated by p53

    T Urano, H Nishimori, HJ Han, T Furuhata, Y Kimura, Y Nakamura, Takashi Tokino

    CANCER RESEARCH   57 ( 15 )   3281 - 3287   1997.8

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  • Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line

    K Nakano, T Mizuno, Y Sowa, T Orita, T Yoshino, Y Okuyama, T Fujita, N OhtaniFujita, Y Matsukawa, T Tokino, H Yamagishi, T Oka, H Nomura, T Sakai

    JOURNAL OF BIOLOGICAL CHEMISTRY   272 ( 35 )   22199 - 22206   1997.8

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  • Complete NotI restriction map covering the entire long arm of human chromosome 11

    F Hosoda, Y Arai, E Kitamura, J Inazawa, M Fukushima, Takashi Tokino, Y Nakamura, C Jones, N Kakazu, T Abe, M Ohki

    GENES TO CELLS   2 ( 5 )   345 - 357   1997.5

  • Genomic structure and chromosomal localization of GML (GPI-anchored molecule-like protein), a gene induced by p53

    Y Kimura, T Furuhata, T Urano, K Hirata, Y Nakamura, T Tokino

    GENOMICS   41 ( 3 )   477 - 480   1997.5

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  • No evidence of mutation in the human PTC gene, responsible for nevoid basal cell carcinoma syndrome, in human primary squamous cell carcinomas of the esophagus and lung

    K Suzuki, Y Daigo, S Fukuda, T Tokino, M Isomura, K Isono, B Wainwright, Y Nakamura

    JAPANESE JOURNAL OF CANCER RESEARCH   88 ( 3 )   225 - 228   1997.3

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  • Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1)

    T Shiratsuchi, H Nishimori, H Ichise, Y Nakamura, T Tokino

    CYTOGENETICS AND CELL GENETICS   79 ( 1-2 )   103 - 108   1997

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  • Mutational analysis of the hMLH1 gene using an automated two-dimensional DNA typing system

    S Sasaki, T Tokino, T Miyatsu, T Muto, Y Nakamura

    HUMAN MUTATION   9 ( 2 )   164 - 171   1997

  • Isolation of a novel GPI-anchored gene specifically regulated by p53; Correlation between its expression and anti-cancer drug sensitivity

    T Furuhata, T Tokino, T Urano, Y Nakamura

    ONCOGENE   13 ( 9 )   1965 - 1970   1996.11

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  • Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage

    N Tanaka, M Ishihara, MS Lamphier, H Nozawa, T Matsuyama, TW Mak, S Aizawa, Takashi Tokino, M Oren, T Taniguchi

    NATURE   382 ( 6594 )   816 - 818   1996.8

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  • Characterization of the human p57(KIP2) gene: Alternative splicing, insertion deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis

    Takashi Tokino, T Urano, T Furuhata, M Matsushima, T Miyatsu, S Sasaki, Y Nakamura

    HUMAN GENETICS   97 ( 5 )   625 - 631   1996.5

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  • Detailed deletion mapping in squamous cell carcinomas of the esophagus narrows a region containing a putative tumor suppressor gene to about 200 kilobases on distal chromosome 9q(1)

    K Miura, K Suzuki, T Tokino, M Isomura, J Inazawa, S Matsuno, Y Nakamura

    CANCER RESEARCH   56 ( 7 )   1629 - 1634   1996.4

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  • Definition of the locus responsible for systemic carnitine deficiency within a 1.6-cM region of mouse chromosome 11 by detailed linkage analysis

    K Okita, T Tokino, H Nishimori, K Miura, H Nikaido, J Hayakawa, A Ono, M Kuwajima, Y Matsuzawa, Y Nakamura

    GENOMICS   33 ( 2 )   289 - 291   1996.4

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  • MAPPING THE MOUSE GENE FOR PRIMARY CARNITINE DEFICIENCY

    K OKITA, T TOKINO, H NISHIMORI, H NIKAIDO, J HAYAKAWA, A OHNO, M KUWAJIMA, Y MATSUZAWA, Y NAKAMURA

    AMERICAN JOURNAL OF HUMAN GENETICS   57 ( 4 )   1890 - 1890   1995.10

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  • TOPOLOGICAL CONTROL OF P21(WAF1/CIP1) EXPRESSION IN NORMAL AND NEOPLASTIC TISSUES

    WS ELDEIRY, Takashi Tokino, T WALDMAN, JD OLINER, VE VELCULESCU, M BURRELL, DE HILL, E HEALY, JL REES, HAMILTON, SR, KW KINZLER, B VOGELSTEIN

    CANCER RESEARCH   55 ( 13 )   2910 - 2919   1995.7

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  • P53-DEPENDENT AND INDEPENDENT EXPRESSION OF P21 DURING CELL-GROWTH, DIFFERENTIATION, AND DNA-DAMAGE

    KF MACLEOD, N SHERRY, G HANNON, D BEACH, T TOKINO, K KINZLER, B VOGELSTEIN, T JACKS

    GENES & DEVELOPMENT   9 ( 8 )   935 - 944   1995.4

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  • 50 NOVEL SEQUENCE-TAGGED SITES (STSS) ON HUMAN-CHROMOSOME 11Q13.4-]Q25 IDENTIFIED FROM MICROCLONES GENERATED BY MICRODISSECTION

    H SOEJIMA, K YOSHIURA, T TAMURA, T TOKINO, Y NAKAMURA, N NIIKAWA, Y JINNO

    CYTOGENETICS AND CELL GENETICS   70 ( 1-2 )   108 - 111   1995

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  • P53 TAGGED SITES FROM HUMAN GENOMIC DNA

    T TOKINO, S THIAGALINGAM, WS ELDEIRY, T WALDMAN, KW KINZLER, B VOGELSTEIN

    HUMAN MOLECULAR GENETICS   3 ( 9 )   1537 - 1542   1994.9

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  • SEQUENCE-SPECIFIC TRANSCRIPTIONAL ACTIVATION IS ESSENTIAL FOR GROWTH SUPPRESSION BY P53

    JA PIETENPOL, T TOKINO, S THIAGALINGAM, WS ELDEIRY, KW KINZLER, B VOGELSTEIN

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   91 ( 6 )   1998 - 2002   1994.3

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  • HIGH-RESOLUTION ORDERING OF DNA MARKERS BY MULTICOLOR FLUORESCENT IN-SITU HYBRIDIZATION OF PROPHASE CHROMOSOMES

    J INAZAWA, T ARIYAMA, T TOKINO, A TANIGAMI, Y NAKAMURA, T ABE

    CYTOGENETICS AND CELL GENETICS   65 ( 1-2 )   130 - 135   1994

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  • WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION

    WS ELDEIRY, T TOKINO, VE VELCULESCU, DB LEVY, R PARSONS, JM TRENT, D LIN, WE MERCER, KW KINZLER, B VOGELSTEIN

    CELL   75 ( 4 )   817 - 825   1993.11

  • ABSENCE OF GERMLINE PROHIBITIN MUTATIONS IN EARLY-ONSET BREAST-CANCER

    T TOKINO, N DAVIDSON, K HELZLSOUER, B ZEHNBAUER, Y NAKAMURA, B VOGELSTEIN, D SIDRANSKY

    INTERNATIONAL JOURNAL OF ONCOLOGY   3 ( 4 )   769 - 772   1993.10

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  • IDENTIFICATION AND CHARACTERIZATION OF A 9-KB SOMATIC HOMOZYGOUS DELETION AT 3P21.3-P22 IN A LUNG-CANCER CELL-LINE

    K YAMAKAWA, Y MURATA, M TAMARI, T TAKAHASHI, Y HORIO, K HIBI, S YOKOYAMA, J INAZAWA, T TAKAHASI, Y NAKAMURA

    AMERICAN JOURNAL OF HUMAN GENETICS   53 ( 3 )   390 - 390   1993.9

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  • P53 MUTATION AND MDM2 AMPLIFICATION IN HUMAN SOFT-TISSUE SARCOMAS

    FS LEACH, T TOKINO, P MELTZER, M BURRELL, JD OLINER, S SMITH, DE HILL, D SIDRANSKY, KW KINZLER, B VOGELSTEIN

    CANCER RESEARCH   53 ( 10 )   2231 - 2234   1993.5

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  • MAPPING THE BREAKPOINT OF A CONSTITUTIONAL TRANSLOCATION ON CHROMOSOME-22 IN A PATIENT WITH NF2

    E ARAI, T TOKINO, T IMAI, J INAZAWA, T IKEUCHI, A TONOMURA, Y NAKAMURA

    GENES CHROMOSOMES & CANCER   6 ( 4 )   235 - 238   1993.4

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  • ASSIGNMENT OF 54 COSMID CLONES TO 5 REGIONS OF CHROMOSOME-10

    SE MOLE, MS JACKSON, T TOKINO, Y NAKAMURA, BAJ PONDER

    GENOMICS   15 ( 2 )   457 - 458   1993.2

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    DOI: 10.1006/geno.1993.1090

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  • Mapping of human chromosome 3 and its application to human diseases

    K. Yamakawa, Y. Nakamura, E. Takahashi

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   38 ( 3 )   215 - 227   1993

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  • IDENTIFICATION AND CHARACTERIZATION OF A CDNA, WHICH IS HIGHLY HOMOLOGOUS TO THE RIBONUCLEOPROTEIN GENE, FROM A LOCUS (D10S102) CLOSELY LINKED TO MEN2 (MULTIPLE ENDOCRINE NEOPLASIA TYPE-2)

    S TAKIGUCHI, T TOKINO, T IMAI, A TANIGAMI, K KOYAMA, Y NAKAMURA

    CYTOGENETICS AND CELL GENETICS   64 ( 2 )   128 - 130   1993

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  • IDENTIFICATION OF 57 CONVENTIONAL RFLP AND 6 VNTR SYSTEMS WITH 32 DNA CLONES ON CHROMOSOME-11P15

