The Role of microRNA-221 and microRNA-222 in Androgen-Independent Prostate Cancer Cell Lines

Androgen-dependent prostate cancer typically progresses to castration-resistant prostate cancer (CRPC) after the androgen deprivation therapy. MicroRNAs (mill) are noncoding small RNAs (19-25nt) that play an important role in the regulation of gene expression. Recent studies have shown that mill expression patterns are significantly different in normal and neoplastic prostate epithelial cells. However, the importance of mills in the development of CRPC has not yet been explored. By performing genome-wide expression profiling of mills, we found that expression levels of several mills, in particular miR-221 and miR-222, were significantly increased, in CRPC cells (the LNCaP-derived cell line LNCaP-Abl) compared with those in the androgen-dependent prostate cancer cell line (LNCaP). Overexpression of miR-221 or miR-222 in LNCaP or another androgen-dependent cell line, LAPC-4, significantly reduced the level of the dihydrotestosterone (DHT) induced up-regulation of prostate-specific antigen (PSA) expression and increased androgen-independent growth of LNCaP cells. Knocking down the expression level of miR-221 and miR-222 with antagonist mills in the LNCaP-Abl cell line restored the response to the DHT induction of PSA transcription and also increased the growth response of the LNCaP-Abl cells to the androgen treatment. Changing the expression level of p27/kip1, a known target of miR-221 and miR-222, alone in LNCaP cells affected the DHT-independent cell growth but did not significantly influence the response of PSA transcription to the DHT treatment. In conclusion, our data suggest the involvement of miR-221 and miR-222 in the development or maintenance of the CRPC phenotype. [Cancer Res 2009;69(8):3356-63]