研究者詳細 - 丹下　正一朗

論文 - 丹下　正一朗

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Genetic Characteristics of Cutaneous, Acral, and Mucosal Melanoma in Japan

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 2024年11月

日本の一般健常人集団におけるBRCA1およびBRCA2バリアントの頻度と病原性(The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population)

井戸川雅史, 真里谷奨, 丹下正一朗, 櫻井晃洋, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 83回 J - 1048 2024年09月

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

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

The Journal of dermatology 2024年08月 [国際誌]

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.

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 ( (株)羊土社 ) 42 ( 9 ) 1414 - 1424 2024年06月

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

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

Cancers 16 ( 5 ) 2024年02月 [国際誌]

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.

Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR

Kojiro Ishibashi, Toshiya Ichinose, Riki Kadokawa, Ryo Mizutani, Sadahiro Iwabuchi, Sumihito Togi, Hiroki Ura, Shoichiro Tange, Keiko Shinjo, Jun Nakayama, Shigeki Nanjo, Yo Niida, Yutaka Kondo, Shinichi Hashimoto, Erik Sahai, Seiji Yano, Mitsutoshi Nakada, Eishu Hirata

Developmental Cell ( Elsevier BV ) 2024年02月 [査読有り]

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 ( (一社)日本癌学会 ) 82回 1242 - 1242 2023年09月

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

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

BMC cancer 23 ( 1 ) 85 - 85 2023年01月 [国際誌]

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.

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 ( (一社)日本癌学会 ) 81回 P - 3096 2022年09月

Prevalence of Pathogenic Germline BRCA1/2 Variants and Their Association with Clinical Characteristics in Patients with Epithelial Ovarian Cancer in a Rural Area of Japan

Akiko Abe, Issei Imoto, Shoichiro Tange, Masato Nishimura, Takeshi Iwasa

Genes 2022年06月

Inhibition of EGFR and MEK surmounts entrectinib resistance in a brain metastasis model of NTRK1-rearranged tumor cells.

Chiaki Suzuki, Akihiro Nishiyama, Sachiko Arai, Shoichiro Tange, Atsushi Tajima, Azusa Tanimoto, Koji Fukuda, Yohei Takumi, Hiroshi Kotani, Shinji Takeuchi, Naohiro Yanagimura, Koushiro Ohtsubo, Norio Yamamoto, Koichi Omori, Seiji Yano

Cancer science 113 ( 7 ) 2323 - 2335 2022年04月 [国際誌]

Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology-agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1-G595R. Repotrectinib is a second-generation TRK inhibitor, which is active against NTRK1-G595R. However, its efficacy against entrectinib-resistant tumors has not been fully elucidated. In the present study, we established entrectinib-resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1-rearranged KM12SM cells, and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1-G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal-regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.

Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma

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 77 ( 1 ) 77 - 91 2022年

Background and 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 and Results: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three 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 cadherin-associated protein beta 1 (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. Patients with steatotic HCC, 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.

Detection of novel fusion genes by next-generation sequencing-based targeted RNA sequencing analysis in adenoid cystic carcinoma of head and neck

Eri Shibata, Kei-ichi Morita, Kou Kayamori, Shoichiro Tange, Hiroki Shibata, Yosuke Harazono, Yasuyuki Michi, Tohru Ikeda, Hiroyuki Harada, Issei Imoto, Tetsuya Yoda

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology ( Mosby Inc. ) 132 ( 4 ) 426 - 433 2021年10月

Objective: Adenoid cystic carcinoma (AdCC) is a rare, indolent salivary gland tumor that is reported to be driven by fusion genes. However, MYB/MYBL1-NFIB fusions have been detected in < 60% of all AdCC cases and the oncogenic driver mutations in approximately 40% of AdCC remain unknown. Our aim was to identify novel gene fusions in AdCC. Study Design: We investigated 20 AdCC cases using a targeted RNA sequencing panel to identify gene fusions and performed quantitative real-time reverse transcription polymerase chain reaction to assess MYB, MYBL1, and NFIB expression levels. Results: A total of 36 fusion transcripts in 15 cases were detected and validated by Sanger sequencing. The MYB-NFIB and MYBL1-NFIB fusion genes were detected in 9 and 3 cases, respectively, in a mutually exclusive manner. Furthermore, novel gene fusions, namely, NFIB-EPB41L2, MAP7-NFIB, NFIB-MCMDC2, MYBL1-C8orf34, C8orf34-NFIB, and NFIB-CASC20, were identified. Among them, NFIB-EPB41L2 and NFIB-MCMDC2 are thought to activate MYB and MYBL1 expression, respectively, through the insertion of a genomic segment in proximity to MYB and MYBL1 genes, respectively. Conclusion: Six novel gene fusions other than MYB/MYBL1-NFIB were identified. The detection of novel fusion genes and investigation of the molecular mechanism will contribute to the development of novel molecular targeted therapies for this disease.