    K TAKITA, A TANIGAMI, T TOKINO, C JONES, Y NAKAMURA

    GENOMICS   13 ( 4 )   1296 - 1299   1992.8

  • DETAILED ANALYSIS OF AN AMPLIFIED REGION AT CHROMOSOME-11Q13 IN MALIGNANT-TUMORS

    A TANIGAMI, Takashi Tokino, K TAKITA, M UEDA, F KASUMI, Y NAKAMURA

    GENOMICS   13 ( 1 )   21 - 24   1992.5

  • A HIGH-RESOLUTION CYTOGENETIC MAP OF 168-COSMID DNA MARKERS FOR HUMAN CHROMOSOME-11

    TA HORI, E TAKAHASHI, A TANIGAMI, T TOKINO, Y NAKAMURA

    GENOMICS   13 ( 1 )   129 - 133   1992.5

  • INHERITED P53 GENE-MUTATIONS IN BREAST-CANCER

    D SIDRANSKY, T TOKINO, K HELZLSOUER, B ZEHNBAUER, G RAUSCH, B SHELTON, L PRESTIGIACOMO, B VOGELSTEIN, N DAVIDSON

    CANCER RESEARCH   52 ( 10 )   2984 - 2986   1992.5

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  • IDENTIFICATION OF RAS ONCOGENE MUTATIONS IN THE STOOL OF PATIENTS WITH CURABLE COLORECTAL TUMORS

    D SIDRANSKY, Takashi Tokino, HAMILTON, SR, KW KINZLER, B LEVIN, P FROST, B VOGELSTEIN

    SCIENCE   256 ( 5053 )   102 - 105   1992.4

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  • PREDICTIVE TESTING FOR MULTIPLE ENDOCRINE NEOPLASIA TYPE-1 USING DNA POLYMORPHISMS

    C LARSSON, J SHEPHERD, Y NAKAMURA, C BLOMBERG, G WEBER, B WERELIUS, N HAYWARD, B TEH, T TOKINO, B SEIZINGER, B SKOGSEID, K OBERG, M NORDENSKJOLD

    JOURNAL OF CLINICAL INVESTIGATION   89 ( 4 )   1344 - 1349   1992.4

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  • ASSOCIATION BETWEEN CHROMOSOME-11Q13 AMPLIFICATION AND PROGNOSIS OF PATIENTS WITH ESOPHAGEAL CARCINOMAS

    M MORI, Takashi Tokino, A YANAGISAWA, M KANAMORI, Y KATO, Y NAKAMURA

    EUROPEAN JOURNAL OF CANCER   28A ( 4-5 )   755 - 757   1992.4

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  • THE 11Q23 BREAKPOINT IN ACUTE-LEUKEMIA WITH T(11-19)(Q23-P13) IS DISTAL TO THOSE OF T(4-11), T(6-11) AND T(9-11)

    D CHERIF, H DERSARKISSIAN, J DERRE, T TOKINO, Y NAKAMURA, R BERGER

    GENES CHROMOSOMES & CANCER   4 ( 2 )   107 - 112   1992.3

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  • 31 NEW RFLP SYSTEMS DETECTED BY 24 DNA MARKERS ON HUMAN CHROMOSOME-10

    T TOKINO, S TAKIGUCHI, A TANIGAMI, T BRAGG, C JONES, Y NAKAMURA

    GENOMICS   12 ( 2 )   401 - 402   1992.2

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    DOI: 10.1016/0888-7543(92)90391-5

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  • PHYSICAL MAPPING OF A 950-KB REGION SURROUNDING A LOCUS (D10S102) TIGHTLY LINKED TO THE MEN2A GENE

    T TOKINO, T IMAI, A TANIGAMI, S TAKIGUCHI, Y NAKAMURA

    GENOMICS   12 ( 2 )   394 - 400   1992.2

  • MAPPING OF 262 DNA MARKERS INTO 24 INTERVALS ON HUMAN CHROMOSOME-11

    A TANIGAMI, Takashi Tokino, S TAKIGUCHI, M MORI, T GLASER, JW PARK, C JONES, Y NAKAMURA

    AMERICAN JOURNAL OF HUMAN GENETICS   50 ( 1 )   56 - 64   1992.1

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  • ISOLATION AND MAPPING OF 68 RFLP MARKERS ON HUMAN CHROMOSOME-6

    S SAITO, K OKUI, Takashi Tokino, M OSHIMURA, Y NAKAMURA

    AMERICAN JOURNAL OF HUMAN GENETICS   50 ( 1 )   65 - 70   1992.1

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  • CHROMOSOMAL SITES FOR HEPATITIS-B VIRUS INTEGRATION IN HUMAN HEPATOCELLULAR-CARCINOMA

    T TOKINO, K MATSUBARA

    JOURNAL OF VIROLOGY   65 ( 12 )   6761 - 6764   1991.12

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  • CHROMOSOME DELETIONS ASSOCIATED WITH HEPATITIS-B VIRUS INTEGRATION

    T TOKINO, H TAMURA, N HORI, K MATSUBARA

    VIROLOGY   185 ( 2 )   879 - 882   1991.12

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    DOI: 10.1016/0042-6822(91)90564-R

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  • CLINICAL EPIDEMIOLOGY AND EVALUATION OF GENE AMPLIFICATION AT CHROMOSOME LLQ13 IN THE 90 CASES OF ESOPHAGEAL CARCINOMAS

    M KANAMORI, M MORI, T TOKINO, A YANAGISAWA, Y KATO, Y NAKAMURA

    AMERICAN JOURNAL OF HUMAN GENETICS   49 ( 4 )   121 - 121   1991.10

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  • ISOLATION AND MAPPING OF 62 NEW RFLP MARKERS ON HUMAN CHROMOSOME-11

    T TOKINO, E TAKAHASHI, M MORI, A TANIGAMI, T GLASER, JW PARK, C JONES, TA HORI, Y NAKAMURA

    AMERICAN JOURNAL OF HUMAN GENETICS   48 ( 2 )   258 - 268   1991.2

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  • ALLELOTYPE STUDY OF PRIMARY HEPATOCELLULAR-CARCINOMA

    M FUJIMORI, T TOKINO, O HINO, T KITAGAWA, T IMAMURA, E OKAMOTO, M MITSUNOBU, T ISHIKAWA, H NAKAGAMA, H HARADA, M YAGURA, K MATSUBARA, Y NAKAMURA

    CANCER RESEARCH   51 ( 1 )   89 - 93   1991.1

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  • PRECISE LOCALIZATION OF A GENE RESPONSIBLE FOR ATAXIATELANGIECTASIA ON CHROMOSOME-11Q

    F CORNELIS, D CHERIF, M JAMES, T TOKINO, J DAVIES, D GIRAULT, C BERNARD, MF CROQUETTE, D THEAU, H AVETLOISEAU, J DERRE, M LITT, R BERGER, Y NAKAMURA, M LATHROP, C JULIER

    CYTOGENETICS AND CELL GENETICS   58 ( 3-4 )   1957 - 1957   1991

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  • A HIGH-RESOLUTION CYTOGENETIC MAP OF 149 MARKERS FOR HUMAN CHROMOSOME-11

    TA HORI, EI TAKAHASHI, T TOKINO, Y NAKAMURA

    CYTOGENETICS AND CELL GENETICS   58 ( 3-4 )   1963 - 1963   1991

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  • ISOLATION AND MAPPING OF 226 DNA MARKERS ON HUMAN CHROMOSOME-11

    T TOKINO, A TANIGAMI, S TAKIGUCHI, T GLASER, JW PARK, C JONES, Y NAKAMURA

    CYTOGENETICS AND CELL GENETICS   58 ( 3-4 )   1972 - 1972   1991

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  • DEVELOPMENT OF POLYMORPHIC DINUCLEOTIDE REPEATS ON HUMAN CHROMOSOME-11

    C DUBAY, J HAZAN, Takashi Tokino, Y NAKAMURA, CW RICHARD, D COX, MR JAMES, D CHERIF, M LATHROP, J WEISSENBACH

    CYTOGENETICS AND CELL GENETICS   58 ( 3-4 )   1958 - 1958   1991

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  • AMPLICON AT CHROMOSOME-11Q13 IN ESOPHAGEAL, BREAST AND HEPATOCELLULAR CARCINOMAS

    A TANIGAMI, KI TAKITA, T TOKINO, Y NAKAMURA

    CYTOGENETICS AND CELL GENETICS   58 ( 3-4 )   1971 - 1971   1991

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  • TOWARDS A COMBINED MEIOTIC-BASED, RADIATION-HYBRID-BASED AND YAC-BASED PHYSICAL MAP OF CHROMOSOME-11Q22-Q23

    MR JAMES, C JULIER, F CORNELIS, D CHERIF, R BERGER, Takashi Tokino, Y NAKAMURA, R MYERS, D COX, GM LATHROP, CW RICHARD

    CYTOGENETICS AND CELL GENETICS   58 ( 3-4 )   1964 - 1964   1991

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  • A COMPARISON OF THE MOLECULAR-STRUCTURE OF INTEGRATED HEPATITIS-B VIRUS GENOMES IN HEPATOCELLULAR-CARCINOMA CELLS AND HEPATOCYTES DERIVED FROM THE SAME PATIENT

    N OGATA, T TOKINO, T KAMIMURA, H ASAKURA

    HEPATOLOGY   11 ( 6 )   1017 - 1023   1990.6

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  • INTEGRATION OF HEPATITIS-B VIRUS-DNA AND ITS IMPLICATIONS FOR HEPATOCARCINOGENESIS

    K MATSUBARA, T TOKINO

    MOLECULAR BIOLOGY & MEDICINE   7 ( 3 )   243 - 260   1990.6

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  • CHROMOSOME REGIONAL MAPPING FOR THE HUMAN THYROID STIMULATING HORMONE BETA-SUBUNIT (TSHB) GENE

    Takashi Tokino, Y HAYASHIZAKI, KI TAKATA, MC YOSHIDA, K MATSUBARA

    CYTOGENETICS AND CELL GENETICS   53 ( 2-3 )   140 - 143   1990

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  • CO-AMPLIFICATION OF INTEGRATED HEPATITIS-B VIRUS-DNA AND TRANSFORMING GENE HST-1 IN A HEPATOCELLULAR-CARCINOMA

    HATADA, I, T TOKINO, T OCHIYA, K MATSUBARA

    ONCOGENE   3 ( 5 )   537 - 540   1988.11

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  • MICRODELETION ASSOCIATED WITH THE INTEGRATION PROCESS OF HEPATITIS-B VIRUS-DNA

    T NAKAMURA, T TOKINO, T NAGAYA, K MATSUBARA

    NUCLEIC ACIDS RESEARCH   16 ( 11 )   4865 - 4873   1988.6

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  • REGIONAL LOCALIZATION OF THE LCA ONCOGENE TO HUMAN-CHROMOSOME REGION 2Q14-]Q21

    T TOKINO, H SATOH, MC YOSHIDA, T OCHIYA, K MATSUBARA

    CYTOGENETICS AND CELL GENETICS   48 ( 1 )   63 - 64   1988

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  • CHROMOSOMAL TRANSLOCATION AND INVERTED DUPLICATION ASSOCIATED WITH INTEGRATED HEPATITIS-B VIRUS IN HEPATOCELLULAR CARCINOMAS

