MEX3A调节MMR通路介导MGMTneg型复发胶质瘤TMZ耐药的实验研究

MGMTneg型复发胶质瘤多伴有MMR蛋白-PMS2和MSH2的下调及对TMZ的耐药，但其中的机制不明。前期实验发现TMZ刺激可促进MEX3A的表达，MEX3A的表达又可影响胶质瘤对TMZ的敏感性及PMS2、MSH2的表达。据此，我们提出“MEX3A通过MMR通路调控MGMTneg型复发胶质瘤对TMZ的敏感性”的研究假说。本项目拟在胶质瘤标本中检测MEX3A、PMS2及MSH2的表达及三者间的相互关系；探讨MEX3A影响PMS2、MSH2表达的具体机制；在细胞系和动物模型中证明：MEX3A通过PMS2、MSH2调控MGMTneg型复发胶质瘤的TMZ耐药。预期结果将阐明MEX3A通过MMR通路影响MGMTneg型复发胶质瘤的耐药机制，建立以MMR通路为核心针对MEX3A治疗MGMTneg型复发胶质瘤的新策略。

MGMTneg recurrent gliomas are mostly associated with lower MMR proteins - PMS2 and MSH2 expression, and TMZ resistance. Yet, the mechanism is still obscure. Our preliminary data showed that TMZ treatment remarkably enhanced the expression of MEX3A. And up-regulation of MEX3A promoted TMZ resistance and decreased the expression of PMS2 and MSH2. Thus, we proposed the research hypothesis that MEX3A promotes TMZ resistance in MGMTneg recurrent gliomas through MMR signaling. In the current research program, we will study as follows: the relationship among MEX3A、PMS2 and MSH2 in gliomas tissue samples; the mechanism that MEX3A regulating the expression of MSH2 and PMS2; and whether MEX3A confers TMZ resistance thought deceasing the expression of MSH2 and PMS2. Expected research results will elucidate the mechanism that MEX3A promotes TMZ resistance in MGMTneg recurrent gliomas through MMR signaling and provide a novel treatment strategy targeting MEX3A.