MiR-146-SIAH2-AR Signaling in Castration-Resistant Prostate Cancer
Final rept. 1 Sep 2014-31 Aug 2015
GEORGE WASHINGTON UNIV WASHINGTON DC
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Androgen ablation therapy often fails after significant initial clinical response and PCa patients invariably relapse with more aggressive Castration-Resistant Prostate Cancer CRPC. The mechanism of CRPC development is poorly understood. In order to develop effective therapeutics, understanding the mechanism of progression of CRPC is essential. In this award, we explored the possible role of a non-coding RNA miR-146a in CRPC. Using AR-dependent and -independent PCa cells, we tested a hypothesis that miR-146a is overexpressed in AR-dependent cells and that it targets SIAH2, which is known to regulate AR signaling and overexpressed in CRPC cells. Our results show that miR-146a is overexpressed in ARdependent cells and that its expression negatively correlates with SIAH2 expression in PCa cells. To further confirm this observation, we show that miR-146 inhibition upregulates SIAH2 in AR-dependent cells. Next, we show that miR-146a targets SIAH2 via its seed sequences in the 3UTR of SIAH2 miRNA. We also show that miR-146a overexpression in AR-independent cells strongly inhibits SIAH2 expression and oncogenic phenotype in these cells. Finally, our data suggest that miR-146a inhibition may promote CRPC features in AR-dependent cells by increasing oncogenic properties. In summary, our results demonstrate that miR-146-SIAH2-AR signaling pathway plays an important role in the development of CRPC and that this pathway can be targeted for the development of novel PCa therapeutics.
- Medicine and Medical Research