MicroRNA Linked to Regulation of Prostate Cancer Cells

A recent paper described the mode of action of miR-125b, a microRNA that has been identified as an important regulator in various cancers, including prostate cancer.

Investigators at the University of Colorado (Denver, USA) worked with both LNCaP prostate cancer cells growing in culture and with a mouse model of the androgen deprivation form of prostate cancer, which was induced by castration of the animals.

Expression of miR-125b was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LNCaP prostate cancer cells treated with the antiandrogen drug bicalutamide. Bicalutamide acts as a pure antiandrogen by binding to the androgen receptor (AR) and preventing its activation and subsequent upregulation of androgen responsive genes by androgenic hormones. In addition, bicalutamide accelerates the degradation of the androgen receptor.

Using LNCaP cells, the effect of miR-125b modulation on apoptotic protein and NCOR2 (nuclear receptor co-repressor 2), a corepressor of AR, was examined by Western blot. The NCOR2 protein is a member of a family of thyroid hormone- and retinoic acid receptor-associated corepressors. This protein acts as part of a multisubunit complex, which includes histone deacetylases to modify chromatin structure that prevents basal transcriptional activity of target genes.

Results published in the June 25, 2012, issue of the journal BioResearch Open Access revealed that surgical castration induced an initial increase in the expression of circulating miR-125b in mice, while sham surgery did not. In addition, AR blockade via bicalutamide was associated with the rapid release of miR-125b into the cell culture medium of prostate cancer cells. NCOR2, which is a repressor of AR, was found to be a direct target of miR-125b. The investigators found that NCOR2 protein expression was blocked by mimics of miR-125b, and that a luciferase-binding assay confirmed that NCOR2 was a direct target of miR-125b.

The authors wrote that, "The androgen receptor is a critical therapeutic target in prostate cancer. Our data provide novel evidence that miR-125b is an important regulator of the AR with specific ramification for the effectiveness of antiandrogens and other hormonal therapies in prostate cancer."

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