MED23/HNF4a/ERBB3信号调控胃癌进展的作用及机制研究

胃癌是中国高发癌种，术后复发转移风险高，靶向治疗是突破口。转录中介体（Mediator）是由多亚基构成的蛋白复合体，通过影响特定转录因子功能调控肿瘤的发生发展及治疗抵抗。HNF4a是胃癌中重要的促癌基因，在调控胃癌增殖、迁移中发挥重要作用。我们研究发现，Mediator尾部亚基MED23在胃癌中表达显著下调且与不良预后相关，其功能缺失可通过活化HNF4a表达影响胃癌恶性表型。我们还发现MED23/HNF4a通过下游靶基因ERBB3参与调控ERBB信号，降低曲妥珠单抗介导的ERBB2降解。因此我们认为，MED23/HNF4a/ERBB3信号在调控胃癌进展及靶向治疗抵抗中可能发挥重要作用。本项目拟在前期实验基础上，深入研究MED23/HNF4a参与调控ERBB信号及靶向治疗抵抗的分子机制，并探索MED23/HNF4a/ERBB3作为胃癌协同治疗靶点的可行性，为提高胃癌靶向治疗疗效奠定基础。

Gastric cancer is one of the highest incidence of malignant tumors in China with a high risk of recurrence and metastasis after operation. The targeted therapy is a breakthrough point to improve this disease. Mediator is a multi-protein complex composed with many subunits and regulates the incidence and therapeutic resistance in cancer. HNF4a is an important oncogene and plays a key role in promoting proliferation and migration in gastric cancer. In our previous research, we found that MED23, the key subunit of Mediator tail model, was decreased in tumor tissue and was associated with poor prognosis in gastric cancer. We also found that MED23 downregulation promoted malignant phenotype by activating HNF4a. Furthermore, we found that MED23/HNF4a regulated ERBB signaling by targeting ERBB3 expression and reduced ERBB2 degradation mediated by Trastuzumab. So we proposed a hypothesis that MED23/HNF4a/ERBB3 signaling may play a key role in gastric cancer progression and therapeutic resistance. This project proposal for grant application is designed on the basis of our previous work to elucidate the molecular mechanism of MED23/HNF4a for regulating ERBB signaling and targeted therapeutic resistance. We propose MED23/HNF4a/ERBB3 as a potential therapeutic target synergistically with anti-ERBB2 therapy, which paves a foundation to improve the targeted therapy for gastric cancer.