    T TOKINO, S FUKUSHIGE, T NAKAMURA, T NAGAYA, T MUROTSU, K SHIGA, N AOKI, K MATSUBARA

    JOURNAL OF VIROLOGY   61 ( 12 )   3848 - 3854   1987.12

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  • THE MODE OF HEPATITIS-B VIRUS-DNA INTEGRATION IN CHROMOSOMES OF HUMAN HEPATOCELLULAR-CARCINOMA

    T NAGAYA, T NAKAMURA, T TOKINO, T TSURIMOTO, M IMAI, T MAYUMI, K KAMINO, K YAMAMURA, K MATSUBARA

    GENES & DEVELOPMENT   1 ( 8 )   773 - 782   1987.10

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  • REPLICATION OF MINI-F PLASMID INVITRO PROMOTED BY PURIFIED E-PROTEIN

    K MURAISO, T TOKINO, T MUROTSU, K MATSUBARA

    MOLECULAR & GENERAL GENETICS   206 ( 3 )   519 - 521   1987.3

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    Language:English   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    DOI: 10.1007/BF00428895

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  • REPLICATION AND INTEGRATION OF HEPATITIS-B VIRUS GENOME

    K MATSUBARA, T TSURIMOTO, K UEDA, O CHISAKA, T TOKINO

    JOURNAL OF CELLULAR BIOCHEMISTRY   7 - 7   1987

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    Language:English   Publishing type:Research paper, summary (international conference)  

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  • PURIFICATION AND PROPERTIES OF THE MINI-F PLASMID-ENCODED E-PROTEIN NEEDED FOR AUTONOMOUS REPLICATION CONTROL OF THE PLASMID

    Takashi Tokino, T MUROTSU, K MATSUBARA

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   83 ( 12 )   4109 - 4113   1986.6

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Awards

  • 寿原記念財団研究助成金

    1999  

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  • 日本癌学会奨励賞

    1998  

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  • 財団法人ノバルティス科学振興財団研究助成金

    1998  

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  • 高松宮妃癌研究基金研究助成金

    1996  

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  • 原口記念癌研究助成基金

    1995  

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Research Projects

  • 新規がん治療法の開発をめざしたp53との合成致死に関与する遺伝子群の探索

    Grant number:22K07173  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    時野 隆至

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • p53 pathway and its potential targeted therapeutic approach

    Grant number:19K07645  2019.4 - 2023.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • A better understanding of p53 network for cancer therapy

    Grant number:16K07122  2016.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    TOKINO Takashi

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    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    p53 is one of the most important tumor suppressor genes. Thus, understanding p53 network is an important issue. In this study, we identified BRMS1L and ARVCF as novel p53-target genes. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effects. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. We found that BRMS1L is one of the mediators downstream of the p53 pathway, such as p21 activation and survivin suppression. We also revealed the knockdown of ARVCF inhibited p53-induced apoptosis. Our results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Our study indicates that BRMS1L and ARVCF are involved in tumor suppression, and could be therapeutic targets for human cancer.

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  • 先進ゲノム解析研究推進プラットフォーム

    Grant number:16H06279  2016 - 2021

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)『学術研究支援基盤形成』

    小原 雄治, 加藤 和人, 川嶋 実苗, 豊田 敦, 鈴木 穣, 三井 純, 林 哲也, 時野 隆至, 黒川 顕, 中村 保一, 野口 英樹, 高木 利久, 岩崎 渉, 森下 真一, 浅井 潔, 笠原 雅弘, 伊藤 武彦, 山田 拓司, 小椋 義俊, 久原 哲, 高橋 弘喜, 瀬々 潤, 榊原 康文

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    Grant amount:\7698340000 ( Direct Cost: \5921800000 、 Indirect Cost:\1776540000 )

    ①総括支援活動では、応募の機会増加の要望に応えるため今年度から年2回の公募とした。その結果、合計466の応募課題があり、207課題(44%)を採択した。コロナ禍の影響の中、昨年度より応募数は100件近く増加したが、支援内容の精査や支援経費の限度額設定等により、40%超の採択率を維持した。審査委員はすべてプラットフォーム外の専門家とし、評価が同程度の場合は若手、女性、少額科研費からの課題、初めての応募課題を優先した。支援課題は科研費生物系のほぼすべての分野に渡っており、支援の成果を含む論文として2020年度に161報が発表された。この中には「単核貪食細胞系の分化における遺伝子発現制御機構の包括的解明」(Nature Immunol.)、「キンギョの変異体の表現型多様性を作り上げる分子機構の理解」(Current Biol.)、「植物二次代謝経路のゲノム進化に学ぶ生合成デザイン」(Nature Comm.)など広い分野でのレベルの高い成果が含まれている。拡大班会議や情報解析講習会はオンサイト開催が必要なためにコロナ禍の中で見送ったが、WEB開催としたヒトゲノム研究倫理を考える会は5回開催し、各回約500名が参加した。
    ②大規模配列解析拠点ネットワーク支援活動においては、最先端技術を支援に提供するとともに、染色体レベルの高精度ゲノム配列決定、シングルセル・空間遺伝子発現解析等の支援技術高度化を進めた。
    ③高度情報解析支援ネットワーク活動では、支援から浮かび上がった課題を解決するソフトウェアの開発を進め、実際の課題への適用を進めた。2020年度には、超高速相同性検索ソフトウェアPZLASTの開発、Hi-Cデータを使ったゲノムアセンブリソフトウエア、ロングリードシミュレータPBSIM2の開発などを進め、②と合わせて24報の論文を発表した。

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  • New insights into p53 signaling regulation to cure cancer

    Grant number:25430115  2013.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    TOKINO Takashi

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    Grant amount:\5200000 ( Direct Cost: \4000000 、 Indirect Cost:\1200000 )

    We found that forkhead transcription factor FOXF1 and intercellular adhesion molecule-2 (ICAM2) are novel target genes of p53. The ectopic expression of FOXF1 and ICAM2 inhibited cancer cell invasion and migration, whereas the inactivation of FOXF1 and ICAM2 stimulated cell invasion and migration. Our findings suggest that FOXF1 and ICAM2 induction by p53 are on key pathways in inhibiting cancer cell migration and invasion.
    We also found CRKL oncogene is downregulated by p53 through miR-200s. First, we identified that miR-200s are direct transcriptional targets of p53 and then miR-200b/200c/429 inhibited CRKL mRNA and protein expression by directly targeting its 3’-UTR region. The CRKL oncogene encodes an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains and is reported to be overexpressed in a subset of cancer types. Our results demonstrate that the p53 target miR-200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.

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  • バイオインフォマティクスを活用したp53ネットワーク探索と癌治療への応用

    Grant number:25134715  2013.4 - 2015.3

    日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    時野 隆至

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    Grant amount:\5720000 ( Direct Cost: \4400000 、 Indirect Cost:\1320000 )

    p53結合モチーフ認識アルゴリズムを利用して,全ヒトゲノム配列探索により約64万のp53モチーフを同定した。アデノウイルスベクターでp53を発現させた肺がん細胞H1299における次世代シーケンサーを用いたクロマチン免疫沈降解析(ChIP-seq)によるピークと重複するものが20.0%であった。その内約半数は遺伝子間に存在することから,遺伝子介在性非コードRNA (lincRNA) がp53の標的となっている可能性が高いと考えられた。データベースに登録されている約14,000のヒト lincRNA のうち,その上下流10kbにp53モチーフと重複するChIP-seqピークを持つlincRNAを抽出した。qRT-PCRにより発現解析を行ったところ,23個のlincRNAがp53によって転写誘導されることを確認した。
    さらに機能的解析により,このうち特定のp53標的lincRNAの発現抑制がp53関連アポトーシス誘導を調整したり,特定の遺伝子群の発現を促進したりする結果を得ることができた。この結果は,腫瘍抑制を含めた多様な生理的機能においてp53とlincRNAが複雑な転写ネットワークを形成していることを示唆している。今後はこのようなp53の基礎的研究から新たな診断法やがん治療開発への臨床応用につながる研究をめざしたい。

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  • High-throughput screening for peptides that inhibit the interaction or MDM4 with p53

    Grant number:23659658  2011 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Exploratory Research

    TOKINO Takashi, FURUHATA Tomohisa

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    Grant amount:\3640000 ( Direct Cost: \2800000 、 Indirect Cost:\840000 )

    It is currently of great midical interest to inhibit specific protein-protein interactions between MDM4 and p53. Here, we developed a method using T7 phage display to screen for candidate inhibitors of MDM4-p53 interactions. In primary screening , we identified novel peptide motifs that inhibit the interaction of MDM4 with p53. Then, we designed a number of peptides that are predicted to have higher affinity to MDM4, and identified potential peptides that inhibit the interaction between MDM4 and p53 with higher affinity.

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  • Scientific Support Programs for Cancer Research Grant-in-Aid for Scientific Research on Innovative Areas

