Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
Oncogene. 2013 May 2;32(18):2282-91, 2291.e1-7. doi: 10.1038/onc.2012.251. Epub 2012 Jul 16.
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is expressed in the epithelial cells of a wide range of organs/tissues from which most cancers are derived. Although accumulating reports have indicated the association of cancer incidence with genetic variations in CFTR gene, the exact role of CFTR in cancer development and the possible underlying mechanism have not been elucidated. Here, we report that CFTR expression is significantly decreased in both prostate cancer cell lines and human prostate cancer tissue samples. Overexpression of CFTR in prostate cancer cell lines suppresses tumor progression (cell growth, adhesion and migration), whereas knockdown of CFTR leads to enhanced malignancies both in vitro and in vivo. In addition, we demonstrate that CFTR knockdown-enhanced cell proliferation, cell invasion and migration are significantly reversed by antibodies against either urokinase plasminogen activator (uPA) or uPA receptor (uPAR), which are known to be involved in various malignant traits of cancer development. More interestingly, overexpression of CFTR suppresses uPA by upregulating the recently described tumor suppressor microRNA-193b (miR-193b), and overexpression of pre-miR-193b significantly reverses CFTR knockdown-enhanced malignant phenotype and abrogates elevated uPA activity in prostate cancer cell line. Finally, we show that CFTR gene transfer results in significant tumor repression in prostate cancer xenografts in vivo. Taken together, the present study has demonstrated a previously undefined tumor-suppressing role of CFTR and its involvement in regulation of miR-193b in prostate cancer development.
囊性纤维化跨膜电导调节因子（CFTR）在广泛的器官/组织的上皮细胞中表达，大多数癌症都来源于这些器官/组织。尽管越来越多的报告表明癌症发病率与 CFTR 基因突变有关，但 CFTR 在癌症发展中的确切作用及其潜在的机制尚未阐明。在这里，我们报告 CFTR 表达在前列腺癌细胞系和人前列腺癌组织样本中均显著降低。CFTR 在前列腺癌细胞系中的过表达抑制肿瘤进展（细胞生长、黏附和迁移），而 CFTR 的敲低导致体外和体内的恶性程度增强。此外，我们证明 CFTR 敲低增强的细胞增殖、细胞侵袭和迁移可被针对尿激酶纤溶酶原激活物（uPA）或 uPA 受体（uPAR）的抗体显著逆转，已知这些物质参与癌症发展的各种恶性特征。更有趣的是，CFTR 的过表达通过上调最近描述的肿瘤抑制 microRNA-193b（miR-193b）抑制 uPA 的表达，而过表达 pre-miR-193b 则可显著逆转 CFTR 敲低增强的恶性表型，并消除前列腺癌细胞系中升高的 uPA 活性。最后，我们表明 CFTR 基因转移可导致前列腺癌异种移植瘤在体内的显著抑制。综上所述，本研究首次证明 CFTR 具有以前未定义的肿瘤抑制作用，并参与了前列腺癌发展过程中 miR-193b 的调控。