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

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年09月 [国際誌]

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.

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

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

Cancer biology & therapy 22 ( 10-12 ) 1 - 2 2021年09月 [国際誌]

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.

Genetic analyses of a secondary poroma and trichoblastoma in a HRAS‐mutated sebaceous nevus

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

The Journal of Dermatology 2021年08月

Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1.

Issei Imoto, Masako Saito, Kenichi Suga, Tomohiro Kohmoto, Masanobu Otsu, Keisuke Horiuchi, Hironao Nakayama, Shigeki Higashiyama, Mayumi Sugimoto, Ayumi Sasaki, Yukako Homma, Miki Shono, Ryuji Nakagawa, Yasunobu Hayabuchi, Shoichiro Tange, Shoji Kagami, Kiyoshi Masuda

Scientific reports 11 ( 1 ) 9552 - 9552 2021年05月 [査読有り] [国際誌]

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17-/- mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

Proteasomal degradation of polycomb-group protein CBX6 confers MMP-2 expression essential for mesothelioma invasion

Katsuya Sakai, Takumi Nishiuchi, Shoichiro Tange, Yoshinori Suzuki, Seiji Yano, Minoru Terashima, Takeshi Suzuki, Kunio Matsumoto

Scientific Reports ( Springer Science and Business Media LLC ) 10 ( 1 ) 2020年12月

Abstract The aggressive invasiveness of malignant mesothelioma limits cancer therapy, however, the molecular mechanisms underlying the invasiveness remain largely unknown. Here we found that the matrix metalloproteinase-2 (MMP-2) was required for the invasion of mesothelioma cells in the collagen matrix and the gene expression of MMP-2 was correlated with the invasive phenotype. The MMP-2 gene expression was regulated by DNA and histone methylation around the transcription start site, implicating the involvement of the polycomb repressive complex (PRC). Knockdown of PRC component chromobox 6 (CBX6) promoted MMP-2 expression and invasion of mesothelioma cells. Transcriptome analysis suggested that CBX6 regulates sets of genes involved in cancer cell migration and metastasis. In invasive but not non-invasive cells, CBX6 was constantly unstable owing to ubiquitination and protein degradation. In human tissues, CBX6 localized in the nuclei of normal mesothelium and benign mesothelioma, but the nuclear staining of CBX6 was lost in malignant mesothelioma. These results suggest involvement of proteasomal degradation of CBX6 in mesothelioma progression.

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 ( (一社)日本癌学会 ) 79回 OJ4 - 3 2020年10月

Claudin-6 is a single prognostic marker and functions as a tumor-promoting gene in a subgroup of intestinal type gastric cancer.

Tomohiro Kohmoto, Kiyoshi Masuda, Katsutoshi Shoda, Rizu Takahashi, Sae Ujiro, Shoichiro Tange, Daisuke Ichikawa, Eigo Otsuji, Issei Imoto

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 23 ( 3 ) 403 - 417 2020年05月 [国内誌]

BACKGROUND: We aimed to identify novel tumor-promoting drivers highly expressed in gastric cancer (GC) that contribute to worsened prognosis in affected patients. METHODS: Genes whose expression was increased and correlated with worse prognosis in GC were screened using datasets from the Cancer Genome Atlas and Gene Expression Omnibus. We examined Claudin-6 (CLDN6) immunoreactivity in GC tissues and the effect of CLDN6 on cellular functions in GC cell lines. The mechanisms underlying GC-promoting function of CLDN6 were also investigated. RESULTS: CLDN6 was identified as a gene overexpressed in GC tumors as compared with adjacent non-tumorous tissues and whose increased expression was positively correlated with worse overall survival of GC patients, particularly those with Lauren's intestinal type GC, in data from multiple publicly available datasets. Additionally, membranous CLDN6 immunoreactivity detected in intestinal type GC tumors was correlated with worse overall survival. In CLDN6-expressing GC cells, silencing of CLDN6 inhibited cell proliferation and migration/invasion abilities, possibly via suppressing transcription of YAP1 and its downstream transcriptional targets at least in part. CONCLUSIONS: This study identified CLDN6 as a GC-promoting gene, suggesting that CLDN6 to be a possible single prognostic marker and promising therapeutic target for a subset of GC patients.

p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53.