    Grant number:221S0001  2010.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    IMAI Kohzoh, INOUE Junichiro, NAKAMURA Takuro, ISHIKAWA Fuyuki, YAMAMURA Kenichi, ARAKI Kimi, YAO Ryouji, TAKANO Hiroshi, TAKAKURA Akira, KATOH Hideki, NAKAGATA Naomi, TOYOKUNI Shinya, WANIBUCHI Hideki, OGAWA Katsuhiro, MITSUMORI Kunitoshi, YAMADA Yasuhiro, SHIBUTANI Makoto, IMAIDA Katsumi, FUTAKUCHI Mitsuru, KANDA Hiroaki, TANAKA Hideo, WAKAI Kenji, MIKAMI Haruo, SUZUKI Sadao, MIURA Katsuyuki, WATANABE Yoshiyuki, ARISAWA Kokichi, TANAKA Keitaro, TAKEZAKI Toshiro, FURUSHO Norihiro, NAITO Mariko, OHNAKA Keizo, KITA Yoshikuni, KURIKI Kiyonori, TAMAKAOSHI Akiko, EGUCHI Hidetaka, KUBO Michiaki, HAMAJIMA Nobuyuki, NAGATA Chisato, HINO Okio, TAHARA Hidetoshi, SUGIMURA Haruhiko, TSUGANE Shoichiro, NAKATOCHI Masahiro, TAKAYAMA Tetsuji, AKAZA Hideyuki, TAKAHASHI Satoru, TSUKAMOTO Taiji, NAITO Seiji, MASUMORI Naoya, YOKOMIZO Akira, NAMIKI Mikio, FUJIMOTO Kiyohide, FUJIOKA Tomoaki, HORIE Shigeo, MORI Mitsuru, MORIWAKI Hisataka, Shimizu Masahito, KANNAGI Mari, ISHIDA Takashi, MATSUOKA Masao, YAMAOKA Shoji, TANAKA Yuetsu, WATANABE Toshiki, YASUI Hiroshi, TSUCHIYA Eiju, DAIGO Yataro, MIYAGI Yohei, TAKAHASHI Takashi, YAMORI Takao, SEIMIYA Hiroyuki, UEHARA Yoshimasa, YOSHIDA Minoru, IMOTO Masaya, FUKAZAWA Hidesuke, KAKEYA Hideaki, DAN Shingo, TOMIDA Akihiro, KAWADA Manabu, OSADA Hiroyuki, MATSUURA Masaaki, MIZUKAMI Tamio, MASHIMA Tetsuo, USHIJIMA Masaru, TOKINO Takashi, SUZUKI Hiromu, SHINOMURA Yasuhisa, NOSHO Katsuhiko, MIYAZONO Kohei, INAZAWA Johji, HIROTA Toru, NODA Tetsuo, SUZUKI Misao, TAKEDA Naoki, YAGINUMA Katsuyuki, SUGITANI Yoshinobu, ITO Hidemi, HOSONO Satoyo, IWASAKI Motoki, NAGASE Hiroki, NISHITA Hiroki, KONO Suminori, HASHIMOTO Syuji, YAMAGUCHI Kazunari, TAKANO Atsushi, TERAMOTO Koji, MATSUDA Koichi, TANAKA Yukichi, AOKI Ichiro, OSAMURA Yoshiyuki, NAKAMURA Naoya, SUZUKI Noboru, TAJIRI Michihiko, KAWASAKI Takashi, YOKOSE Tomoyuki, YANAGISAWA Kiyoshi, HIRAKAWA Akihiro, IIJIMA Yoshihiko, ZEMBUTSU Hitoshi, SASAKI Yasushi, IDOGAWA Masashi, MARUYAMA Reo, KAI Masahiro

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    We started this project first supporting scientists who aim to overcome cancer, and from 2014 we extended our support to scientists in life sciences. The outcome has been as follows: General Support Group fostered young scientists and those who will be involved in research support in the future, and developed international academic exchanges. Our support services such as providing genetically modified mice and providing bioresources including cancer tissues enabled many scientists to conduct international and cutting-edge researches. All Japan Cohort Group and ATL Study Group (originated in Japan) collected more than 110,000 important samples and contributed for many scientists to produce their results. Chemotherapy Group and Genome and Epigenome Group also achieved more than their original goals. Further, we organized open lectures for general public to inform the importance of scientific support.

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  • RNA干渉技術を駆使してアポトーシス誘導シグナルを増強した遺伝子治療法の開発

    Grant number:21659323  2009 - 2010

    日本学術振興会  科学研究費助成事業  挑戦的萌芽研究

    時野 隆至, 古畑 智久

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    Grant amount:\3000000 ( Direct Cost: \3000000 )

    癌抑制遺伝子p53の導入による遺伝子治療が有効であると考えられるが、必ずしも著効するとは限らず、さらなる工夫が必要である。これまでに、我々はp21発現抑制miRNA/p53共発現アデノウイルスベクター(Ad-p53/miR-p21)を開発することで癌治療効果を増強することに成功した。そこで、更に別の標的遺伝子のひとつであるMDM2を特異的に発現抑制する人工miRNAの設計を行った。この設計配列を元に4種類のDNAオリゴを合成し発現プラスミドベクターに組み込んだ。このベクターをp53発現ベクターと共に大腸癌細胞HCT116にトランスフェクションしたところ、p53が強発現しているにもかかわらずMDM2の蛋白発現誘導の抑制が認められた。次に、相同組み換えを用いて、このベクターをアデノウイルスベクターAd-miR-MDM2を作成した。このアデノウイルスベクターをAd-p53/miR-p21と共に大腸癌細胞DLD-1に感染させたところ、MDM2の発現抑制によりp53の発現上昇と、それに伴うアポトーシスの増強効果が認められた。肝癌細胞Hep3Bおよび大腸癌細胞SW480にアドリアマイシンを併用した場合においても、miR-MDM2はAd-p53/miR-p21によるアポトーシス誘導を増強した。
    本研究において、p53発現ベクターにp21抑制miRNAおよびMDM2抑制miRNAベクターを併用することでアポトーシス増強効果を得ることに成功した。miRNA発現ベクターは、他のmiRNAをタンデムに接続することで複数の標的遺伝子の発現を抑制することが可能である。このため、他のアポトーシス阻害的な遺伝子に対するmiRNA設計し、複数を組み合わせることで相乗効果を得ることができる。この研究成果により、更なるp53遺伝子治療効果の増強および治療耐性の回避が期待できる。

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  • Expression analysis of SFRP family genes for development of molecular targeted therapy for oral cancer

    Grant number:21792021  2009 - 2010

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    SOGABE Yohei, OGI Kazuhiso, HIRATSUKA Hiroyoshi, TOKINO Takashi

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    In the present study, we examined the relationship between Wnt signaling and epigenetic alteration of the secreted frizzled-related protein (SFRP) genes in OSCC. Our results confirm the frequent methylation and silencing of SFRP genes in OSCC, and suggest that their loss of function contributes to activation of Wnt signaling that leads to cell proliferation during oral carcinogenesis.

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  • Functional analysis of CHFR: Diagnostic and therapeutic application for oral squamous cell cancer

    Grant number:20390519  2008 - 2010

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    TOKINO Takashi, HIRATSUKA Hiroyoshi, OGI Kazuhiro

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    Grant amount:\19240000 ( Direct Cost: \14800000 、 Indirect Cost:\4440000 )

    The mitotic checkpoint gene CHFR is silenced by promoter hypermethylation or mutated in various human cancers, suggesting that CHFR is an important tumor suppressor. Recent studies have reported that CHFR functions as an E3 ubiquitin ligase, resulting in the degradation of these proteins. To better understand how CHFR suppresses cell cycle progression and tumorigenesis, we sought to identify CHFR-interacting proteins using affinity purification combined with mass spectrometry. Herein, we showed poly(ADP-ribose) polymerase-1 (PARP-1), which catalyzes polyADP-ribosylation, to be a novel CHFR interacting protein. In CHFR expressing cells, mitotic stress induced the autoPARylation of PARP-1, resulting in an enhanced interaction between CHFR and PARP-1 and an increase in the polyubiquitination/degradation of PARP-1. The decrease in PARP-1 protein levels promoted cell cycle arrest at antephase, suggesting that the cells expressing CHFR were resistant to microtubule inhibitors. By contrast, in CHFR-silenced cells, polyubiquitination following autoPARylation of PARP-1 was not induced in response to mitotic stress. Thus, PARP-1 protein levels did not decrease, and cells progressed into mitosis under mitotic stress. Furthermore, we found that cells from Chfr knockout mice and CHFR-silenced primary gastric cancer tissues expressed higher levels of PARP-1 protein, strongly supporting our data that the interaction between CHFR and PARP-1 plays an important role in cell cycle regulation and cancer therapeutic strategies. Based on our studies, we demonstrate a significant advantage for use of combinational chemotherapy with PARP inhibitors for cancer cells resistant to microtubule inhibitors.

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  • デジタル ゲノム スキャニング法の開発と胃癌関連遺伝子探索への応用

    Grant number:19659344  2007 - 2008

    日本学術振興会  科学研究費助成事業  萌芽研究

    時野 隆至, 古畑 智久, 見田 裕章, 明石 浩史

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    Grant amount:\3300000 ( Direct Cost: \3300000 )

    癌遺伝子の増幅や癌抑制遺伝子の欠失を伴う染色体変化は癌細胞の特徴である.本研究では短いゲノム断片を解析しゲノム上のDNAコピー数以上を示す領域を検出する方法としてデジタルゲノムスキャニング(DGS: Digital Genome Scanning)法を開発し,胃癌細胞株におけるゲノムコピー数異常の検出を試みた.
    DGS法を利用して,ヒト胃癌細胞株においてKRASCACNAIC (calcium channel, viltage-dependent, 1 type, alpha-1c subunit)を含む2つの約500kbのゲノム領域を染色体12p12.1と12p13.33に同定した.KRAS遺伝子増幅を有する胃癌細胞株では,KRASのmRNAおよびタンパクレベルはKRAS遺伝子コピー数とよく相関していた.正常型KRASが遺伝子増幅した胃癌細胞では,血清刺激後に高レベルのGTP-KRASおよびリン酸化p44/42が検出された.一方,変異型KRASが遺伝子増幅した別の胃癌細胞では,恒常的に高レベルの活性型KRASおよびp44/42が検出された.この結果は,細胞増殖において正常型KRASの遺伝子増幅が無刺激条件下で選択優位性をもたらすのみならず,増殖因子刺激や高栄養環境の条件では点変異KRAS遺伝子と同様に著しい選択優位性を獲得可能なことを強く示唆している.
    以上より,DGS法は癌を代表とするゲノムコピー数異常を呈する疾患の原因遺伝子探索において有効な手法となりうることを実証した.

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  • Diagnostic and therapeutic application of cell-cycle checkpoint genes for oral squamous cell cancer.

    Grant number:18390545  2006 - 2007

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    TOKINO Takashi, HIRATSUKA Hiroyoshi, OGI Kazuhiro

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    Grant amount:\17750000 ( Direct Cost: \15500000 、 Indirect Cost:\2250000 )

    CHFR which contains a RING domain and has ubiquitin ligase activity, a novel mitotic checkpoint gene delays chromosome condensation in cells treated with microtubule poisons. CHFR is inactivated by promoter methylation, and cancer cells lacking CHFR are sensitive to microtubule inhibitors.
    (1) Proteins interacting with CHFR, mitotic-checkpoint ubiquitin ligase.
    In this study, we isolated cellular proteins capable of interacting with CHFR using yeast two-hybrid method to clarify the function of CHFR. As a result of the screening, we isolated canonical and noncanonical E2 ubiquitin conjugating enzymes as CHFR interacting proteins, which are involved in proteolytic and non-proteolytic ubiquitination respectively. This raises the possibility that CHFR is switching canonical and noncanonical ubiquitination depending on the situation of cells.On the other hand, we isolated gadd34 which interacted with the FHA domain of CHFR. Furthermore, CHFR moved in part from nucleus to cytoplasm in the presence of microtubule inhibitor docetaxel, which enabled colocalization of CHFR and gadd34 in cytoplasm. This colocalization was followed by cell death. These suggest that gadd34 and CHFR cooperate to mediate cell death in response to mitotic stress.
    (2) CHFR mitotic checkpoint protein inhibits the transcriptional activity of NF-kB.
    To clarify the molecular mechanisms by which CHFR modulates tumor growth, our analysis focused on transcriptional regulation mediated by CHFR. Using microarray analysis, we found that CHFR downregulated NF-kB signaling. NF-kB-dependent luciferase assay demonstrated that overexpression of CHFR inhibited NF-kB signaling. Moreover, knockdown of CHFR activated the NF-kB activity. Furthermore, we found that IL-8, one of the NF-kB target genes, was regulated by CHFR. mRNA and protein levels of IL-8 were significantly repressed by overexpression of CHFR. Altogether, our findings reveal a novel function of CHFR as a regulator of NF-kB signaling, and which might account for tumor suppression by CHFR.

