NF-κB通路调节蛋白α-catenin对非小细胞肺癌上皮间质转化及肿瘤干细胞标志物的调控作用及其分子机制的研究

肿瘤干细胞(CSC)和肿瘤上皮间质转化(EMT)是肿瘤转移的重要原因，但两者之原理，尤其是调控机制及相关信号转导尚不清楚。对此开展研究对抑制肿瘤转移、改善预后具有重要意义。我们前期研究发现cadherin-catenin连接复合物成员α-catenin可抑制结直肠癌(CRC)细胞发生EMT，且其表达与CRC病人肿瘤转移负相关；而NF-κB通路可下调α-catenin表达而增强CRC细胞迁移能力；并观察到在低分化非小细胞肺癌(NSCLC)组织中α-catenin分子的表达显著下降，及NF-κB转录因子p65的上调，并可见CSC标志物SOX2及OCT4的表达，提示三者间可能存在某种联系。本课题拟用高、低分化NSCLC细胞系，通过siRNA及免疫共沉淀，分析α-catenin对NF-κB通路的调控机制及对侵袭力、EMT、CSC标志物表达的影响，为开发联合抗EMT及CSC的分子药物作有益探索。

Cancer stem cell(CSC) and epithelial to mesenchymal transion(EMT) are key inducers of cancer metastasis, while their mechanism, especially the related regulation and signaling events remain elusive, making additional work valuable to conquer metastasis and improve the prognosis. Our preliminary data indicated that α-catenin, a member of the cadherin-catenin complex, can inhibit the EMT of colorectal cancer (CRC) cells and its expression was negatively related with the metastatic ratio of CRC patients. Further work unveiled the roll of NF-κB in enhancing the mobility of the CRC cells via down regulating their expression of α-catenin. Moreover, our recent data showed that α-catenin expression was almost abolished in poorly differentiated NSCLC tissues, which exhibited a mesenchymal appearance, accompanied by enhanced p65 and the CSC markers: SOX2 and OCT4 expression，suggesting possible relationship between them. Here we plan to utilize shRNA to knockdown α-catenin expression in highly or poorly differentiated NSCLC cell lines, investigating its mechanism in NF-κB regulation and further influence on cancer invasion, EMT and CSC marker expression. Our work will be valuable to develop pluripotent molecular drugs which are able to block both EMT and CSC generation of NSCLC.