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

Oncogene 39 ( 10 ) 2202 - 2211 2020年03月 [査読有り] [国際誌]

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.

Renal angiomyolipoma (AML) harboring a missense mutation of TSC2 with copy-neutral loss of heterozygosity (CN-LOH)

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 2019年12月 [査読有り] [国際誌]

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.

A novel long non-coding RNA from the HOXA6-HOXA5 locus facilitates colon cancer cell growth

Shoichiro Tange

BMC Cancer 2019年12月 [査読有り]

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 ( (一社)日本癌学会 ) 78回 J - 3018 2019年09月

Prognostic significance of GAD1 overexpression in patients with resected lung adenocarcinoma

Mitsuhiro Tsuboi, Kazuya Kondo, Kiyoshi Masuda, Shoichiro Tange, Koichiro Kajiura, Tomohiro Kohmoto, Hiromitsu Takizawa, Issei Imoto, Akira Tangoku

Cancer Medicine 8 ( 9 ) 4189 - 4199 2019年06月 [査読有り] [国際誌]

BACKGROUND AND OBJECTIVES: In a previous genome-wide screening, we identified hypermethylated CpG islands around glutamate decarboxylase 1 (GAD1) in lung adenocarcinoma (LADC). In this study, we aimed to investigate the methylation and expression status of GAD1 and its prognostic value in patients with LADC. METHODS: GAD1 methylation and mRNA expression status were analyzed using 33 tumorous and paired non-tumorous LADC samples and publicly available datasets. The prognostic value of GAD1 overexpression was investigated using publicly available datasets of mRNA levels and 162 cases of LADC by immunohistochemistry. RESULTS: The methylation and mRNA expression levels of GAD1, each having a positive correlation, were significantly higher in LADC tumors than in paired non-tumorous tissues. LADC patients with higher GAD1 mRNA expression showed significantly poorer prognosis for overall survival in publicly available datasets. Higher immunoreactivity of GAD1 was significantly associated with the pathological stage, pleural invasion, lymph vessel invasion, and poorer prognosis for cancer-specific and disease-free survival. Multivariate analysis revealed that GAD1 protein overexpression is an independent prognosticator for disease-free survival. CONCLUSIONS: GAD1 mRNA and protein expression levels were significant prognostic factors in LADC, suggesting that they might be useful biomarkers to stratify patients with worse clinical outcomes after resection.

Retinoblastoma inactivation induces a protumoral microenvironment via enhanced CCL2 secretion

Fengkai Li, Shunsuke Kitajima, Susumu Kohno, Akiyo Yoshida, Shoichiro Tange, Soichiro Sasaki, Nobuhiro Okada, Yuuki Nishimoto, Hayato Muranaka, Naoko Nagatani, Misa Suzuki, Sayuri Masuda, Tran C. Thai, Takumi Nishiuchi, Tomoaki Tanaka, David A. Barbie, Naofumi Mukaida, Chiaki Takahashi

Cancer Research ( American Association for Cancer Research ({AACR}) ) 79 ( 15 ) canres.3604.2018 - 3915 2019年06月 [査読有り] [国際誌]

