Sun Ting Ting, Wang Yan, Cheng Hong, Xiao Hu Zhang, Xiang Juan Juan, Zhang Jie Ting, Yu Siu Bun Sydney, Martin Tracey Amanda, Ye Lin, Tsang Lai Ling, Jiang Wen Guo, Xiaohua Jiang, Chan Hsiao Chang
Biochim Biophys Acta. 2014 Mar;1843(3):618-28. doi: 10.1016/j.bbamcr.2013.12.013.
How mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains an open question. Here we report the interaction between CFTR and an adherens junction molecule, AF-6/afadin, and its involvement in the development of colon cancer. We have found that CFTR and AF-6/afadin are co-localized at the cell-cell contacts and physically interact with each other in colon cancer cell lines. Knockdown of CFTR results in reduced epithelial tightness and enhanced malignancies, with increased degradation and reduced stability of AF-6/afadin protein. The enhanced invasive phenotype of CFTR-knockdown cells can be completely reversed by either AF-6/afadin over-expression or ERK inhibitor, indicating the involvement of AF-6/MAPK pathway. More interestingly, the expression levels of CFTR and AF-6/afadin are significantly downregulated in human colon cancer tissues and lower expression of CFTR and/or AF-6/afadin is correlated with poor prognosis of colon cancer patients. The present study has revealed a previously unrecognized interaction between CFTR and AF-6/afadin that is involved in the pathogenesis of colon cancer and indicated the potential of the two as novel markers of metastasis and prognostic predictors for human colon cancer.
CFTR的突变或功能障碍如何增加各种组织中恶性肿瘤的风险仍是一个悬而未决的问题。在此，我们报告CFTR与一种黏附连接分子AF-6/afadin之间的相互作用及其在结肠癌发生发展中的作用。我们发现CFTR和AF-6/afadin在结肠癌细胞系中的细胞-细胞接触部位共定位且相互之间存在物理性相互作用。敲低CFTR会导致上皮紧密性降低和恶性程度增强，同时AF-6/afadin蛋白的降解增加且稳定性降低。CFTR敲低细胞增强的侵袭表型可通过AF-6/afadin过表达或ERK抑制剂完全逆转，这表明AF-6/MAPK信号通路参与其中。更有趣的是，在人类结肠癌组织中CFTR和AF-6/afadin的表达水平显著下调，且CFTR和/或AF-6/afadin的低表达与结肠癌患者的不良预后相关。本研究揭示了CFTR与AF-6/afadin之间一种此前未被认识到的相互作用，该相互作用参与结肠癌的发病机制，并表明这两者作为人类结肠癌转移新标志物和预后预测指标的潜力。
