The androgen receptor (AR) plays an important role in the initiation and progression of prostate cancer (CaP). Preliminary data show that expression of microRNA Let-7c is downregulated in CaP cells and tissues compared to benign prostate. Let-7c suppresses AR expression and overexpression of let-7c reduces AR activity, suggesting that let-7c may contribute to AR modulation in CaP cells. Additional studies suggest that let-7c- mediated AR suppression is via c-myc, an AR activator that is consistently overexpressed in prostate cancer. In addition, let-7c decreases the growth of CaP cells in vitro and in vivo. Furthermore, analysis of specimens from human prostate indicates a reverse correlation between Let-7c and AR expression. These data suggest that Let-7c plays an important role in regulating AR signaling and the development and progression of CaP. This proposal is aimed at understanding a novel microRNA (miRNA) let-7c-myc- mediated AR signaling pathway and the interaction between them.
Three specific aims are proposed to this study.
Aim 1 is to determine the effect of let-7c on cell growth and androgen responsiveness. We will knockdown Let-7c expression in androgen- responsive human prostate cancer cell lines, and assess the effects of such downregulation on the growth and on the androgen responsiveness of the cells. Conversely, we will overexpress Let-7c in castration-resistant prostate cancer cells to determine whether it can suppress cell growth and cause a reversal to an androgen- dependent state.
Aim 2 is to characterize let-7c as a modulator of AR and c-myc. We will characterize the potential mechanisms of let-7c-mediated AR suppression and the role of c-myc in this process. We will study whether let-7c suppresses AR expression and its transcriptional functions, and whether it is via suppression of c-myc. We will determine whether let-7c directly targets c-myc RNA and whether c-myc recruitment to AR promoter is affected. Furthermore, we will explore how let-7c expression is regulated in prostate cancer cells.
Aim 3 is to determine the relationship between let-7c, AR, and c- myc expression and prostate cancer progression. We will test the relationship of Let-7c, AR and c-myc in clinical prostate cancer specimens, and determine whether the levels of these three important molecules correlate with disease progression and castration resistance in specimens from patients with prostate cancer. If a novel pathway that connects AR, c-myc, and microRNAs is identified, it will gain a better understanding of the molecular mechanisms leading to prostate cancer development and progression.
Androgen receptor signaling plays critical roles in prostate development and cancer progression. We propose to explore the roles of microRNA let-7c in androgen receptor signaling and prostate cancer progression. Understanding the mechanisms of androgen receptor regulation and identification of molecular targets would greatly benefit to patients with prostate cancer.
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