Cancer cell-intrinsic properties caused by oncogenic mutations have been well characterized; however, how specific oncogenes and tumor suppressors impact the tumor microenvironment (TME) is not well understood. Here, we present a novel non-cell-autonomous function of the retinoblastoma (RB) tumor suppressor in controlling the TME. RB inactivation stimulated tumor growth and neoangiogenesis in a syngeneic and orthotropic murine soft-tissue sarcoma model, which was associated with recruitment of tumor-associated macrophages (TAM) and immunosuppressive cells such as Gr1+CD11b+ myeloid-derived suppressor cells (MDSC) or Foxp3+ regulatory T cells (Treg). Gene expression profiling and analysis of genetically engineered mouse models revealed that RB inactivation increased secretion of the chemoattractant CCL2. Furthermore, activation of the CCL2-CCR2 axis in the TME promoted tumor angiogenesis and recruitment of TAMs and MDSCs into the TME in several tumor types including sarcoma and breast cancer. Loss of RB increased fatty acid oxidation (FAO) by activating AMP-activated protein kinase that led to inactivation of acetyl-CoA carboxylase, which suppresses FAO. This promoted mitochondrial superoxide production and JNK activation, which enhanced CCL2 expression. These findings indicate that the CCL2-CCR2 axis could be an effective therapeutic target in RB-deficient tumors. SIGNIFICANCE: These findings demonstrate the cell-nonautonomous role of the tumor suppressor retinoblastoma in the tumor microenvironment, linking retinoblastoma loss to immunosuppression.

Upregulation of CHOP participates in caspase activation and virus release in human astrovirus-infected cells.

Isobe T, Tange S, Tasaki H, Kanamori K, Kato A, Nakanishi A

The Journal of general virology ( Microbiology Society ) 100 ( 5 ) 778 - 792 2019年05月 [査読有り]

Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer.

Kitajima S, Ivanova E, Guo S, Yoshida R, Campisi M, Sundararaman SK, Tange S, Mitsuishi Y, Thai TC, Masuda S, Piel BP, Sholl LM, Kirschmeier PT, Paweletz CP, Watanabe H, Yajima M, Barbie DA

Cancer discovery 9 ( 1 ) 34 - 45 2018年10月 [査読有り] [国際誌]

KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL)-mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS-mutant lung cancers, remains obscure. Here, we report that LKB1 loss results in marked silencing of stimulator of interferon genes (STING) expression and insensitivity to cytoplasmic double-strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape. SIGNIFICANCE: Oncogenic KRAS-mutant lung cancers remain treatment-refractory and are resistant to ICB in the setting of LKB1 loss. These results begin to uncover the key underlying mechanism and identify strategies to restore STING expression, with important therapeutic implications because mitochondrial dysfunction is an obligate component of this tumor subtype.See related commentary by Corte and Byers, p. 16.This article is highlighted in the In This Issue feature, p. 1.

RNA結合蛋白質の機能調節を目指した食道癌治療戦略

増田清士, 河本知大, 丹下正一朗, 井本逸勢

細胞 ( (株)ニュー・サイエンス社 ) 50 ( 11 ) 599 - 602 2018年10月

ゲノムDNA上の遺伝子情報が、機能分子である蛋白質に翻訳されるまでの間には、様々な品質管理や制御機構が介在している。中でもDNAから転写された後のRNAレベルでの遺伝子発現制御機構(転写後調節機構)は、発生や分化といった高次生命現象において重要な役割を担うだけでなく、その機能異常が癌を含む様々な疾患形成に関与していることが明らかとなり、注目されている。我々は、この中核を担う因子であるRNA結合蛋白質(RBP)に着目して研究を行い、食道扁平上皮癌で癌促進的に機能するRBPを複数同定した。本稿では、我々が見いだした癌促進型RBPの機能とこれに関わる分子機構ならびにこれらの効果的修飾法の探索について概説する。(著者抄録)

Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.

Kitajima S, Asahina H, Chen T, Guo S, Quiceno LG, Cavanaugh JD, Merlino AA, Tange S, Terai H, Kim JW, Wang X, Zhou S, Xu M, Wang S, Zhu Z, Thai TC, Takahashi C, Wang Y, Neve R, Stinson S, Tamayo P, Watanabe H, Kirschmeier PT, Wong KK, Barbie DA

Cancer cell 34 ( 3 ) 439 - 452.e6 2018年09月 [査読有り] [国際誌]

Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.

Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion-Positive Tumor Cells in a Brain Metastasis Model.

Akihiro Nishiyama, Tadaaki Yamada, Kenji Kita, Rong Wang, Sachiko Arai, Koji Fukuda, Azusa Tanimoto, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Noritaka Furuya, Takayoshi Kinoshita, Seiji Yano

Clinical cancer research : an official journal of the American Association for Cancer Research 24 ( 10 ) 2357 - 2369 2018年05月 [査読有り] [国際誌]

Purpose: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. The CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics.Experimental Design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors.Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1 The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation.Conclusions: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases. Clin Cancer Res; 24(10); 2357-69. ©2018 AACR.

