Abstract
Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here, we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression and activity in human prostate cancer cells by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation of human prostate cancer cells. Down-regulation of Let-7c in prostate cancer specimens is inversely correlated with AR expression, whereas the expression of Lin28 (a repressor of let-7) is correlated positively with AR expression. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer.
Highlights
Let-7c is a microRNA down-regulated in prostate cancer
Our data showed that the levels of let-7c were lower in the castration-resistant cell lines C4-2B, LNCaP-s17, and LN-IL6ϩ (LNCaP chronically treated with IL-6), which express higher levels of androgen receptor (AR) compared with parental LNCaP cells that express lower levels of AR (Fig. 1, A and B) [29, 30], indicating an inverse relationship between AR and let-7c
Overexpression of let-7c was confirmed by qRT-PCR. These results suggested that let-7c inhibits AR expression in Prostate cancer (PCa) cells
Summary
Let-7c is a microRNA down-regulated in prostate cancer. Results: Let-7c suppresses androgen receptor expression by targeting its transcription via c-Myc. Significance: Our study demonstrates that let-7c plays an important role in regulation of androgen signaling and prostate cancer proliferation. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer. The study of factors that regulate expression and activation of the AR will enhance our understanding of the mechanisms leading to castration resistance and will play a key role in devising therapeutic strategies to combat this lethal cancer. Our results imply that AR signaling can be regulated by let-7c in PCa by decreasing survival and proliferation of tumor cells
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