Na,K-ATPaseβ1亚基在TGF-β诱导的肺癌EMT中的作用及其调节机制

Na,K-ATPase β1 subunit is a kind of cell adhesion molecule, and can maintain the intercellular tight junction together with E-cadherin. The expression of Na,K-ATPase β1 subunit was downregulated in poorly differentiated and highly invasive tumors, and the cancer patients with low Na,K-ATPase β1 had a high risk of death，which indicated that β1 subunit was involved in tumor metastasis. The mechanism and role of the Na,K-ATPase β1 downregulation in cancer cells aren’t clear. The downregulation of E-cadherin expression is one sign of epithelial-mesenchymal transition(EMT). The expression of Na,K-ATPase β1 subunit was inversely proportional to the expression of Snail in cancer cells and Snail is a kind of transcription factor involved in transforming growth factor-β（TGF-β）-induced EMT. All these indicated that Na,K-ATPase β1 may be involved in EMT induced by TGF-β. TGF-β signaling contributes to tumor progression by inducing EMT, thereby promoting the conversion of epithelial tumors to invasive, metastatic tumors. We also have shown that TGF-β downregulated the expression of Na,K-ATPase β1 subunit in human lung A549 cancer cells and the cells showed EMT-like morphology after Na,K-ATPase β1 knockout. This project is designed to investigate the role and regulatory mechanism of Na,K-ATPase β1 in EMT induced by TGF-β. This study will increase our knowledge about mechanisms involved in EMT induced by TGF-β and role of Na,K-ATPase β1 in the tumor metastasis. It will provide new thinking and target for treatment of tumor metastasis and add information for the Na,K-ATPase β1 research.

Na,K-ATPase β1亚基作为一种细胞黏附分子可和E-钙粘蛋白结合，共同维持细胞间的紧密连接，在低分化高侵袭的肿瘤，其表达明显降低，且降低程度越低，患者死亡率越高，提示β1亚基与肿瘤转移密切相关，但其下调机制及参与肿瘤转移的途径尚不清楚。上皮间质转化（EMT）是肿瘤转移的重要机制，E-钙粘蛋白下调是EMT的特征之一，肿瘤中β1亚基表达和Snail表达呈反比关系，Snail是转化生长因子（TGF）-β诱导EMT通路中的转录因子，这提示β1亚基可能与TGF-β诱导的EMT有关。我们前期研究发现TGF-β可下调人肺癌A549细胞β1亚基的表达，且基因敲除β1亚基可诱导细胞出现EMT样的形态变化。本研究拟在A549细胞上探讨Na,K-ATPase β1亚基在TGF-β诱导EMT中的作用及其下调机制。研究结果将明确β1亚基的下调机制和参与肿瘤转移的途径，为肿瘤转移的防治提供新的理论及靶点。