A rare male patient with classic Rett syndrome caused by MeCP2_e1 mutation.

Narumi Tokaji, Hiromichi Ito, Tomohiro Kohmoto, Takuya Naruto, Rizu Takahashi, Aya Goji, Tatsuo Mori, Yoshihiro Toda, Masako Saito, Shoichiro Tange, Kiyoshi Masuda, Shoji Kagami, Issei Imoto

American journal of medical genetics. Part A 176 ( 3 ) 699 - 702 2018年03月 [査読有り] [国際誌]

Rett syndrome (RTT) is a severe neurodevelopmental disorder typically affecting females. It is mainly caused by loss-of-function mutations that affect the coding sequence of exon 3 or 4 of methyl-CpG-binding protein 2 (MECP2). Severe neonatal encephalopathy resulting in death before the age of 2 years is the most common phenotype observed in males affected by a pathogenic MECP2 variant. Mutations in MECP2 exon 1 affecting the MeCP2_e1 isoform are relatively rare causes of RTT in females, and only one case of a male patient with MECP2-related severe neonatal encephalopathy caused by a mutation in MECP2 exon 1 has been reported. This is the first reported case of a male with classic RTT caused by a 5-bp duplication in the open-reading frame of MECP2 exon 1 (NM_001110792.1:c.23_27dup) that introduced a premature stop codon [p.(Ser10Argfs*36)] in the MeCP2_e1 isoform, which has been reported in one female patient with classic RTT. Therefore, both males and females displaying at least some type of MeCP2_e1 mutation may exhibit the classic RTT phenotype.

In vivo imaging xenograft models for the evaluation of anti-brain tumor efficacy of targeted drugs.

Kenji Kita, Sachiko Arai, Akihiro Nishiyama, Hirokazu Taniguchi, Koji Fukuda, Rong Wang, Tadaaki Yamada, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Mitsutoshi Nakada, Kazuo Yasumoto, Yoshiharu Motoo, Takashi Murakami, Seiji Yano

Cancer medicine ( Wiley ) 6 ( 12 ) 2972 - 2983 2017年12月 [査読有り] [国際誌]

Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)-dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3-NTRK1 gene fusion. We investigated the efficacy of targeted drugs by comparison with their effect in extracranial models. In vitro, H1975 cells were sensitive to the third-generation epidermal growth factor receptor inhibitor osimertinib. Moreover, HGF stimulated the proliferation of NUGC4 cells, that was inhibited by crizotinib, which has anti-MET activity. KM12SM cells were sensitive to the tropomyosin-related kinase-A inhibitors crizotinib and entrectinib. In in vivo H1975 cell models, osimertinib inhibited the progression of both brain and subcutaneous tumors. Furthermore, in in vivo NUGC4 cell models, crizotinib remarkably delayed the progression of brain tumors, and that of peritoneal carcinomatosis. Interestingly, in in vivo KM12SM cell models, treatment with crizotinib delayed the progression of liver metastases, but not that of brain tumors. Conversely, treatment with entrectinib discernibly delayed the progression of both tumor types. Thus, the effect of targeted drugs against brain tumors can differ from the one reported in extracranial tumors. Moreover, the same multikinase inhibitory drug can display different efficacies in brain tumor models containing different drivers. Therefore, our in vivo imaging model for brain tumors may prove useful for preclinical drug screening against brain metastases.

KH-type splicing regulatory protein is involved in esophageal squamous cell carcinoma progression.

Yuji Fujita, Kiyoshi Masuda, Junichi Hamada, Katsutoshi Shoda, Takuya Naruto, Satoshi Hamada, Yuko Miyakami, Tomohiro Kohmoto, Miki Watanabe, Rizu Takahashi, Shoichiro Tange, Masako Saito, Yasusei Kudo, Hitoshi Fujiwara, Daisuke Ichikawa, Akira Tangoku, Eigo Otsuji, Issei Imoto

Oncotarget 8 ( 60 ) 101130 - 101145 2017年11月 [査読有り] [国際誌]

KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC.

Construction of a combinatorial pipeline using two somatic variant calling methods for whole exome sequence data of gastric cancer.