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  • p53 family : function and cancer therapy

    Grant number:17013072  2005 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Priority Areas

    TOKINO Takashi

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    Grant amount:\47000000 ( Direct Cost: \47000000 )

    Our in silico approach is powerful for identification of p53 target genes and for further understanding the function of p53 in tumorigenesis. We identified that PEDF, FLOT2, and APOD are direct transcriptional targets of the p53 family member genes. We found that significant antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines in a mouse model. Furthermore, the histone deacetylase inhibitor FK228 was found to enhance adenovirus-mediated p53 family gene therapy in cancer models.

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  • p53遺伝子ファミリーの機能解析とがん治療への応用

    Grant number:17013702  2005 - 2009

    日本学術振興会  科学研究費助成事業 

    時野 隆至

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    p53遺伝子治療とヒストン脱アセチル化酵素阻害剤FK228との併用効果の検討
    p53遺伝子治療の奏効率を高めるためには,p53依存性アポトーシス誘導に抵抗性の癌を克服する必要がある。最近,ヒストン脱アセチル化酵素阻害剤(HDACI:histone deacetylase inhibitor)には細胞周期停止や細胞死誘導効果が報告されており,腫瘍細胞の増殖を抑制する新規の抗がん剤として注目されている。また,白血病などで第2相臨床試験が行われている天然化合物HDACIのFK228(depsipeptide)はCAR(coxsackievirus adenovirus receptor)の発現を増強させることによって,アデノウイルス感染を促進することが報告されている。
    本研究では,腫瘍細胞の増殖抑制におけるFK228前処理とAd-p53遺伝子導入の相乗効果を,細胞レベルおよびマウスモデルで検討した。その結果,FK228前処理はCARの発現増強を介してAd-p53感染効率を2-5倍増加させることによって,癌細胞のアポトーシス誘導を増強した。また,FK228はp53タンパクのアセチル化も促進し,その結果Noxaの発現誘導を特異的に増加させた。さらに,FK228とAd-p53との併用は,Baxタンパクのミトコンドリアへの移行を促進した。アポトーシス誘導におけるFK228とAd-p53の相乗効果は,siRNAを用いたNoxaとBaxのノックダウンによって顕著に阻害された。ヌードマウスin vivo皮下移植モデルにおいて,p53遺伝子導入単独では増殖抑制の見られなかった癌細胞株においても,FK228との併用によってアポトーシスが誘導され,増殖抑制効果が認められた。本研究により,FK228はp53遺伝子治療との併用薬剤として有望と考えられる。

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  • デジタルゲノムスキャニング法の開発と消化器癌関連遺伝子探索への応用

    Grant number:17659415  2005 - 2006

    日本学術振興会  科学研究費助成事業  萌芽研究

    時野 隆至, 古畑 智久

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    Grant amount:\3300000 ( Direct Cost: \3300000 )

    癌遺伝子の増幅や癌抑制遺伝子の欠失を伴う染色体変化はがん細胞の特徴である.本研究では短いゲノム断片を解析しゲノム上のDNAコピー数以上を示す領域を検出する方法としてデジタルゲノムスキャニング(DGS: Digital Genome Scanning)法を開発し,胃癌細胞株におけるゲノムコピー数異常の検出を試みた.
    胃癌細胞株ゲノムDNAを制限酵素処理した断片を回収し,連結したクローニングしたDNA断片の塩基配列を決定した.取得した塩基配列をヒトゲノム上にマップし,ゲノム上での断片の分布密度をもとにコピー数異常を示す領域を推定した.DGSで予測されたゲノム増幅領域に存在する癌遺伝子の候補については,次に,Southern blot, FISH, real-time RT-PCR, Western blot法などの分子生物学的手法で検証を行った.このDGS解析により,胃癌細胞株の第12番染色体短腕約0.5Mbのゲノム増幅が同定され,同領域に存在する癌遺伝子K-rasのゲノム増幅を確認した.K-ras領域のゲノム増幅は胃癌細胞株18種中4種で,また臨床胃悪性腫瘍50例中4例で検出された.また,K-rasの遺伝子増幅を示した胃癌細胞株ではMAP kinase(ERK1/2)の恒常的活性化が観察された.
    以上より,DGS法はがんを代表とするゲノムコピー数異常を呈する疾患の原因遺伝子探索において有効な手法となりうることを実証した.

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  • p53転写制御因子ファミリーの細胞分化における役割

    Grant number:16026236  2004 - 2005

    日本学術振興会  科学研究費助成事業  特定領域研究

    佐々木 泰史, 時野 隆至

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    Grant amount:\3700000 ( Direct Cost: \3700000 )

    p53転写制御因子ファミリー(p53,p73,p63)は多彩な機能を有している.p53が代表的な癌抑制遺伝子であるのに対し,p63は,外胚葉性器官の発生や分化に,またp73は神経系の発生,炎症,アレルギーに関与していることが明らかになっている.我々もこれまでにp63およびp73がNotchシグナルを活性化できること,またp73がIL-4シグナルを介してT細胞の分化に関与していることを明らかにしてきた.本研究ではこれらの知見をさらに押し進め,p53ファミリーがどのような機構で増殖,分化,アポトーシスに関与しているかを明らかにすることを目標とし,以下の成果をあげた.
    1)p73,p63に特異的な標的遺伝子としてpigment epithelium derived factor(PEDF)を同定した。PEDF遺伝子のプロモーターにはp73,p63に特異的な応答性配列が認められ,PEDFの発現はp73またはp63によって誘導されたが,p53では誘導されなかった.また,p73を強制発現させたヒト大腸癌細胞株の培養上清を骨由来細胞に添加したところ,細胞の分化を誘導した.この効果はPEDFに対する中和抗体によって阻害されたことより,PEDFがp73,p63の下流で細胞分化に関わっていることが示唆された。
    2)p73,p63に特異的な標的遺伝子として細胞膜raftの主要構成分子をコードするflotillin-2を同定した.flotillin-2遺伝子のプロモーターにはp73,p63に特異的な応答性配列が認められた.さらに,p63を強発現させた細胞ではIL-6のシグナル経路が活性化しており,その効果はflotillin-2のsiRNAによって阻害された.以上の結果はp63あるいはp73がflotillin-2の発現調節を介して,細胞分化,炎症に関わっていることを示唆している.
    3)ゲノムデータベースからのp53ファミリーに特異的な結合配列を抽出し,その近傍の遺伝子を解析した.その結果vitamin D receptor遺伝子など,p53ファミリーの機能を媒介し直接実行する標的遺伝子を同定した.

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  • Diagnostic and therapeutic application of checkpoint gene CHFR in oral squamous cell cancer.

    Grant number:16390597  2004 - 2005

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    TOKINO Takashi, HIRATSUKA Hiroyoshi, KIDO Sachie

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    Grant amount:\13900000 ( Direct Cost: \13900000 )

    Alterations in the function of cell cycle checkpoints are frequently detected in oral squamous cell carcinomas (OSCCs), and are often associated with the sensitivity of the cancer cells to chemotherapeutic drugs. Recently, a mitotic checkpoint gene, Chfr, was shown to be inactivated by promoter methylation and point mutations in various human tumors. Here we show that the absence of its product, CHFR, is associated with mitotic checkpoint dysfunction, and that cancer cells lacking CHFR are sensitive to microtubule inhibitors. Checkpoint impairment appears to be caused by a prophase defect in this case, as OSCC cells lacking CHFR showed phosphorylation of histone H3 on Ser10 and translocation of cyclin B1 to the nucleus. When CHFR-deficient OSCC cells were treated with a microtubule inhibitor (docetaxel or paclitaxel), significant numbers of apoptotic cells were observed. Moreover, disruption of CHFR using small interfering RNA (siRNA) impaired the mitotic checkpoint, thereby reducing the ability of OSCC cells to arrest at G2/M phase and making them more sensitive to microtubule inhibitors. Our results suggest that CHFR could be a useful molecular target for chemotherapy.

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  • 卵巣癌におけるエピジェネティクスの異常の解析と治療への応用についての研究

    Grant number:15591769  2003 - 2005

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    藤井 美穂, 寒河江 悟, 豊田 実, 時野 隆至

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    Grant amount:\3400000 ( Direct Cost: \3400000 )

    MCA法による新しい遺伝子の同定:卵巣癌細胞株を用いMCA(methylated CpG island amplification)法により、正常細胞とでサブトラクションを行うことにより、卵巣癌での異常メチル化している多数の遺伝子を同定した。これは卵巣癌に抑制的に働く新たな遺伝子の発見につながるもので、現在遺伝子データベースを利用し各遺伝子について検討している。同時に各遺伝子のエピジェネティクな異常と卵巣癌での分子生物学的特徴について検討中である。
    TCF2遺伝子についての解析:上記のMCA法により、メチル化によりサイレンシングしている遺伝子の一つとしてTCF2遺伝子を同定した。TCF2は細胞の分化に関与する転写因子であり、各種腫瘍において発現異常が報告されている。実際卵巣癌ではTCF2遺伝子のメチル化は、卵巣癌細胞株16例中8例(50%)、卵巣癌症例68例中16例(23.5%)に認めた。メチル化を認める細胞株においては、発現の低下あるいは消失を認め、DNAメチル化阻害剤により遺伝子の再発現を認めた。また、プロモーター領域のヒストン脱アセチル化を認め、メチル化による遺伝子発現抑制にヒストン修飾が関与することが示唆された。さらに組織型別では明細胞性腺癌ではメチル化による抑制は少なく高頻度な発現が認められた。これは卵巣癌の中でも予後不良な明細胞性腺癌の生物学的解明につながる可能性がある。(投稿中)
    癌での細胞周期M期の制御の解析:これまで細胞周期M期に関わる遺伝子の異常と微小管阻害剤の感受性を検討してきた。ドセタキセルを暴露させたMitotic Indexの高い細胞株は抗癌剤に高い感受性を示し、CyclinBの核への集積が認められた。発現を調節している分子としてBUB1,MAD, Auroraなどの分子について検討中である。さらにCHFR遺伝子を細胞株に導入することによって、M期での分子制御機構の解明や抗癌剤の感受性の変化についても検討中である。

