RASSF10招募FBXW11泛素化降解WASH1抑制自噬在胃癌化疗增敏中的机制研究

自噬是肿瘤细胞在化疗条件下存活的重要机制，抑制自噬是胃癌化疗增敏的重要策略。前期发现胃癌中RASSF10的表达与多西他赛（DTX）化疗敏感性相关，过表达RASSF10可抑制自噬，促进凋亡，提高DTX的化疗敏感性。进一步研究发现RASSF10可分别与自噬相关蛋白WASH1和E3泛素连接酶FBXW11相互结合，过表达RASSF10通过招募FBXW11泛素化降解WASH1，进而抑制胃癌细胞自噬。我们推断：RASSF10招募FBXW11泛素化降解WASH1，抑制自噬，提高胃癌对DTX的化疗敏感性。本项目拟在体外细胞实验、体内动物实验及人群组织样本中，运用一系列分子细胞实验明确RASSF10在胃癌增敏中的作用，阐明RASSF10泛素化降解WASH1的机制及其对胃癌细胞自噬及化疗敏感性的影响。本项目研究结果为提高胃癌化疗敏感性，寻找胃癌个体化治疗的方法提供理论及实验依据。

Autophagy is an important mechanism for chemotherapy tolerance, thus, inhibition of autophagy is a potential strategy for the efficacy of chemotherapy in gastric cancer. It has been previously found that the expression of RASSF10 in gastric cancer is related to the sensitivity of docetaxel (DTX). The overexpression of RASSF10 can inhibit autophagy, promote apoptosis, and improve the sensitivity of DTX on gastric cancer. Further studies showed that RASSF10 could bind to autophagy-related protein WASH1 and E3 ubiquitin ligase FBXW11, respectively, and overexpression of RASSF10 recruit FBXW11 to ubiquitylate and degrade WASH1, thereby inhibiting autophagy in gastric cancer cells. We hypothesize that RASSF10 enhances the sensitivity of gastric cancer to DTX by inhibiting autophagy via recruiting FBXW11 to ubiquitylate and degrade WASH1. This project intends to use a series of molecular cell experiments, including in vitro cell experiments, animal models and human tissue samples to clarify the role of RASSF10 in gastric cancer sensitivity to chemotherapy, and reveal the mechanism of RASSF10 regulating the ubiquitin degradation of WASH1 and its effect on autophagy and chemosensitivity of gastric cancer cells. The results of this study provide theoretical and experimental basis for improving the efficiency of chemotherapy for gastric cancer and developing an individualized therapy for gastric cancer.