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miR-21: An Androgen Receptor–Regulated MicroRNA that Promotes Hormone-Dependent and Hormone-Independent Prostate Cancer Growth

¹ The James Buchanan Brady Urological Institute, ² McKusick-Nathans Institute of Genetic Medicine, Departments of Pediatrics and Molecular Biology and Genetics, and ³ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Shawn E. Lupold, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Park 209, Baltimore, MD 21287. Phone: 410-502-4822; Fax: 410-502-7711; E-mail: slupold{at}jhmi.edu.

Key Words: Prostate cancer • microRNA • Androgen Receptor

Androgen receptor (AR)–mediated oncogenic pathways have not been fully elucidated. In this study, we used high-throughput microarray analysis on two AR-positive prostate cancer (CaP) cell lines to identify 16 AR-responsive microRNAs (miRNA). We focused on miR-21 because of its previously reported oncogenic activity in other cancers. We show androgen-induced AR binding to the defined miR-21 promoter, miPPR-21, suggesting direct transcriptional regulation. Inhibition of miR-21 diminished androgen-induced CaP cell proliferation, providing new evidence that miRNAs can contribute to androgen-driven cell growth. Elevated expression of miR-21 enhanced CaP tumor growth in vivo and, surprisingly, was sufficient for androgen-dependent tumors to overcome castration-mediated growth arrest. Thus, elevated miR-21 expression alone is sufficient to impart castration resistance. Moreover, quantitative reverse transcription-PCR analysis revealed elevated miR-21 expression in CaP when compared with adjacent normal tissue. These results suggest that miR-21 may contribute to CaP pathogenesis. [Cancer Res 2009;69(18):7165–9]