Abstract
Prostate cancer (PCa) is one of the most common cancers to affect men worldwide. Androgen receptor (AR) signaling is central to PCa and PCa therapy. MicroRNAs (miRNAs) play crucial roles in the regulation of prostate cancer through modulation of signaling pathways. In the present study, we illustrate the functional significance and therapeutic benefit of miR-299-3p, an AR targeting microRNA, in PCa progression. We noted loss of expression of miR-299-3p in prostate tumors compared to noncancerous prostate tissues. Replenishment of miR-299-3p in C4-2B, 22Rv-1 and PC-3 cells contributed to cell cycle arrest, reduced proliferation, migration and increased expression of apoptotic markers. Additionally, overexpression of miR-299-3p induced a reduction of AR, PSA and VEGFA expression. AGO-RNA pulldown experiment showed enrichment of AR, VEGFA and miR-299-3p in C4-2B cells overexpressing miR-299-3p. miR-299-3p overexpression also inhibited epithelial mesenchymal transition, expression of Slug, TGF-β3, phospho-AKT and phospho-PRAS40, but increased expression of E-cadherin. Furthermore, miR-299 overexpression resulted in reduced tumor growth in xenograft models and increased drug sensitivity. Overall, this study has identified novel mechanisms of antitumor and antimigration function of miR-299-3p through modulation of AR and VEGFA signaling pathways which lead to improved drug sensitivity of PCa.
Highlights
Www.nature.com/scientificreports apoptosis during treatment, thereby, causing the recurrence of the cancer[7]
Our data suggest that miR-299-3p is frequently downregulated in Prostate cancer (PCa) cells and tissues and exerts a tumor suppressor role through the bimodal targeting of Androgen receptor (AR) and VEGFA to inhibit different signaling cascades that are constitutively active in PCa
Because VEGFA is transcriptionally regulated by AR through binding to the VEGFA promoter in a complex with Sp124, we studied the expression of VEGFA in these cells
Summary
Www.nature.com/scientificreports apoptosis during treatment, thereby, causing the recurrence of the cancer[7]. MiRNAs often target a spectrum of genes and could offer advantages over monotherapies targeting a single pathway To exploit this characteristic of miRNAs, a better understanding of their involvement in PCa is necessary. A number of miRNAs are involved in progression from localized disease to aggressive PCa including miR-2188, -1439, -14510 and let7c11, whereas, restored expression of the miR-17-92a cluster miRNAs has tumor suppressor effects in metastatic PCa cells[12]. We studied the overall effect of miR299-3p on different phenotypic characteristics associated with cancer progression including activation of signaling cascades, tumor growth and drug sensitivity using cell culture and xenograft models. Our data suggest that miR-299-3p is frequently downregulated in PCa cells and tissues and exerts a tumor suppressor role through the bimodal targeting of AR and VEGFA to inhibit different signaling cascades that are constitutively active in PCa
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