YES激酶相关蛋白YAP1在幽门螺杆菌感染促进恶性转化中的功能与机制

项目名称： YES激酶相关蛋白YAP1在幽门螺杆菌感染促进恶性转化中的功能与机制

项目编号： No.81501720

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 于晗

作者单位： 山东大学

项目金额： 18万元

中文摘要： 幽门螺杆菌介导胃粘膜恶性转化机制是重要的科学问题。申请者发现幽门螺杆菌感染向恶性转化演变过程中，YES激酶相关蛋白YAP1表达逐步升高。进一步，以幽门螺杆菌作用胃上皮细胞系，促进了YAP1入细胞核，增强转录因子FoxM1表达，FoxM1结合于YAP1上游启动子区，YAP1转录表达；此外，鉴于YAP1是Hippo通路的效应分子。申请者科学假设是：“幽门螺杆菌通过Hippo非依赖（FoxM1）和Hippo依赖两机制激活YAP1表达与核转位，被激活的YAP1入细胞核与TEAD形成转录复合体，促进IL-11的表达，进而激活STAT3信号通路，介导细胞恶性转化”。主要研究内容：（1）分子细胞水平解析YAP1在幽门螺杆菌感染介导恶性转化中调控机制；（2）实验动物与人体病理组织水平验证YAP1与幽门螺杆菌感染介导恶性转化的关联性。旨在为制定幽门螺杆菌感染相关恶性转化的早期识别和干预策略提供理论依据。

中文关键词： 病原细菌；细菌感染；恶性转化

英文摘要： The mechanism of malignant transformation in gastric mucosal induced by Helico-bacter pylori (H. pylori) infection isan important scientific problem. Previously, we found that YAP1 (Yes-associated protein65) expression increased gradually in the malignant transformation of gastric mucosa tissues induced by Helicobacter pylori infection. Furthermore, after being infected by H. pylori, gastric cancer cell lines showed a higher level of YAP1 nuclear translocation, leading to enhanced FoxM1(Forkhead box protein M1) expression. We also observed that FoxM1 could bind to the promoter region of YAP1 and promoted its expression on the transcrip-tional level. As YAP1 is an effector molecule of Hippo pathway, we raised our scien-tific hypothesis: H. pylori promoted YAP1 expression and nuclear translocation by both “Hippo-independent”and “Hippo-dependent”ways, then YAP1 and TEAD formed a transcription complex which is targeting to the downstream molecule IL-11, finally they induced malignant transformation of gastric mucosa tissue for the reason that IL-11 activates STAT3 pathway. The research contents are as follows: (1) To re-veal the mechanism of malignant transformation of gastric mucosal epithelial cells induced by H. pylori through regulating YAP1 on a molecular level. (2) To verify the correlation of H. pylori-associated malignant transformation and YAP1 by clinical tissue samples and animal experiments. Therefore, this project can provide the theo-retical basis on YAP1 to being the potential target molecule for the early diagnosis and intervention of gastric cancer.

英文关键词： pathogenic bacteria;bacterial infection;malignant transformation