EpCAM通过招募PDLIM2增强细胞粘附抑制肺癌转移的机制研究

肿瘤转移是肺癌治疗失败的主要原因之一。表皮细胞粘附因子EpCAM是广泛使用的肿瘤标记分子，在原位癌中常常上调表达，一般认为可以促进肿瘤生长。我们前期研究发现，EpCAM在转移肺癌中下调表达；过表达EpCAM可以抑制肺癌的转移；EpCAM可以和抑癌蛋白PDLIM2相互作用，但是其中机制有待深入研究。本项目首先分析EpCAM下调对细胞粘附、迁移、侵润、凋亡和增殖等与转移相关功能的影响，揭示EpCAM对肺癌转移的抑制功能。进而研究EpCAM是如何与PDLIM2相互作用的，阐述EpCAM招募PDLIM2的分子机制。最后研究PDLIM2对EpCAM下游信号通路靶基因的表达与亚细胞定位的调节作用，探索EpCAM抑制肺癌转移的分子机制。本项目将阐述EpCAM通过招募PDLIM2增强细胞粘附抑制肺癌转移的信号通路，有望为转移肺癌的临床治疗提供新的靶点和理论基础。

Metastasis is one of the major causes leading to failure in lung cancer therapy. Epithelial cell adhesion molecule (EpCAM), extensively utilized as tumor cell marker, is frequently upregulated in many primary cancer types, thus considered to promote tumor growth. Our preliminary studies found EpCAM was downregulated in metastatic lung cancer, whereas EpCAM reconstitution could impede lung cancer metastasis and EpCAM could interact with tumor suppressor PDLIM2; however, the detailed mechanisms underlying lung cancer metastasis inhibition and PDLIM2 recruitment by EpCAM remain to be investigated. In this project, initially, the impact of EpCAM repression on cell adhesion, migration, invasion, apoptosis, and proliferation will be inspected, further revealing the inhibition of lung cancer metastasis by EpCAM. Secondly, the protein interaction between EpCAM and PDLIM2 will be explored, thus clarifying the mechanism of PDLIM2 recruitment by EpCAM. Finally, the effect of PDLIM2 on the expression levels and subcellular locations of EpCAM’s target genes will be analyzed, thereby uncovering the mechanisms underlying inhibition of lung cancer metastasis by EpCAM. If this project is supported, the mechanism underlying EpCAM recruitment of PDLIM2 to enhance cell adhesion to prevent lung cancer metastasis will be addressed, and importantly, these findings will provide a novel therapeutic target and theoretical basis for metastatic lung cancer treatment.