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  • 遺伝子あるいは発現プロテオミクス解析を用いた婦人科癌抗癌剤耐性の分子標的の研究

    Grant number:15591768  2003 - 2005

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    寒河江 悟, 寺澤 勝彦, 時野 隆志, 工藤 隆一

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    Grant amount:\2700000 ( Direct Cost: \2700000 )

    寒河江、寺澤らは、Paclitaxel, Docetaxel、新規抗癌剤Oxaliplatinに対してそれぞれ感受性のある細胞株、それらに対する耐性株を用いて、これら細胞株に一定時間、各種抗癌剤を暴露した後、その投与前後における薬剤耐性関連遺伝子群発現のパターンの変化をcDNAアレイなどを用いて検討した。現在、CDDP、Paclitaxel、Docetaxel、254-Sに対するCDDP、Paclitaxel感受性株、耐性株の薬剤投与前後のアレイパターンを解析して、それぞれの薬剤、細胞株に特異的な遺伝子群を検討し、薬剤耐性の機序を解析している。
    さらに寒河江、寺澤らは、蛋白レベルでの検討のため手術摘出物より極力プロテオリーシスの起きない状況下で蛋白サンプルを採取し、これを電気泳動により展開し、蛋白レベルでの抗癌剤耐性に関与する蛋白の変化をmRNAレベルでの変化と比較検討した。また蛋白質を2-D電気泳動で展開、分離し、2-Dマップを作製、薬剤毎、抗癌剤感受注毎にデータベース化を試みている。今後、こうしたDifferential proteomic displayにより、変化のあったスポットを酵素消化後、質量分析計あるいはシークエンサーにて同定を試みる予定である。これにより、各薬剤毎に薬剤感受性、耐性に関与する蛋白、特にアポトーシス関連蛋白を選定し、同蛋白に対する抗体の作製、及び同抗体の抗癌剤感受性及び耐性に及ぼす影響の実験の基礎としたいと考えている。

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  • Investigation of causative gene of familial occurrence of idiopathic occlusion of Willis ring

    Grant number:14370441  2002 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HOUKIN Kiyohiro, TOKINO Takashi, TADA Mitsuhiro

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    Grant amount:\13600000 ( Direct Cost: \13600000 )

    Purpose and Background:
    It is estimated that some genetic factors are closely related to the familial moyamoya disease. Previous microsatellite analysis has suggested that related genes may be located on chromosomes 3,8,12 and 17. However, the responsible gene has not been identified yet. This study aimed to identify the responsible genes that are located in the 17825 locus. In addition, clinical anticipation and the presence of triplet repeat was investigated and the basic FGF and HGF of the cerebrospinal fluid of moyamoya patients were measured.
    Methods and Results:
    Considering the function, we selected nine genes as candidates from a total of 65 genes identified in the 9-cM region of D17S785-D17S836 in chromosome 17825, and performed sequence analysis on the DNA samples obtained from a pedigree of familial moyamoya disease, which showed a complete linkage to the region by a haplotype analysis. Also, we attempted to identify candidate genes that have not been known but might be functionally relevant to the disease among a total of 2,100 expressed sequence tag (EST) sequences using bioinformatics techniques. As results, the sequence analysis could detect no mutation in the nine genes. Nor could we identify a novel candidate gene by the EST analysis.
    Clinical anticipation study was done based on 141 cases with moyamoya disease. This analysis revealed that apparent clinical anticipation was observed in familial moyamoya disease. No triplet repeat was found in 17g25 locus.
    Cerebrospinal fluid was obtained from the patients during surgery. Control value was measured using asymptomatic cerebral aneurysm patients and other ischemic cerebrovascular disease. As results, high value of basic FGF and HGF was seen in the cerebrospinal fluid of moyamoya patients compared to the control group.
    Conclusions:
    Clinical anticipation observed in familial moyamoya patients suggests that some triplet repeat may located in some gene in moyamoya disease. Further studies using alternative approaches are warranted to clarify the pathogenesis of moyamoya disease. However, our results of high level of some cytokines including basicFGF and HGF suggests that some gene abnormality related to these cytokines are closely involved the pathogenesis of moyamoya disease.

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  • 転写制御因子p63の発生,分化における役割

    Grant number:14033239  2002 - 2003

    日本学術振興会  科学研究費助成事業  特定領域研究

    佐々木 泰史, 時野 隆至

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    Grant amount:\4800000 ( Direct Cost: \4800000 )

    1.正常の発生段階あるいは細胞分化においてp53ファミリーメンバーの機能を媒介し直接実行する標的遺伝子を決定するために,p53ファミリーをいくつかのヒト癌細胞株に導入し、cDNA microarrayによる発現解析を行った.その結果,p73の特異的標的遺伝子としてIL-4Rα遺伝子を同定した.さらにIL-4Rαゲノムにp73タンパクと細胞内で特異的に結合する部位を同定し,p73がこの配列に結合することによりコファクターがリクルートされ,ヒストンのアセチル化が促進されることを明らかにした.またp73が活性化した細胞をIL-4で刺激すると,STAT6の活性化とアポトーシスが誘導され,この効果はIL-4Rの中和抗体により抑制された.この結果はp73がIL-4シグナルを介して細胞の分化,炎症,アレルギーに関わっていることを示唆している.
    2.p53ファミリー共通の標的遺伝子としてosteopontin(OPN)を同定した.OPNは主に活性化T細胞から分泌されるサイトカインで,骨組織の形成に不可欠だけでなく,B細胞の分化増殖や抗体産生能に重要な役割を果たしていることが示された.この結果はp53ファミリーの機能に関する新しい知見と考えられる.
    3.p53ファミリーにおいて最も最も高親和性で結合するDNA配列には違いがあり,スペイサーが介在するp53結合モチーフ配列RRRCWWGYYYの3コピー以上で構成される配列が,p63あるいはp73の高親和性応答配列として働くことが示唆された.従ってp53ファミリーは結合配列に対する親和性の違いにより標的遺伝子の使い分けをしており,生体においては単純に機能が重複している遺伝子ファミリーではないことを明らかにした.

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  • Function of p53 and its target genes

    Grant number:12213115  2000 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Priority Areas

    TOKINO Takashi

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    Grant amount:\66900000 ( Direct Cost: \66900000 )

    1. Novel p53-target genes : Tumor suppressor p53 is a transcription factor that induces growth arrest and/or apoptosis in response to cellular stress. To identify novel p53-inducible genes, we compared the expression of genes in normal mouse embryo fibroblasts to p53-null cells by cDNA representational difference analysis (RDA). We have identified that expression of endogenous SCN3B (sodium channel subunit beta 3) and OPN (osteopontin) are upregulated in mouse embryonic fibroblasts by DNA damage in a p53-dependent manner. The p53-directed regulation of OPN expression suggests a novel model of p53 participation in immunosurveillance, involving interaction with the host immune system to prevent damaged cells from undergoing malignant transformation. The results presented above also suggest that SCN3B mediates a p53-dependent apoptotic pathway and may be a candidate for gene therapy combined with anticancer drugs.
    2. Biological functions of the p53 family member genes : p63 and p73 were recently identified as members of the p53 gene family. In contrast to p53 however, p63 and p73 are rarely mutated in human cancers. To determine how p63 and p73 are involved in carcinogenesis and normal development, we attempted to identify target genes that are specifically regulated by p63 and/or p73 but not p53. We identified the JAG1 and JAG2 genes, encoding ligands for the Notch receptors, and the PEDF gene are direct target of p63 and p73. We also found that IL4 receptor alpha is upregulated by p73. These findings show an association between the p53 family genes and Notch signaling and suggest a potential molecular mechanism for the involvement of the p53 family genes in normal development. Our data also suggest that IL-4Ralpha could mediate, in part, certain immune responses and p73-dependent cell death.
    3. Adenovirus-mediated transfer of the p53 family genes, p73 and p63 induces cell cycle arrest and apoptosis in human cancer cell lines : p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro) are resistant to p53. To explore the potential use of two p53 homologues, p73 and p63, in cancer gene therapy, we introduced p53, p73 and p63 into colorectal cancer cell lines via adenoviral vectors, and compared their effects on cell growth. Among 10 cell lines tested, six cell lines displayed a similar response following transduction of p53, p73beta or p63gamma ; two lines underwent cell-cycle arrest, three lines exhibited apoptosis and one line showed no-effect following transduction. The effect on cell-cycle progression was variable in the other four cell lines. Interestingly, three cell lines were resistant to p53-mediated apoptosis, including two lines having endogenous wild-type p53 alleles, but underwent apoptosis after transduction of p73beta or p63gamma. Transduction of p73beta and p63gamma also reduced the tumorigenicity of two colorectal cancer cells in vivo. These results suggest that adenovirus-mediated p73beta and p63gamma transfer are potential novel approaches for the treatment of human cancers, particularly for tumors that are resistant to p53 gene therapy.

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  • Genetic analyses for DNA replication error, beta-catenin gene, SKT11 etc.among the patients with gynecologic cancer

    Grant number:11671636  1999 - 2001

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    SAGAE Satoru, KUDO Ryuichi, TOKINO Takashi, ISHIOKA Shinichi

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    Grant amount:\2200000 ( Direct Cost: \2200000 )

    The recent studies showed that the RER abnormalities were detected in 23 % for endometrial cancer and 3 % of ovarian cancer, which genetic changes were detected in only endometrioid type of cancer. The prognosis of RER positive patients (pts) with endometrial caner tended to be worse and among them a case with MMR gene mutation (hMLH1 etc) was detected.
    The mutation of beta-catenin gene were detected in 5 cases (8 %) of 61 ovarian cancer pts and 5 cases (14 %) of 35 endometrial cancer pts, and a micro metastasis of pelvic lymph node had a mutaton of beta-catenin gene,which might be useful for molecular diagnosis of lymph node metastasis.
    The putative SKT11 gene, which function is Serine/Threonine Kinase, was reported as causative gene of Peutz-Jegher Syndrome. We performed the mutational analysis of STK11 gene in 30 ovarian cancer pts by SSCP-Sequence method. Only one case showed its mutation of CCG-CTG(Pro281-Leu)at exon 6 and two cases showed extra bands at exon 5.
    A new anticancer drug group, Taxanes (Paclitaxel or Decetaxel) has been introduced for the treatment of ovarian cancer. However, chemosensitivities of these drugs are not determined before treatment of ovarian cancer. We tried to find out the possibilities of early detection of chemosensitivity by using genetic alteration, such as p53, BAX, Bcl-2 etc, and to analyze the mechanism of drug resistance. We showed that Paclitaxel-induced apoptosis played important roles of two different signal transductions, such as p53 independent pathway and stress-induced pathway in ovarian cancer cell lines, Blocking of these pathways and overexpression of bag-1 or hsp70 might be essential for the acquired resistance for Paclitaxel.

