Role of miRNAs in the Progression of Prostate Cancer from Androgen- Dependent to Androgen-Independent Stages.

摘要

The androgen receptor (AR) stimulates and represses gene expression to promote the initiation and progression of prostate cancer. Here we report that androgen represses the miR-99a/let7c/125b-2 cluster through AR. Androgen- activated AR binds to the host gene of the miR-99a/let7c/125b-2 cluster, LINC00478. The repression is partially mediated by the polycomb protein EZH2. Bioinformatic analysis reveals a significant enrichment of targets of miR-99a, let-7c and miR-125b in androgen-induced gene sets, suggesting that downregulation of the miR-99a/let7c/125b-2 cluster by androgen protects many of their target mRNAs from degradation and indirectly assists in the gene induction. We validated the hypothesis with twelve potential targets of the miR- 99a/let7c/125b-2 cluster induced by androgen: nine out of the twelve mRNAs are downregulated by the microRNA cluster. To ascertain the biological significance of this hypothesis we focused on IGF1R, a known prostate cancer growth factor that is induced by androgen and predicted to be targeted by the miR- 99a/let7c/125b-2 cluster. IGF1R is directly repressed by miR-99a and let-7c and expression of a microRNA-resistant form of IGF1R protects prostate cancer cells from inhibition by the miR-99a/let7c/125b-2 cluster. Finally, the androgen induced cell proliferation is ameliorated by preventing the repression of the microRNAs or induction of IGF1R. These results indicate that a thorough understanding of how androgen stimulates prostate cancer growth requires not only an understanding of genes directly induced/repressed by AR but also of genes indirectly induced by AR through the repression of key microRNAs.