GEF5及其可变剪切体调控肺腺癌侵袭转移的功能与机制研究

肺腺癌患者术后不良和复发的根源来自癌细胞的侵袭转移。此过程主要由癌细胞通过上皮间质转换(EMT)来完成，并依赖基质金属蛋白酶(MMP)对基底膜的降解，其具体调控机制尚不清楚。我们的前期研究发现，GEF5可变剪切体(GEF5-Vs)在肺腺癌组织和细胞中异常升高，具有促进肺腺癌细胞侵袭转移的功能；且介导EMT的关键转录因子以及MMP2的表达。这些结果提示，GEF5-VS可能通过促MMP2表达和EMT介导肺腺癌侵袭转移。本项目拟结合临床样本检测和细胞功能实验，明确在肺腺癌侵袭转移中，GEF5的不同可变剪切体各自所具备的功能，并通过磷酸化蛋白组学技术手段分析它们分别所调控的信号通路。在此基础上，重点围绕靶信号介导GEF5对EMT及MMP2的调控作用，阐明GEF5及其可变剪切体调控肺腺癌侵袭转移的具体机制。研究有望为肺腺癌的临床诊疗提供理论依据和新的药物靶点，并拓展对GEF5分子功能的认识。

The invasion and metastasis of tumor cells is a major cause of poor prognosis and recurrence in lung adenocarcinoma patients. This process is primarily mediated by epithelial mesenchymal transition (EMT) accompanied with basement membrane degradation by matrix metalloproteineases, but the underlying mechanism remains obscure. Our previous studies have shown that the expression of GEF5-Vs, a GEF5 splice variant, is abnormally high in some of lung adenocarcinoma tissue samples and cell lines, and improve the invasion and metastasis of lung adenocarcinoma cell. Moreover, GEF5-Vs may promote lung adenocarcinoma invasion and metastasis by regulating EMT and MMP2 expression. In this study, the roles of GEF5 splice variants in lung adenocarcinoma invasion and metastasis are identified by clinical sample analysis and functional assays. Then the GEF5-regulated signaling pathways are studies by phosphoproteomics. Based on these data, the proposed functions of GEF5 in EMT induction and MMP2 expression are investigated, and the molecular mechanisms underlying the effects of GEF5 on lung adenocarcinoma invasion and metastasis will be clarified. These studies would expand our knowledge of GEF5 functions, revise our approaches for clinical diagnosis of lung adenocarcinoma, and may provide new therapeutic opportunities against such diseases.