Kohmoto T, Masuda K, Naruto T, Tange S, Shoda K, Hamada J, Saito M, Ichikawa D, Tajima A, Otsuji E, Imoto I

The journal of medical investigation : JMI 64 ( 3.4 ) 233 - 240 2017年 [査読有り] [国内誌]

High-throughput next-generation sequencing is a powerful tool to identify the genotypic landscapes of somatic variants and therapeutic targets in various cancers including gastric cancer, forming the basis for personalized medicine in the clinical setting. Although the advent of many computational algorithms leads to higher accuracy in somatic variant calling, no standard method exists due to the limitations of each method. Here, we constructed a new pipeline. We combined two different somatic variant callers with different algorithms, Strelka and VarScan 2, and evaluated performance using whole exome sequencing data obtained from 19 Japanese cases with gastric cancer (GC); then, we characterized these tumors based on identified driver molecular alterations. More single nucleotide variants (SNVs) and small insertions/deletions were detected by Strelka and VarScan 2, respectively. SNVs detected by both tools showed higher accuracy for estimating somatic variants compared with those detected by only one of the two tools and accurately showed the mutation signature and mutations of driver genes reported for GC. Our combinatorial pipeline may have an advantage in detection of somatic mutations in GC and may be useful for further genomic characterization of Japanese patients with GC to improve the efficacy of GC treatments. J. Med. Invest. 64: 233-240, August, 2017.

DOT1L histone methyltransferase regulates the expression of BCAT1 and is involved in sphere formation and cell migration of breast cancer cell lines

Dulamsuren Oktyabri, Akihiko Ishimura, Shoichiro Tange, Minoru Terashima, Takeshi Suzuki

BIOCHIMIE ( ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER ) 123 20 - 31 2016年04月 [査読有り]

DOT1L is a histone H3 lysine 79 (H3K79) methyltransferase mainly implicated in leukemia. Here we analyzed the function of DOT1L in breast cancer cells. The expression of DOT1L was up-regulated in malignant breast cancer tissues. Over-expression of DOT1L significantly increased the sphere formation and the cell migration activities of MCF7 breast cancer cell line. In contrast, knockdown of DOT1L reduced the cell migration activity of MDA-MB-231 breast cancer cell line. BCAT1, which encodes a branched-chain amino acid transaminase, was identified as one of the target genes controlled by DOT1L through the regulation of H3K79 methylation. Mechanistic investigation revealed that BCAT1 might be an important regulator responsible for DOT1L-mediated sphere formation and cell migration in breast cancer cells. (C) 2016 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

Examination of a plasmid-based reverse genetics system for human astrovirus

Benoit Chapellier, Shoichiro Tange, Hidetaka Tasaki, Kazuhiro Yoshida, Yan Zhou, Naomi Sakon, Kazuhiko Katayama, Akira Nakanishi

MICROBIOLOGY AND IMMUNOLOGY ( WILEY-BLACKWELL ) 59 ( 10 ) 586 - 596 2015年10月 [査読有り]

A plasmid-based reverse genetics system for human astrovirus type 1 (HAstV1) is examined. Upon transfection into 293T cells, the plasmid vector, which harbors a HAstV1 expression cassette, expressed astroviral RNA that appeared to be capable of viral RNA replication, as indicated by the production of subgenomic RNA and capsid protein expression irrespective of the heterologous 5 ends of the transcribed RNA. Particles infectious to Caco-2 cells were made in this system; however, their infectivity was much lower than would be expected from the amount of particles apparently produced. Using Huh-7 cells as the transfection host with the aim of improving viral capsid processing for virion maturation partially restored the efficiency of infectious particle formation. Our results support the possibility that the DNA transfection process induces a cellular response that targets late, but not early, stages of HAstV1 infection.