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  • ヨーロッパなどががん研究先進国との研究交流

    Grant number:09042009  1999

    日本学術振興会  科学研究費助成事業  特定領域研究(A)

    黒木 登志夫, 石川 冬木, 樋野 興夫, 菊池 章, 開 祐司, 宮園 浩平, 佐谷 秀行, 貝淵 弘三, 山本 雅, 時野 隆至, 秋山 徹, 高橋 雅英, 田中 信之, 武藤 誠, 堀井 明

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    Grant amount:\28700000 ( Direct Cost: \28700000 )

    1.研究背景: がん遺伝子の発見をきっかけに、がん研究は遺伝子の時代に入り、欧米のがん研究先進国を中心に激しい研究競争を繰り広げている。地理的に隔離されているわが国の研究者は、研究者との直接の討論、情報、資料交換に自ら制限があり、ともすると孤立しかねない。この問題点を克服するため、わが国の第一線の研究者を積極的にがん研究先進国に送る必要がある。本研究は、ヨーロッパのがん研究先進諸国との研究交流を目的に組織された。特に、日独、日仏がんワークショップはそれぞれ一年毎にヨーロッパ本国と日本と場所をかえて行われているが、本年度は日独をヨーロッパで、日仏を日本で開催した。本年度は10名をヨーロッパ諸国に派遣した。
    2.日独がん研究連絡会議: 1999年7月29〜31日独国・エッセン、エッセン大学において「分子細胞生物学的がん研究」に関する日独がんワークショップを開催した。わが国から黒木登志夫(昭和大・腫瘍分子研)、秋山 徹(東大・分生研)、菊池 章(広島大・医)、樋野興夫(癌研)、石川冬木(東工大・生命理工学)が本研究費で出席した。
    3.日仏がん研究連絡会議: 1999年9月8〜10日、東北大学・医学部において、「21世紀のがん研究に向けての新しい戦略」をテーマに日仏ワークショップが開催された。フランス側から12名、わが国からは黒木登志夫(昭和大・腫瘍分子研)、石川冬木(東工大・生命理工学)、宮園浩平(癌研)、広橋説御、塚田俊彦、落合孝広(国立がんセ・研)、渋谷正史、中村祐輔(東大・医科研)、中山敬一(九大・生医研)、月田承一郎、武田俊一(京大・医)、伊藤嘉明(京大・ウイルス研)、菅野晴夫(癌研)、豊島久真男(住友病院)が本研究費で出席した。
    4.その他の派遣者: 宮園浩平(癌研)、藤井穂高(東大・医)、丸義朗(東大・医科研)、開祐司(京大・再生医研)、千葉英樹(札幌医大・医)をヨーロッパの先進研究室に派遣した。

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  • Functional analysis of p53-target genes.

    Grant number:11138246  1999

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Priority Areas (A)

    TOKINO Takashi

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    Grant amount:\12500000 ( Direct Cost: \12500000 )

    We isolated p53-binding sites by genetic approach in yeast and then identified novel p53-target genes. One of these, called BAl1 , which was expressed in brain and repressed in 8/9 glioblastomas, was further characterized to inhibit neovascularization in the rat cornea by basic FGF.To investigate the in vivo anti-angiogenic effect of BAl1 gene on a human glioblastoma cell line, p53-defective human glioblastoma cells U373MG were transduced with the BAl1 gene using a recombinant adenoviral vector. In vivo neovascularization assay of the BAl1-infected glioblastoma cells was then performed using skinfold chamber system transplanted in SCID mice and revealed that BAl1 transduction resulted in reduced neovascurization in SCID mice.
    Expression of the glycosyl-phosphatidylinositol-anchored molecule-like protein (GML) gene, another p53 target, correlates with the sensitivity of some cancer cell lines to anticancer drugs and ionizing radiation. To investigate the function of GML further, we introduced the GML cDNA into various cancer cell lines under control of the tetracycline-regulated system. When we introduced GML into human glioblastoma cell line T98G, which lacks wild-type p53 and expresses no endogenous GML, we observed significant growth suppression accompanied by G2/M arrest in two independent, stable cell lines. We confirmed introduction of apoptosis by fluorescence-activated cell sorting (FACS) analysis and nuclear staining. Our results indicated that GML could induce apoptosis of T98G without functional p53, and implied that GML plays a crucial role in the apoptosis pathway in some cancer cells.

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  • 罹患同胞対法を用いた胃がん関連遺伝子の解明

    Grant number:10152102  1999

    日本学術振興会  科学研究費助成事業  特定領域研究(A)

    笹月 健彦, 松野 正紀, 横田 淳, 伊東 文生, 磨伊 正義, 三輪 晃一, 時野 隆至

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    Grant amount:\74000000 ( Direct Cost: \74000000 )

    胃がんの発症に寄与するがん関連遺伝子の単離を目的として、胃がん罹患同胞対検体収集、若年発症弧発胃がん症例検体の収集を継続し、罹患同胞対法による全ゲノムスキャニングを行った。
    1.17施設の臨床グループにより、胃がん同胞発症対から、インフォームド・コンセントに基づいて採血を行い、DNAの抽出・保存を行った。これまでに70組の同胞対検体が収集された。
    2.上記の胃がん同胞発症対57組に対して、4施設の解析グループにより400個のマイクロサテライトマーカーを用いたDNA多型解析を行った。MAPMAKER/SIBのプログラムを用いた連鎖解析を、全染色体について終了した。第1、8、9、11、21染色体において1.0以上のLOD値を示す領域を見出した。
    3.健常対対照群326人のDNAを利用して、日本人集団における各マーカーのアリル同定の作業を4施設の解析グループにより完了した。
    4.若年胃がん発症例(弧発例)の末梢血の採取を開始し、これまでに100人(発症時平均年齢41.6歳)のDNAが抽出・保存された。
    これまでの57組を対象とした解析において、1以上のLOD値を示す上記染色体が同定されたことは注目に値する。解析数を増やすこと、若年発症弧発例を用いて解析すること等により胃がん発症との関連を確認する。

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  • BAI1 expression in human glioma

    Grant number:10557127  1998 - 1999

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    ARITA Norio, NAKANO Atsuhisa, MATSUMOTO Tsuyoshi, KABA Keizo, TOKINO Takashi

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    Grant amount:\13400000 ( Direct Cost: \13400000 )

    BAI1, brain angiogenesis inhibitor 1, was originally isolated as a p53-target gene. BAI1 gene has a p53-binding sequence, and it was directly induced by wild-type p53. BAI1 protein has thrombospondin type 1 repeats which inhibit angiogenesis. In human gliomas, p53 mutation has been frequently observed. It might be possible that in gliomas with mutant p53, BAI1 expression reduced resulting in increased angiogenesis and enhanced tumor growth. We examined relationship between BAI1 expression, p53 mutation and aniogenesis using human glioma tissues. 〔Materials and methods〕 Using human glioma tissues obtained by surgery, (1) expression of the BAI1 gene, (2) mutation of the p53 gene, (3) correlation between BAI1 expression and p53 mutation, and (4) correlation between BAI1 expression and angiogenesis were studied. 〔Results〕 (1) BAI1 mRNA was semiquantitatively assayed by RT-PCR. Compared with that of normal brain tissue, it was reduced in 70% of the glioma examined. BAI1 expression was more frequently reduced in high grade gliomas. (2) Mutation of the p53 gene was analyzed by PCR-SSCP. P53 gene was mutated in 30% of the glioma. These mutation occurred in the locus affecting the transcription regulating capacity of the p53 gene. (3)No significant correlation was found between BAI1 expression and p53 mutation. (4) Glioma tissues were immunostained by an anti -CD34 antibody to examine the density of the tumor vessel. In the glioma in which BAI1 expression was reduced, number of the tumor vessels was increased as compared that of the glioma with normal BAI1 expression. 〔Discussion〕 These results indicate that in some glioma, BAI1 expression might be reduced by other factors than p53 mution. BAI1 protein overproduction by BAI1 gene transfer may inhibit angiogenesis in glioma with reduced BAI1 expression. In T98G and U87MG glioma cell lines, BAI1 gene is now tried to be transferred using Tet-On system to investigate how inhibition of the angiogenesis may influence on the glioma cell growth in vivo.

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  • Positional cloning of carnitine trasporter gene and its comtribution to the pathophysiological changes

    Grant number:08457267  1996 - 1997

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    KUWAJIMA Masamichi, TOKINO Takashi, MURAKAMI Takashi, NOMA Yoshihiko

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    Grant amount:\4700000 ( Direct Cost: \4700000 )

    The exact roles playd by carnitine in vivo have remained unclear. Our recent discovery of mice with systemic carnitine dificiency (JVS mice) offers the possibility of improvement of this circumstance. These JVS mice show symptoms such as fatty liver, hyperammonemia, hypoglycemia, cardiomegaly and skeletal muscle degeneration. We have been analyzin the histological, biochemical and molecular biological features of tissues from various sites of their bodies, focusing on the analysis of the relationship between carnitine deficiency and the diverse symptoms exhibited by these mice.
    We have obtained the following findings :
    1. As early as 2 weeks of age, JVS mice had higher absolute heart weights and higher retios of heart weight to body weight than controle mice. Hypertrophy of my ocardial cells was seen, and the nuclei of these cells tended to be larger in JVS mice. When observed under an electron microscope, the nuclei were slightly hypertrophic and not a few cells showed marked increase in mitochondria. The levels of carnitine palmitoyl transferase I (CPTI) mRNA and CPT II mRNA differted from those in controle mice.
    2. High-affinity carnitine transport activity was absent in the fibroblasts of JVS mice. This indicates that JVS mice can serve as an animal model of human primary carnitine dificiency.
    3. The symptoms seen in JVS mice are genetically transmitted in an autosomal recessive manner. It is thougt that a single gene is responsible for all these symptoms. The JVS gene was located on chromosome 11.

