抑癌基因KLF4失活在幽门螺旋杆菌感染致胃癌发生发展的作用及其分子机制

项目名称： 抑癌基因KLF4失活在幽门螺旋杆菌感染致胃癌发生发展的作用及其分子机制

项目编号： No.81472330

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 魏道严

作者单位： 安徽医科大学

项目金额： 90万元

中文摘要： 胃癌是严重危害人类健康的恶性肿瘤之一。已有资料表明，幽门螺杆菌（HP感染是胃癌的第一类生物致癌因子，但对其致病机制及 HP如何与宿主基因相互作用影响胃癌的发生发展知之甚少。本组研究发现：抑癌基因 KLF4 表达的丢失和失活与胃癌的发生发展及预后关系密切，但其在胃癌中失活的分子机制尚不清楚。预实验中发现: 较正常胃粘膜组织，胃癌组织中 KLF4 基因启动子存在明显的甲基化，KLF4 mRNA 表达显著降低;HP 感染或 CagA 基因转染可显著抑制 KLF4 蛋白的表达。我们假设：HP 感染可能通过不同的机制引起KLF4 基因失活，从而促进胃癌的发生发展。本课题拟用已经建立的条件性胃 Klf4基因敲除小鼠模型，相应的细胞系，胃癌组织标本及相关的临床资料，分别从动物，细胞分子生物学及人体水平三个层次观察HP感染致KLF4失活及促胃癌作用的因果关系，并阐明其分子机制，并为胃癌的防治提供新的靶点。

中文关键词： C07_胃肿瘤；幽门螺杆菌；KLF4；分子机制

英文摘要： Gastric cancer is one of the most malignant diseases that cause serious harm to human health. The existing data indicate that Helicobacter pylori (HP) infection is the class I bacterial carcinogenic factor for stomach, but little is known about the molecular pathogenesis, especially how HP interacts with host genes to affect the development and progression of gastric cancer. In our previous studies we found: loss or inactivation of KLF4 expression closely correlated with gastric cancer origin, development and prognosis, but the underlying molecular mechanisms leading to KLF4 inactivation in gastric cancer remain unclear. In preliminary experiments we found that: 1) compared with that in normal gastric mucosa, significant promoter methylation and reduced mRNA expression of KLF4 were observed in gastric cancer tissues; 2) HP infection or CagA gene transfection significantly inhibited KLF4 expression. On the basis of these data, we hypothesize that HP infection leads to inactivation of KLF4 tumor suppressor in gastric epithelial/cancer cells through different mechanisms, and thus, promotes the development and progression of gastric cancer. In this project, we plan to use established conditional klf4 gene knockout mouse model, related cell lines, gastric cancer tissue samples and associated clinical data to investigate the causal relationship between HP infection and KLF4 inactivation in the development and progression of gastric cancer, and further elucidate the underlying molecular mechanisms. It is anticipated that the results from this study will provide new insights into and a novel gene target for gastric cancer prevention and treatment.

英文关键词： gastric cancer;Helicobacter pylori;KLF4;molecular mechanism