肺癌患者获得性耐药是治疗过程中的主要障碍。研究显示上皮间质转化（EMT）参与肿瘤耐药的产生。EMT是细胞分化的一种形式。酪氨酸磷酸酶SHP2参与了多种细胞分化的过程。本课题前期研究结果显示SHP2正向调控肺癌上皮细胞EMT的过程。SHP2沉默及酶活抑制剂可以抑制EMT的过程，并鉴定出了EMT过程中负向调控SHP2活化的一种新的相互作用蛋白Hook1。Hook1是一种微管结合蛋白，提示其可能参与细胞骨架的重构过程。而细胞骨架的调控与肿瘤药物治疗密切相关。本课题将进一步探究EMT过程中SHP2参与细胞骨架重排的机制以及对TGFβ1/smads通路的调控机制，并通过细胞与转基因动物模型探究SHP2在肺癌发生、进展、治疗中的作用，同时结合临床样品分析SHP2表达与肿瘤耐药及患者预后的关系。本课题预期将明确SHP2调控EMT的分子机制，为肺癌临床转化研究、诊断与治疗奠定基础。

Acquired drug resistance is a major obstacle in clinical management of lung cancer. Studies showed that epithelial mesenchymal transition (EMT) participated in cancer drug resistance. EMT is an important form of cell differentiation. Tyrosine phosphatase SHP2 participated in the differentiation of various cells. Our studies showed SHP2 promoted epithelial mesenchymal transition of lung cancer cells. Shp2 knockdown or SHP2 inhibitor inhibited EMT of lung cancer cells. And we identified a binding protein of SHP2-Hook1, which negatively regulated activation of SHP2 in EMT. Hook1 is a binding protein of microtubule, suggested that it may participate in the reorganization of cytoskeleton. Moreover, the regulation of cytoskeleton was closely related with drug therapy. The study will further investigate the molecular mechanism of SHP2 in reorganization of cytoskeleton and activation of TGFβ1/smads pathways in EMT and its role in the initiation, progression and therapy of lung cancer. Also, clinical samples will be collected to analysis the ralationship of SHP2 with tumor drug resistance and prognosis. This study will further explicit the molecular mechanisms of SHP2 in EMT and provide basis for clinical transformation research, diagosis and therapy of lung cancer.