miR-221 regulates proliferation, invasion, apoptosis and progression of prostate cancer cells by modulating E-cadherin/Wnt/8 catenin axis

MicroRNA-221 (miR-221) is aberrantly expressed in various tumours including prostate carcinoma and can act as either tumour suppressor or oncogene depending on the tumour system and stage. Epithelial-mesenchymal transition (EMT) is a plastic transition in tumour progression characterized by decreased expression of epithelial markers and increased expression of mesenchymal markers and has been known to play a critical role in promoting metastases. In this study, we have demonstrated the functional role of miR-221 in regulating epithelialmesenchymal transition in prostate cancer. Expression of miR-221 was found to be downregulated in androgenindependent prostate cancer cells and was found to be inversely correlated with EMT. Ectopic expression of miR221 potentially inhibited invasion and migration of androgen-independent prostate cancers cells and inhibition of miR-221 expression rescued the anti-invasive effects of miR-221. Flow cytometric analysis further revealed that miR-221 could induce cell cycle arrest with simultaneous induction of apoptosis. Additionally, transfection with miR-221 mimic upregulated negative regulators of Wnt/8 catenin pathway such as GSK-38 thereby inhibiting it and downregulated mesenchymal markers viz., N-cadherin and Vimentin with simultaneous upregulation of epithelial marker E-cadherin as revealed by real-time PCR and Western blot analysis. A study using xenograft model further confirmed the anti-tumorigenic and anti-metastatic role of miR-221 in prostate cancer. We believe that his study is the first report documenting the miR-221- Wnt/8 catenin signaling-EMT regulatory circuit in prostate cancer.