研究者詳細 - 時野　隆至

論文 - 時野　隆至

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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 ( (一社)日本癌学会 ) 73回 P - 2072 2014年09月

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 ( (一社)日本癌学会 ) 73回 P - 2065 2014年09月

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 ( (一社)日本癌学会 ) 73回 P - 2079 2014年09月

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 ( (一社)日本癌学会 ) 73回 P - 3277 2014年09月

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 ( (一社)日本癌学会 ) 73回 P - 2277 2014年09月

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

Idogawa M, Ohashi T, Sasaki Y, Maruyama R, Kashima L, Suzuki H, Tokino T

Human molecular genetics 23 ( 11 ) 2847 - 57 2014年06月 [査読有り] [国際誌]

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 PubMed

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

Ohashi T, Idogawa M, Sasaki Y, Suzuki H, Tokino T

Molecular cancer research : MCR 11 ( 12 ) 1554 - 63 2013年12月 [査読有り] [国際誌]

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.

DOI PubMed

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 ( (一社)日本癌学会 ) 72回 105 - 105 2013年10月

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 ( (一社)日本癌学会 ) 72回 253 - 253 2013年10月

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 ( (一社)日本癌学会 ) 72回 104 - 104 2013年10月

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 ( (一社)日本癌学会 ) 72回 253 - 253 2013年10月

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 ( (一社)日本癌学会 ) 72回 253 - 253 2013年10月

Methylation of a panel of microRNA genes is a novel biomarker for detection of bladder cancer.

Shimizu T, Suzuki H, Nojima M, Kitamura H, Yamamoto E, Maruyama R, Ashida M, Hatahira T, Kai M, Masumori N, Tokino T, Imai K, Tsukamoto T, Toyota M

European urology 63 ( 6 ) 1091 - 100 2013年06月 [査読有り] [国際誌]

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 PubMed

DNA methyltransferase 1 is essential for initiation of the colon cancers.

Morita R, Hirohashi Y, Suzuki H, Takahashi A, Tamura Y, Kanaseki T, Asanuma H, Inoda S, Kondo T, Hashino S, Hasegawa T, Tokino T, Toyota M, Asaka M, Torigoe T, Sato N

Experimental and molecular pathology 94 ( 2 ) 322 - 9 2013年04月 [査読有り] [国際誌]

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.

DOI PubMed

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

生物物理 ( 一般社団法人日本生物物理学会 ) 53 ( 1 ) S163 2013年

DOI CiNii

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

Sasaki Y, Koyama R, Maruyama R, Hirano T, Tamura M, Sugisaka J, Suzuki H, Idogawa M, Shinomura Y, Tokino T

Cancer biology & therapy 13 ( 14 ) 1512 - 21 2012年12月 [査読有り] [国際誌]

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.

DOI PubMed

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 ( NATURE PUBLISHING GROUP ) 19 ( 11 ) 749 - 756 2012年11月

The p53 tumor suppressor belongs to a gene family that includes two other structurally and functionally related members: p73 and p63. The regulation of p53 activity differs significantly from that of p73 and p63. To enhance the tumor suppressive activity of p53, we constructed six recombinant adenoviruses that encode hybrid proteins with three functional domains derived from either p53 or TAp63 gamma. The potency of these hybrid molecules in suppressing tumorigenesis was evaluated using in vitro and in vivo models. Of the hybrid molecules tested, one hybrid named p63-53O was the most potent activator of apoptosis in human cancer cells. The p63-53O hybrid is composed of the transcriptional activation domain and DNA-binding domain of TAp63 gamma and the oligomerization domain of p53. The p63-53O hybrid efficiently transactivated p53AIP1. Moreover, silencing of p53AIP1 partially abolished the apoptotic response to p63-53O in human cancer cells. The p53-p63 hybrid molecule is a novel potent anti-proliferative agent for the treatment of cancer.

DOI PubMed

Molecular dissection of premalignant colorectal lesions reveals early onset of the CpG island methylator phenotype.

Yamamoto E, Suzuki H, Yamano HO, Maruyama R, Nojima M, Kamimae S, Sawada T, Ashida M, Yoshikawa K, Kimura T, Takagi R, Harada T, Suzuki R, Sato A, Kai M, Sasaki Y, Tokino T, Sugai T, Imai K, Shinomura Y, Toyota M

The American journal of pathology 181 ( 5 ) 1847 - 61 2012年11月 [査読有り] [国際誌]

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 PubMed

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

Takahashi A, Torigoe T, Tamura Y, Kanaseki T, Tsukahara T, Sasaki Y, Kameshima H, Tsuruma T, Hirata K, Tokino T, Hirohashi Y, Sato N

Cell stress & chaperones 17 ( 6 ) 757 - 63 2012年11月 [査読有り] [国際誌]

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.

DOI PubMed

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

Takamaru H, Yamamoto E, Suzuki H, Nojima M, Maruyama R, Yamano HO, Yoshikawa K, Kimura T, Harada T, Ashida M, Suzuki R, Yamamoto H, Kai M, Tokino T, Sugai T, Imai K, Toyota M, Shinomura Y

Cancer prevention research (Philadelphia, Pa.) 5 ( 10 ) 1203 - 12 2012年10月 [査読有り] [国際誌]

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 PubMed

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