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

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.

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。

胃癌发生是非可控性炎症和细胞过度增殖结合的复杂过程，幽门螺杆菌（Helicobacter pylori, Hp）作为胃癌的I类致病因子，探讨其介导胃粘膜恶性转化机制是重要的科学问题，目前尚未阐明。本项目的研究结果揭示以下问题：（1）Hp可通过促进YAP1的表达和核转位，加速炎症的恶性转化；（2）YAP1和TEAD结合形成复合体，作为转录激活子，结合在IL-1β的启动子区域并促进其表达；（3）IL-1β的过表达通过激活肿瘤细胞的过度增殖促进胃癌的发生发展。简言之，我们揭示了Hp-YAP1-IL-1β信号传导通路，该通路将幽门螺杆菌感染、组织炎症和肿瘤发生结合起来，为阐明胃癌发生发展的分子机制研究提供新线索。另外，我们利用维替洛芬阻断YAP1-TEAD结合物的形成，可以有效抑制胃癌的发展过程，该结果提示YAP1可能成为胃癌治疗的新靶点，为研究药物的新用途和新药开发提供思路。