Androgen Receptor and miR-200b in the Inhibition of Prostate Cancer.

摘要

Prostate cancer (PCa) is the second most frequently diagnosed cancer in elderly men in the United States. Androgen receptor (AR) is a nuclear steroid hormone receptor whose activation is central in increased proliferation observed in this cancer. Current first-line therapy for invasive and metastatic prostate cancer is androgen ablation (surgical or chemical castration), which causes gross cell death of androgen-dependent cancer cells and normal prostate epithelium. Persistent ablation results in the emergence of Castrate-Resistant Prostate Cancer (CRPC), characterized by aberrant AR signaling and lack of response to androgen ablation, ultimately leading to metastasis and death. Data from our lab and others show that re-activation of AR signaling decreases proliferation, reduces tumorigenicity, and increases differentiation and senescence of tumor cells. These results indicate the normal function of AR in the prostate and early-stage prostate cancer is tumor suppression. Seeking mechanisms underlying AR tumor suppression, we found that it regulates multiple microRNA including miRNA 200b. Dysregulation of miR-200b has been previously determined as a factor that allows epithelial-to-mesenchymal transition (EMT) and metastasis in many human cancers. In normal cells, miR-200b maintains epithelial phenotype by binding to the 3' UTR of pro-metastatic transcriptional repressors ZEB1 and ZEB2, which block E-cadherin. To date, few studies have addressed the function of miR-200b in PCa. We sought to determine the effect of miR-200b downstream of AR on the primary tumor and metastasis of prostate cancer by using AR-null PC-3 PCa cell line as a model. Using microarray and real time RT-PCR analyses of PC-3 cells engineered to inducibly express AR (PC3-AR) we demonstrated a potent increase of miR-200b expression due to AR activation. Overexpression of miR-200b in AR-null PC-3 cells resulted in decreased tumorigenicity and metastasis in heterotopic and orthotopic mouse models. Moreover, miR-200b expression resulted in elevated levels of markers characteristic of differentiated prostate epithelium, Cytokeratin 8 and 18 and decreased levels of mesenchymal markers fibronectin, vimentin, and ZEB1. MicroRNA 200b also caused increased expression of the epithelial marker E-cadherin. Our results confirm the function of miR-200b in promoting epithelial fate and demonstrate its potential therapeutic efficacy in control of prostate cancer growth and metastasis.