Microsatellite instability and aberrant methylation in gastrointestinal cancer and its application to molecular target therapy

胃肠道肿瘤微卫星不稳定性和异常甲基化及其在分子靶向治疗中的应用

• 批准号: 13854016
• 负责人: IMAI Kohzoh
• 金额: $ 62.48万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13854016/
• 关键词: Genetic instability; DNA methylation; Epigenetics; Molecular target therapy; Gastrointestinal cancer; メチル化; ヒストン; メチル化異常; 癌発生; 前癌病変; 消化器癌

Microsatellite instability (MSI) caused by the defect of DNA mismatch repair genes plays a role in Hereditary non-polyposis colorectal cancer (HNPCC). MSI also plays a role in sporadic colorectal and gastric cancers. In the current study, we identified the genes inactivated by MSI and/or aberrant methylation in gastrointestinal cancers, and examined their role in development and progression of gastrointestinal cancers. DNA methylation is an epigenetic change that can be reversed by methyltransferase inhibitors. We examine basic research that leads to development of molecular target therapy in gastrointestinal cancers. We examined the relationship between MSI and methylation changes in gastrointestinal cancers. We found that 80% of sporadic colorectal cancers with MSI were caused by epigenetic inactivation of hMLH1 associated with CpG island methylator phenotype (CIMP). CIMP positive colorectal cancers showed distinct genetic and epigenetic features including high frequency of methylation of p16 and mutations of BRAF, and low frequency of p53 mutations. These results indicated that CIMP positive colorectal cancer arises in a different pathway compared to HNPCC. We also showed that epigenetic inactivation of the regulators of WNT and Ras play a role in activation of WNT and Ras signaling pathways. Inhibition of DNA methylation by a methyltransferase inhibitor results in induction of pro-apoptotic genes, which results in enhancement of apoptosis in cancer cells. Our results indicated that DNA methylation can be a molecular target for therapy of gastrointestinal cancers.

DNA错配修复基因缺陷引起的微卫星不稳定性（MSI）在遗传性非息肉病性结直肠癌（HNPCC）中起重要作用。MSI在散发性结直肠癌和胃癌中也起作用。在目前的研究中，我们确定了在胃肠道癌症中因MSI和/或异常甲基化而失活的基因，并检查了它们在胃肠道癌症发生和进展中的作用。DNA甲基化是一种表观遗传变化，可以通过甲基转移酶抑制剂逆转。我们检查导致胃肠道肿瘤分子靶向治疗发展的基础研究。我们研究了胃肠道肿瘤中MSI和甲基化变化之间的关系。我们发现80%的散发性结直肠癌MSI是由与CpG岛甲基化表型（CIMP）相关的hMLH 1表观遗传失活引起的。CIMP阳性的结直肠癌表现出明显的遗传和表观遗传特征，包括高频率的p16甲基化和BRAF突变，以及低频率的p53突变。这些结果表明，与HNPCC相比，CIMP阳性结直肠癌发生在不同的途径中。我们还发现，表观遗传失活的WNT和Ras的调节发挥作用，激活WNT和Ras信号通路。甲基转移酶抑制剂对DNA甲基化的抑制导致促凋亡基因的诱导，这导致癌细胞中凋亡的增强。我们的研究结果表明，DNA甲基化可以作为胃肠道肿瘤治疗的分子靶点。

项目成果

Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta.

• 发表时间: 2002
• 期刊: The EMBO journal
• 作者: M. Takekawa;K. Tatebayashi;F. Itoh;M. Adachi;K. Imai;H. Saito

Poly(ADP-ribose) polymerase-1 (PARP-1) is a component of the oncogenic T-cell factor-4 (TCF-4)/β-catenin complex

聚（ADP-核糖）聚合酶-1 (PARP-1) 是致癌 T 细胞因子 4 (TCF-4)/β-连环蛋白复合物的组成部分

• 发表时间: 2005
• 期刊: Gastroenterology 128(In press)
• 作者: Idogawa M;Imai K et al.
• 通讯作者: Imai K et al.

Sato A, Imai K, et al.: "Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer."Cancer Res.. (in press). (2003)

Sato A、Imai K 等人：“胃癌中 CHFR 的表观遗传失活和对微管抑制剂的敏感性。”Cancer Res..（出版中）。

Adenovirus-mediated transfection of caspase-8 augments anoikis and inhibits peritoneal dissemination of human gastric carcinoma cells.

• 发表时间: 2001-10
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Susumu Nishimura;Masaaki Adachi;Tadao Ishida;Takahiro Matsunaga;Hiroaki Uchida;Hirofumi Hamada;Kohzoh Imai

Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence.

• 发表时间: 2003
• 期刊: Nature
• 影响因子: 64.8
• 作者: A. Takaoka;S. Hayakawa;H. Yanai;D. Stoiber;Hideo Negishi;H. Kikuchi;S. Sasaki;K. Imai;T. Shibue;K. Honda;T. Taniguchi