miR-200家族调控Hippo信号通路关键分子在胃癌EMT中的作用与机制研究

Gastric cancer is a highly aggressive malignancy with high incidence and mortality worldwide. Epithelial-mesenchymal transition (EMT) is an important event in the occurrence and metastasis of gastric cancer. Our preliminary results of integrated analysis of microRNA and mRNA genome-wide expression profiles on 90 gastric cancer cases showed that the miRNA-200 family regulates EMT of gastric cancer and affects prognosis. In addition, its downstream targets include such as FRMD6, TEAD and LATS2. In this study, we will firstly focus on the association of Hippo-signaling pathway molecules with the EMT progress and prognosis of gastric cancer. Then we will study on the relationship between miR-200s and the predicted targets FRMD6, TEAD and LATS2. By using other molecular and cell biological methods, we will investigate the alteration of EMT after changing of hippo signaling pathway. Finally, some studies will conduct to validate the conclusions by animal model in vivo. Our preliminary study will elucidate the molecular mechanism of miR-200 family-Hippo pathway-EMT intermodulation mechanism, and provide a theoretical basis and experimental basis for the molecular mechanism of gastric cancer research and treatment.

胃癌是具有高度侵袭性并对生命有危害性的恶性肿瘤，上皮间质转化（EMT）是胃癌发生和转移过程中的重要事件。我们前期对90例胃癌病例mRNA及miRNA全基因组表达谱芯片进行整合分析，结果显示miRNA-200家族调控胃癌EMT，影响预后，其下游包括FRMD6，TEAD及LATS2等Hippo信号通路关键分子。本研究首先将在临床组织水平研究Hippo通路相关分子与胃癌EMT及预后的关联，随后采用分子和细胞生物学方法研究miR-200家族对FRMD6，TEAD及LATS2等靶向调控作用，以及改变Hippo信号通路后引发的EMT改变。最后将用体内动物实验证实部分研究结论。本研究将从机制上初步阐明miR-200家族通过靶向Hippo通路调控EMT的分子机制，为胃癌的分子机理研究和治疗靶标的筛选提供理论依据和实验基础。

本研究对胃癌中基于芯片整合分析的与预后相关的miRNAs进行了功能研究。首先在临床组织水平研究了Hippo通路相关分子与胃癌EMT及预后的关联，随后采用体外实验方法研究miR-200家族对FRMD6，TEAD及LATS2等靶向调控作用，以及改变Hippo信号通路后引发的EMT改变。并构建了相关胃癌细胞系裸鼠皮下移植瘤模型，对体外研究结论进行了证实。除了低表达的miRNA-200家族外，发现高表达的miRNA-125b也对胃癌预后和胃癌的进展起重要作用。同时，miR-125b的上游受雄激素受体AR调控，与hippo信号通路存在协同调控作用，对胃癌细胞的EMT和凋亡发生，都存在交互作用。所以在进行本项课题研究同时，把miR-125b和胃癌的EMT，凋亡的研究也纳入进去进行共同研究分析。研究结果较为深入地探索了胃癌EMT转移发生的分子机制，为疾病的预后和临床治疗提供新的思路。