GSK3β激活CAP1磷酸化在调控p-Cofilin/F-actin通路及NSCLC恶性进展的机制研究

肺癌的侵袭和转移是患者死亡的主要原因。申请人前期研究发现：CAP1在NSCLC的发生发展中起着促癌基因的作用，与转移和预后相关，但其调控NSCLC转移的机制并不清楚。进一步预实验发现：敲低CAP1表达降低NSCLC细胞F-actin聚合，且pCofilin水平下降；质谱分析显示，GSK3与CAP1位点相互作用。基于此，提出假说：GSK3β激活CAP1位点磷酸化，进而通过pCAP1-pCofilin通路调控F-actin聚合和重构，影响NSCLC的侵袭和迁移能力。我们拟通过构建CAP1磷酸化稳定突变的NSCLC细胞株，结合GSK3β高选择性抑制剂，在体内和体外水平上探索GSK3β对CAP1的磷酸化调控和pCAP1-pCofilin/F-actin信号轴在NSCLC恶性进展的作用及机制研究。以期为CAP1作为NSCLC防治转移的新的分子靶点提供理论依据。

The invasion and metastasis of lung cancer is the leading cause of death in patients. Previous studies showed that CAP1 plays a role of oncogene in the development and progression of NSCLC and has a correlation with metastasis and prognosis. However, the mechanism by which CAP1 regulates NSCLC metastasis is not clear. Further preliminary experiments showed that:knock down CAP1 expression reduce F-actin polymerization, and pCofilin levels; Mass spectrometry analysis showed that GSK3 interacts with CAP1,Based on this, we intend to explore the phosphorylation of CAP1 by GSK3β and the mechanism of pCAP1-pCofilin/F-actin signaling in malignant progression of NSCLC with stable CAP1 phosphorylation mutation combined with GSK3β highly selective inhibitor in vivo and vitro. It provides a theoretical basis for CAP1 as a new molecular target for the prevention and control of metastasis of NSCLC.