CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer

Abstract

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.

Ion channels/transporters as epigenetic regulators? —a microRNA perspective

“…Besides, defective or dysregulated CFTR can activate NF-B, which has been demonstrated to be one of the major transcriptional factors to activate miRNAs [71,72]. Interestingly, we have also found that CFTR knockdown leads to enhanced activation of NFB in cancer cell lines [95]. In addition, we have shown that NFB inhibitor reverses CFTR knockdown-enhanced cancer progression [95].…”

“…Interestingly, CFTR-mediated HCO 3  transport has been shown to activate a soluble form of adenylyl cyclase and cAMP-dependent pathway in sperm [53] and lung epithelial cells [55], which may lead to activation of some cAMP dependent transcription factors, such as CREB, and thus transcription of related miRNAs. As discussed earlier, our recent study has shown that miRNA expression is greatly influenced by extracellular HCO3  concentration [60], and that CFTR manipulation affects miRNA expression profile in prostate cancer cell lines [95]. Besides, defective or dysregulated CFTR can activate NF-B, which has been demonstrated to be one of the major transcriptional factors to activate miRNAs [71,72].…”

“…Interestingly, we have also found that CFTR knockdown leads to enhanced activation of NFB in cancer cell lines [95]. In addition, we have shown that NFB inhibitor reverses CFTR knockdown-enhanced cancer progression [95]. Moreover, we have also shown that activation of miR-125b during preimplantation embryo development was mediated by sAC/ PKA-dependent nuclear shuttling of NF-B (Figure 1) [60].…”

“…In other words, the hypoxia-induced downregulation CFTR may be responsible for the miRNAs alteration seen in various cancers. Indeed, our recent study investigating the role of CFTR in the de-velopment of prostate cancer has revealed a direct association of CFTR with miR-193b expression in prostate cancer [95]. MiR-193b has been recently identified as an epigenetically regulated putative tumor suppressor in various types of cancer [66,67] and shown to target urokinase-type plasminogen activator (uPA) [68].…”

The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia

“…We also reported the upregulation of rat miR-193b after nitrofen exposure. Others attributed cystic fibrosis transmembrane conductor regulator replenishment and cancer regression to the upregulation of miR-193b in human (17). Thus, miR-193b may rescue cystic fibrosis transmembrane conductor regulator downstream of nitrofen in rat lung hypoplasia-a finding that warrants further investigation.…”