The Role of miRNAs in the Progression of Prostate Cancer from Androgen-Dependent to Androgen-Independent Stages
Annual summary 1 Sep 2011-31 Aug 2012
VIRGINIA UNIV CHARLOTTESVILLE
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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-99alet7c125b-2 cluster through AR. Androgen-activated AR binds to the host gene of the miR-99alet7c125b-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-99alet7c125b-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-99alet7c125b-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-99alet7c125b-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-99alet7c125b-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 inducedrepressed by AR but also of genes indirectly induced by AR through the repression of key microRNAs.
- Anatomy and Physiology
- Medicine and Medical Research