Zhang Jie Ting, Jiang Xiao Hua, Xie Chen, Cheng Hong, Da Dong Jian, Wang Yan, Fok Kin Lam, Zhang Xiao Hu, Sun Ting Ting, Tsang Lai Ling, Chen Hao, Sun Xiao Juan, Chung Yiu Wa, Cai Zhi Ming, Jiang Wen Guo, Chan Hsiao Chang
Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; Key Laboratory for Regenerative Medicine, Ji Nan University-The Chinese University of Hong Kong, Ministry of Education of The People's Republic of China, China.
Biochim Biophys Acta. 2013 Dec;1833(12):2961-2969. doi: 10.1016/j.bbamcr.2013.07.021. Epub 2013 Aug 2.
The epithelial-to-mesenchymal transition (EMT), a process involving the breakdown of cell-cell junctions and loss of epithelial polarity, is closely related to cancer development and metastatic progression. While the cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-) and HCO3(-) conducting anion channel expressed in a wide variety of epithelial cells, has been implicated in the regulation of epithelial polarity, the exact role of CFTR in the pathogenesis of cancer and its possible involvement in EMT process have not been elucidated. Here we report that interfering with CFTR function either by its specific inhibitor or lentiviral miRNA-mediated knockdown mimics TGF-β1-induced EMT and enhances cell migration and invasion in MCF-7. Ectopic overexpression of CFTR in a highly metastatic MDA-231 breast cancer cell line downregulates EMT markers and suppresses cell invasion and migration in vitro, as well as metastasis in vivo. The EMT-suppressing effect of CFTR is found to be associated with its ability to inhibit NFκB targeting urokinase-type plasminogen activator (uPA), known to be involved in the regulation of EMT. More importantly, CFTR expression is found significantly downregulated in primary human breast cancer samples, and is closely associated with poor prognosis in different cohorts of breast cancer patients. Taken together, the present study has demonstrated a previously undefined role of CFTR as an EMT suppressor and its potential as a prognostic indicator in breast cancer.
上皮-间质转化（EMT）是一个涉及细胞间连接破坏和上皮极性丧失的过程，与癌症发展和转移进程密切相关。囊性纤维化跨膜传导调节因子（CFTR）是一种在多种上皮细胞中表达的Cl(-)和HCO3(-)传导阴离子通道，虽已被证实与上皮极性调节有关，但CFTR在癌症发病机制中的具体作用及其在EMT过程中的可能参与情况尚未阐明。在此我们报告，通过其特异性抑制剂或慢病毒miRNA介导的敲低来干扰CFTR功能，可模拟TGF-β1诱导的EMT，并增强MCF-7细胞的迁移和侵袭能力。在高转移性MDA-231乳腺癌细胞系中异位过表达CFTR可下调EMT标志物，并在体外抑制细胞侵袭和迁移，在体内抑制转移。发现CFTR的EMT抑制作用与其抑制NFκB靶向尿激酶型纤溶酶原激活剂（uPA）的能力有关，已知uPA参与EMT的调节。更重要的是，在原发性人类乳腺癌样本中发现CFTR表达显著下调，且与不同队列乳腺癌患者的不良预后密切相关。综上所述，本研究证明了CFTR作为EMT抑制因子的先前未明确的作用及其作为乳腺癌预后指标的潜力。