JARID2 Is Involved in Transforming Growth Factor-Beta-Induced Epithelial-Mesenchymal Transition of Lung and Colon Cancer Cell Lines

Shoichiro Tange, Dulamsuren Oktyabri, Minoru Terashima, Akihiko Ishimura, Takeshi Suzuki

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 9 ( 12 ) e115684 2014年12月 [査読有り]

担当区分：筆頭著者

Histone methylation plays a crucial role in various biological and pathological processes including cancer development. In this study, we discovered that JARID2, an interacting component of Polycomb repressive complex-2 (PRC2) that catalyzes methylation of lysine 27 of histone H3 (H3K27), was involved in Transforming Growth Factor-beta (TGF-beta)-induced epithelial-mesenchymal transition (EMT) of A549 lung cancer cell line and HT29 colon cancer cell line. The expression of JARID2 was increased during TGF-beta-induced EMT of these cell lines and knockdown of JARID2 inhibited TGF-beta-induced morphological conversion of the cells associated with EMT. JARID2 knockdown itself had no effect in the expression of EMT-related genes but antagonized TGF-beta-dependent expression changes of EMT-related genes such as CDH1, ZEB family and microRNA-200 family. Chromatin immunoprecipitation assays showed that JARID2 was implicated in TGF-beta-induced transcriptional repression of CDH1 and microRNA-200 family genes through the regulation of histone H3 methylation and EZH2 occupancies on their regulatory regions. Our study demonstrated a novel role of JARID2 protein, which may control PRC2 recruitment and histone methylation during TGF-beta-induced EMT of lung and colon cancer cell lines.

EED regulates epithelial-mesenchymal transition of cancer cells induced by TGF-β.

Oktyabri D, Tange S, Terashima M, Ishimura A, Suzuki T

Biochemical and biophysical research communications ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 453 ( 1 ) 124 - 130 2014年10月 [査読有り]

Histone methylation is involved in various biological and pathological processes including cancer development. In this study, we found that EED, a component of Polycomb repressive complex-2 (PRC2) that catalyzes methylation of lysine 27 of histone H3 (H3K27), was involved in epithelial-mesenchymal transition (EMT) of cancer cells induced by Transforming Growth Factor-beta (TGF-beta). The expression of EED was increased during TGF-beta-induced EMT and knockdown of EED inhibited TGF-beta-induced morphological conversion of the cells associated with EMT. EED knockdown antagonized TGF-beta-dependent expression changes of EMT-related genes such as CDH1, ZEB1, ZEB2 and microRNA-200 (miR-200) family. Chromatin immunoprecipitation assays showed that EED was implicated in TGF-beta-induced transcriptional repression of CDH1 and miR-200 family genes through the regulation of histone H3 methylation and EZH2 occupancies on their regulatory regions. Our study demonstrated a novel role of EED, which regulates PRC2 activity and histone methylation during TGF-beta-induced EMT of cancer cells. (C) 2014 Elsevier Inc. All rights reserved.

KDM5B histone demethylase controls epithelial-mesenchymal transition of cancer cells by regulating the expression of the microRNA-200 family.

Zanabazar Enkhbaatar, Minoru Terashima, Dulamsuren Oktyabri, Shoichiro Tange, Akihiko Ishimura, Seiji Yano, Takeshi Suzuki

Cell cycle (Georgetown, Tex.) 12 ( 13 ) 2100 - 12 2013年07月 [査読有り] [国際誌]

Histone methylation is implicated in various biological and pathological processes including cancer development. In this study, we discovered that ectopic expression of KDM5B, a histone H3 lysine 4 (H3K4) demethylase, promoted epithelial-mesenchymal transition (EMT) of cancer cells. KDM5B increased the expression of transcription factors, ZEB1 and ZEB2, followed by downregulation of E-cadherin and upregulation of mesenchymal marker genes. The expression of the microRNA-200 (miR-200) family, which specifically targets ZEB1 and ZEB2, was reduced in the cells with KDM5B overexpression. We found that KDM5B repressed the expression of the miR-200 family by changing histone H3 methylation status of their regulatory regions. The introduction of miR-200 precursor in the cells inhibited EMT induction by KDM5B, suggesting that miR-200 family was a critical downstream mediator of KDM5B-promoted EMT. Furthermore, knockdown of KDM5B was shown to affect the expression of EMT-related genes, indicating the involvement of endogenous KDM5B. Our study demonstrated a novel role of KDM5B histone lysine demethylase in EMT, which may contribute to malignant progression of cancer.

