MicroRNA-21 inhibits p57^Kip2 expression in prostate cancer

Background: p57^Kip2, a cyclin-dependent kinase inhibitor, is considered to be a candidate tumor suppressor gene that has been implicated in Beckwith-Wiedemann syndrome and sporadic cancers. In addition, decreased expression of p57^Kip2 protein has been frequently observed in pancreatic, lung, breast, bladder, gastrointestinal tract and prostate cancers. However, p57^Kip2 gene mutations are rare in these cancers suggesting that other unknown mechanisms might be at play in reducing its expression. The aim of this study was to investigate the molecular mechanism of down-regulation of p57^Kip2 in prostate cancer. Findings: We observed a significant negative correlation between the expression of p57^Kip2 and microRNA-21 (miR-21) in prostate cancer samples and after androgen deprivation with castration in the CWR22 human prostate cancer xenograft model. We report that miR-21 targeted the coding region and decreased p57^Kip2 mRNA and protein levels in prostate cancer cells. Conversely, inhibition of endogenous miR-21 by an anti-miR-21 inhibitor strongly induced p57^Kip2 expression. Furthermore, we found that knockdown of p57^Kip2 reversed the effects of the anti-miR-21 inhibitor on cell migration and anchorage-independent cell growth. Conclusions: Our results indicate that miR-21 is able to downregulate p57^Kip2 expression by targeting the coding region of the gene and is also able to attenuate p57^Kip2 mediated functional responses. This is the first report demonstrating that p57^Kip2 is a novel target of miR-21 in prostate cancer and revealing a novel oncogenic function of this microRNA.