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  • 癌抑制遺伝子の単離とそのヒト癌における遺伝子異常の解明

    Grant number:06283226  1995

    日本学術振興会  科学研究費助成事業  重点領域研究

    時野 隆至, 中村 祐輔, 江見 充, 藤原 義之

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    Grant amount:\60000000 ( Direct Cost: \60000000 )

    32人の食道癌患者の種々の段階の106病変(異形成・早期癌・進行癌)における遺伝子異常を、マイクロサテライトマーカーを利用した染色体欠失を指標として解析し、3p,17pの癌抑制遺伝子の不活性化が異形成の段階ですでに起こっていることや9p,9qの癌抑制遺伝子の不活性化は癌化の段階で重要な役割をしていることなど、食道癌においても多段階的に遺伝子異常が蓄積されていることを明らかにした。また、種々の臓器の扁平上皮癌の発生に共通して関与していると考えられる第9染色体長腕の遺伝子については、数百kbの範囲まで癌抑制遺伝子の存在部位を限局化することができた。遺伝性癌の原因遺伝子のひとつであるMLH1遺伝子の変異を効率よく検索し発症前診断に応用するために、この遺伝子の全エキソンを1枚のゲルで解析するスクリーニング法を確立した。この方法によって全エキソンの変異の有無の検索を24時間以内に行うことが可能となった。さらに、リンパ節転移の有無を原発巣において認められる遺伝子異常を指標として遺伝子レベルで診断することの臨床的意義を調べるため、120例の病理組織学的にリンパ節転移陰性と診断された大腸癌患者についてレトロスペクティブに検討を行った。その結果、遺伝子診断はより正確な予後判定指標であり、術後の化学療法の適否を判断するための有用な指標になりうることが示唆された。また、抗p53抗体による免疫組織学的な検討の結果と遺伝子診断の結果との対比から、MASA法による解析によって生きた癌細胞のみならず、免疫細胞に呑食された癌細胞をも検出可能であることが示唆された。次に、p53蛋白の結合すると考えられるDNA断片を有するコスミドクローンを単離し、それらをもとに正常p53蛋白によって発現が誘導される2種類の新規の遺伝子の単離に成功した。

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  • がんの遺伝子診断

    Grant number:06282116  1994 - 1996

    日本学術振興会  科学研究費助成事業  重点領域研究

    珠玖 洋, 安井 弥, 高橋 隆, 森下 和廣, 時野 隆至, 金子 安比古, 谷口 直之

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    Grant amount:\100500000 ( Direct Cost: \100500000 )

    1.胃癌組織40例において、CDC25Aは45%、CDC25Bは70%(28症例)において発現増強が認められ、CDC25Cは全てで低発現だった。CDC25Bは低分化腺癌症例、ステージの進んだ症例に発現増強が認められた。又、分子病理診断の一つとしてCAr ep eatを2ローカス、polyAを2ローカス検討し、約5%の症例でreplication errorを同定した。分子病理診断は9000例にいたった。
    2.208症例の非小細胞癌症例でcyclinD1およびRb遺伝子の検討を行ったところ、cyclinD1遺伝子発現の消失がみられた腺癌症例は、有意に短い術後生存期間を示した。多変量解析でもcyclinD1はp53、病期と共に独立した有意な予後因子だった。
    3.神経芽腫106例を対象として、1p36のD1Z1と1q12のD1Z1プローブを用いてFISH法で検討した。D1Z1の数(n数)、およびD1Z1数に比してのD1Z2数(D1Z1>D1Z2;b;D1Z1=D1Z2;a)更に、RFLPマーカーによる1pのLCH、及びN-myc増幅を合わせて検討した。その結果、2nb、4nb腫瘍は予後不良、3n、5n腫瘍は予後良好、2na、4na腫瘍はその中間であった。
    4.急性骨髄性白血病における第三染色体の異常をEVI1遺伝子を中心として解析した。t(3;7)転座を有する症例、t(1;3)転座を有する症例の切断点および遺伝子を同定した。又40症例の白血病においてガングリオシドGM3からのGD3の合成酵素、α2,8シアル酸糖転移酵素の発現を検討したところ、T-ALLで中等度の、ATLで高い遺伝子発現が認められた。
    5.p53の下流標的遺伝子の検索を進め、8種類の正常型p53により発現制御される遺伝子を同定した。そのひとつはGPl anchor ed mol eculeに属する新しい遺伝子であり、その発現は食道癌細胞株の抗癌剤感受性と強い相関性を示した。
    6.AFPやγ-GTPの糖鎖に癌性変化を起こすα1,6 fucosyltr ansfer aseの精製を行いそのcDNAを単離した。

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  • 癌抑制遺伝子解析のためのヒト第3染色体遺伝的地図の作成および遺伝子の同定

    Grant number:02404080  1990 - 1991

    日本学術振興会  科学研究費助成事業  一般研究(A)

    中村 祐輔, 土屋 永寿, 北川 知行, 時野 隆至, 佐藤 孝明

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    Grant amount:\17700000 ( Direct Cost: \17700000 )

    癌における癌抑制遺伝子の異常は一般的に一方の染色体側の欠失と他方の染色体側の小さな変異(点変異や小さいDNA断片の挿入・欠失)として認められる。したがって、対象とする腫瘍組織において欠失している染色体部位を詳細に検討することにより、その腫瘍の発生に関与する癌抑制遺伝子の存在する位置を同定することが可能である。われわれは肺の非小細胞癌の発生に関わる癌抑制遺伝子を単離することを目的として49例の腺癌・18例の扁平上皮癌におけるヒト第3染色体短腕領域の欠失について、19のRFLPマ-カ-を利用して調べた。この結果、49例の腺癌のうち33例(67%)がこの染色体の欠失を起こしていたことが明かとなった。また、比較的多くの症例がこの染色体の一部分だけを欠失していることがわかった。さらに複数の腫瘍に共通して欠失している領域は3p21.3と3p14.1ー21.1の2領域であることが同定され、第3染色体上には肺の腺癌の発生に関与する癌抑制遺伝子は少なくとも2個存在すると推測される。さらに、染色体欠失の頻度とステ-ジを比較したところ、ステ-ジ1・2では30例中17例が欠失していた(57%)のに対し、ステ-ジ3では19例中16例(84%)の高頻度の欠失を認めた。また、病理学的分化度との対比では高分分子化癌では22例中12例(55%)の欠失頻度であったのに対し、未分化癌では7例中7例とも欠失していた。このことから、第3染色体上の癌抑制遺伝子の異常は肺腺癌の増悪因子としてとらえられるのではと考察される。また、扁平上皮癌では18例すべてにおいて、第3染色体短腕の欠失を認め、欠失領域も腺癌と比べて大きな領域であった。したがって、どの染色体の部位に問題となる遺伝子が存在するかを特定することはできなかった。今後は、さらに用いるRFLPマ-カ-の数を増やして、多数のサンプルを調べ、遺伝子の単離を目指したい。

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  • DNA増幅法(PCR法)による高多型VNTRマ-カ-の単離

    Grant number:02807212  1990 - 1991

    日本学術振興会  科学研究費助成事業  一般研究(C)

    時野 隆至

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    Grant amount:\1500000 ( Direct Cost: \1500000 )

    最近、多用されているミクロサテライトDNAの多型を効率よく同定する方法をテストした。ヒトゲノムコスミドライブラリ-に対してオリゴヌクレオチドCACACACACACACACACACAを用いてスクリ-ニングしたところ、約40%のクロ-ンが陽性であった。ミクロサテライト多型はくり返し配列の両側の配列を決定し、この配列からプライマ-を設計してPCR法(Polymerase Chain Reaction法)によりヒトゲノムDNAを増幅し、アクリルアミドゲル電気泳動によって長さに従ってDNAを分離することによって同定される。この際、最も労費を要するのはくり返し配列両側のDNAの配列を決定することである。そこでこのステップを簡便化するためにCAを10回くり返したオリゴヌクレオチドの3'側にA,GあるいはTを加えたもの、CC、CT、もしくはCGを加えたものの6種類のプライマ-をミックスしたものを直接コスミドのDNA配列を決定するプライマ-として用いた。この結果、約30%のクロ-ンがこれで直接配列を決定することが可能であった。3種類ずつにしたものでは約70%のクロ-ンがシ-クエンス可能であった。今後、この方法を利用してCAのくり返しによる多型を同定していくことが可能であると考える。

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  • 乳癌・大腸癌における癌抑制遺伝子の単離

    Grant number:02152121  1990

    日本学術振興会  科学研究費助成事業  がん特別研究

    中村 祐輔, 三木 義男, 西庄 勇, 時野 隆至, 佐藤 孝明

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    Grant amount:\10000000 ( Direct Cost: \10000000 )

    乳癌に関しては200例の乳癌患者の正常および癌組織よりDNAを抽出し、RFLPマ-カ-による染色体の欠失を調べた。全染色体にわたる40個のRFLPマ-カ-によって検索した結果、第3染色体(45%)、第13染色体長腕(28%)、第16染色体長腕(46%)、第17染色体短腕(57%)、第17染色体長腕(38%)に高頻度の欠失を認めたことから、これらの部位に癌抑制遺伝子の存在することが示唆された。また、erbB2遺伝子領域の増幅と第17染色体短腕の欠失との間強い相関(p<0.001)が認められたことから染色体の異常は独立しておこるのではなく、ひとつの異常が他の異常を起こし易くする可能性が考えられた。また、第13染色体の欠失も第17染色体の欠失が影響している可能性が示されるとともに、この染色体上の癌抑制遺伝子の欠失が、癌の増悪に関係することが病理学的な診断との比較により示唆された。また、それぞれの染色体における共通欠失領域の同定も行い、第3・16・17染色体については5〜10cMの領域に癌抑制遺伝子の存在部位を限定している。大腸癌については、第5染色体の家族性大腸腺腫症の原因遺伝子の検索を中心に研究を行った。一人の患者からの複数個の腺腫と癌における染色体欠失を調べたところすべての腫瘍が同一領域を欠失していたことから染色体欠失はランダムに起きるのではなく特別なメカニズムによって起こっていることが示唆された。さらに、家族性大腸腺腫症患者において同定した200kbの欠失領域近傍より単離した3種類のcDNAのひとつが大腸癌において欠損あるいはアミノ酸置換をおこす点変異を起こしていることが明かとなった。この遺伝子はG蛋白活性化ドメインと考えられる領域を有し、大腸癌の発生に関与する癌抑制遺伝子であり、MCC(Mutated in colorectal carcinoma)遺伝子と名付けた。

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