Roles of histone methyl-modifying enzymes in development and progression of cancer

Takeshi Suzuki, Minoru Terashima, Shoichiro Tange, Akihiko Ishimura

Cancer Science ( Wiley ) 104 ( 7 ) 795 - 800 2013年05月

Initiation of human astrovirus type 1 infection was blocked by inhibitors of phosphoinositide 3-kinase

Shoichiro Tange, Yan Zhou, Yuko Nagakui-Noguchi, Takeshi Imai, Akira Nakanishi

VIROLOGY JOURNAL ( BIOMED CENTRAL LTD ) 10 153 2013年05月 [査読有り]

Background: Upon initial contact with a virus, host cells activate a series of cellular signaling cascades that facilitate viral entry and viral propagation within the cell. Little is known about how the human astrovirus (HAstV) exploits signaling cascades to establish an infection in host cells. Recent studies showed that activation of extracellular signal-regulated kinase 1/2 (ERK1/2) is important for HAstV infection, though the involvement of other signaling cascades remains unclear. Methods: A panel of kinase blockers was used to search for cellular signaling pathways important for HAstV1 infection. To determine their impact on the infectious process, we examined viral gene expression, RNA replication, and viral RNA and capsid protein release from host cells. Results: Inhibitors of phosphoinositide 3-kinase (PI3K) activation interfered with the infection, independent of their effect on ERK 1/2 activation. Activation of the PI3K signaling cascade occurred at an early phase of the infection, judging from the timeframe of Akt phosphorylation. PI3K inhibition at early times, but not at later times, blocked viral gene expression. However, inhibiting the downstream targets of PI3K activation, Akt and Rac1, did not block infection. Inhibition of protein kinase A (PKA) activation was found to block a later phase of HAstV1 production. Conclusions: Our results reveal a previously unknown, essential role of PI3K in the life cycle of HAstV1. PI3K participates in the early stage of infection, possibly during the viral entry process. Our results also reveal the role of PKA in viral production.

An SV40 mutant defective in VP4 expression exhibits a temperature-sensitive growth defect

Shoichiro Tange, Takeshi Imai, Akira Nakanishi

VIRUS RESEARCH ( ELSEVIER SCIENCE BV ) 157 ( 1 ) 116 - 120 2011年04月 [査読有り]

On reexamination of temperature-sensitive D-type (tsD) mutants of simian virus 40 (SV40), we found that the tsD222 mutant is identical to the VP2 M228I mutant, which is defective in VP4 expression, at the nucleotide level. Although a previous study reported that lack of VP4 caused defects in viral dissemination in BSC-1 cells, this mutant showed a temperature-sensitive growth defect in CV-1 cells. tsD101:VP3 Q113K and tsD202:VP3 P108S exhibited a growth phenotype similar to that of tsD222, and they retained the VP4 open reading frame (ORF). These three mutants did not complement each other, suggesting that their defects were functionally indistinguishable. Transduction of the SV40 vector expressing wild-type VP4 in tsD222-infected cells did not ameliorate the growth defect at the non-permissive temperature. The results indicate that tsD mutation in minor capsid proteins has a more profound impact on viral propagation, and that lack of VP4 ORF seems to have little influence on viral growth. (C) 2011 Elsevier B.V. All rights reserved.

Phosphorylation of histone H3 at Ser10: Its role in cell transformation by v-Src

Shoichiro Tange, Satoko Ito, Takeshi Senga, Michinari Hamaguchi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 386 ( 4 ) 588 - 592 2009年09月 [査読有り]

We found that transformation by v-src constitutively activated phosphorylation of histone H3 at Ser10 in a transformation-specific manner. While nontransforming mutant of v-src did not activate H3 phosphorylation, H3 phosphorylation in cells expressing temperature-sensitive mutant of v-src was temperature-dependent. Inhibition of Ras signaling by Gap1m, a GTPase-activation protein for Ras, or S17N Ras, a dominant negative form of Ras, substantially suppressed the Ser10 phosphorylation of H3. Similarly, treatment of cells with manumycin A, a potent inhibitor of Ras-falnesyl transferase, clearly suppressed the H3 phosphorylation. In contrast, inhibition of STAT3 signaling or PI3K signaling did not perturb H3 phosphorylation. We found, however, inhibition of MEK or MSK1 markedly suppressed H3 phosphorylation. In addition, inhibition of MSK1 expression by its siRNA substantially suppressed H3 phosphorylation and anchorage-independent growth of transformed cells. Taken together, Our results strongly suggest the importance of MSK1 and H3 phosphorylation in cell transformation by v-Src. (C) 2009 Elsevier Inc. All rights reserved.

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