MiR-181a promotes epithelial to mesenchymal transition of prostate cancer cells by targeting TGIF2

Abstract

Objective: Prostate cancer is the most commonly diagnosed cancer, and metastatic prostate cancer often leads to poor outcomes for patients. During the metastasis processes, cancer cells acquire a migratory and invasive phenotype. Epithelial to mesenchymal transition (EMT) has been implicated in multiple processes of prostate cancer development including migration, chemoresistance, and carcinogenesis.

Patients and methods: Expressions of miR-181a in prostate tumor samples and cancer cells were measured by qRT-PCR. Epithelial or mesenchymal markers were detected by Western blot. Nuclear translocation of Smad 2/3 was measured by immunostaining of prostate cancer cells.

Results: In this study, we report an oncogenic role of microRNA-181a in prostate cancer cells and patients. MiR-181a is upregulated in metastatic prostate tumor samples compared with primary prostate tumors. Interestingly, we found that overexpression of miR-181a promotes prostate cancer cell migration and invasion. Moreover, we observed that overexpression of miR-181a contributes to an epithelial to mesenchymal transition phenotype in prostate cancer cells: the epithelial marker, E-cadherin was downregulated, and mesenchymal markers, N-cadherin, vimentin, and snail were upregulated. Consistently, the phosphorylation of Smad 2/3 and the nuclear localization of Smad 2/3 were increased by miR-181a expression. We identified that TGIF2 - a repressor of the Smad pathway - is a direct target of miR-181a in prostate cancer cells. Importantly, restoration of TGIF2 in miR-181a overexpressing prostate cancer cells inhibited the Smad pathway and EMT processes.

Conclusions: This research identifies a molecular mechanism for microRNA-mediated cancer metastasis and improvement novel therapeutic avenue for metastatic prostate cancer patient treatments.