Role of DNA repair gene MGMT, hMLHI and hMSH2 in oncogenesis and progression of human gastrointestinal, hepatobiliary carcinoma

DNA修复基因MGMT、hMLHI和hMSH2在人胃肠道、肝胆癌发生和进展中的作用

基本信息

批准号：
12470263
负责人：
MIYAZAKI Kohji
金额：
$ 1.66万
依托单位：
Saga Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470263/
关键词：
MGMT hMLH1 hMSH2 Hypermethylation 胃癌胆道癌肝細胞癌 GC-AT transiton Hypermethylation 予後予測

项目摘要

O^6-Methylguanine-DNA methyltansferase(MGMT) is a DNA repair enzyme that transfers methyl groups from O^6-Methylguanine to itself When MGMT expression is impaired, the O^6-Methylguanine mispairs with thymine during DNA replication, resulting in G:C→A:T transitional mutation in DNA. We have previously demonstrated that the deficient expression of MGMT was correlated with a poor prognosis of patients with biliary tract, hepatocellular and gastric carcinoma in immunohistochemical study. We consequently prompted two possible hypotheses how MGMT loss contributes to tumor progression. One is that MGMT loss in carcinoma may cause an accumulation of DNA mutation in oncogenes and tumor suppressor genes, which brings about tumor progression leading to poor prognosis. Thus, we investigated using gall bladder (GB) carcinoma specimens whether or not gene mutation including K-ras, p53 and β-catenin correlates with MGMT status, and assessed whether the gene mutation exhibit a G:C→A:T transition origi … More nated from MGMT loss. DNA seguencing study defined that frequency of gene mutations were 11.5% in K-ras, 40% in p53 and 10% in β catenin. Although significant correlation between MGMT loss and DNA mutation in the candidate genes, G:C→A:T transition in K-ras gene was observed in several specimens with MGMI loss. Another possible mechanism is by epigenetic DNA modification, that hypermethylation on promoter region may simultaneously occur in MGMT as well as other genes. Indeed, we found that MGMT gene silencing was caused by CpG methylation of the MGMT promoter in Hepatocellular carcinoma. We are examining in GB carcinoma whether promoter hypermetylation may occur in MGMT, E-cadherin and p16 genes by methylation specific PCR method. Currently, we have revealed that GB carcinoma cell line with MGMT(-)hMLH1(+) exerted high sensitivity and apoptosis to alkylating drug. In this study, we propose that abortive mismatch repair function in addition to MGMT loss contributes to cytotoxic effects of alkylating agents. We are attempting molecular targetting chemotherapy using alkylating agents based on MGMT and hMLH1 status. Less

O^6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 是一种 DNA 修复酶，可将甲基从 O^6-甲基鸟嘌呤转移到自身。当 MGMT 表达受损时，O^6-甲基鸟嘌呤在 DNA 复制过程中与胸腺嘧啶错配，导致 G DNA :C→A:T 过渡突变我们之前已经证明 MGMT 的表达缺陷与患者的不良预后相关。因此，我们提出了两种可能的假设：MGMT 缺失如何促进肿瘤进展。一是癌症中 MGMT 缺失可能导致癌基因和抑癌基因 DNA 突变的积累，从而导致肿瘤发生。因此，我们使用胆囊 (GB) 癌标本研究了 K-ras、p53 和 β-catenin 等基因突变是否与 MGMT 状态相关。评估基因突变是否表现出 G:C→A:T 转变起源于 MGMT 丢失研究，确定基因突变频率在 K-ras 中为 11.5%，在 p53 中为 40%，在 β 连环蛋白中为 10%。尽管 MGMT 缺失与候选基因中的 DNA 突变之间存在显着相关性，但在多个 MGMI 缺失的样本中观察到 K-ras 基因中的 G:C→A:T 转变。另一种可能的机制是通过表观遗传 DNA。事实上，我们发现在肝细胞癌中，MGMT 启动子的 CpG 甲基化可能会同时发生启动子区域的高甲基化。目前，我们已经通过甲基化特异性PCR方法揭示了GB癌细胞系中的MGMT、E-cadherin和p16基因。 MGMT(-)hMLH1(+)对烷化药物具有高敏感性和细胞凋亡作用。在这项研究中，我们提出除了MGMT丧失之外，失配修复功能也有助于烷化剂的细胞毒性作用。我们正在尝试使用烷化剂进行分子靶向化疗。基于 MGMT 和 hMLH1 状态更少。