MIR-1256b Induces Androgen-Independent Growth Of Prostate Cancer Cells

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 08 Jun 2008 - 0:00 PDT

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ORLANDO, FL (UroToday.com) - Increasing evidence has shown that some aberrantly-expressed microRNAs (miRNAs) are involved in human carcinogenesis. Recently, a group of researchers from UC Davis found that androgen-independent (AI) LNCaP sublines (cds cells) express markedly increased miR-125b compared to the parental LNCaP cells, suggesting that this miRNA may play a role in the pathogenesis of prostate cancer (CaP). Since the association of miR-125b with CaP is totally unknown, the purpose of this study was to understand the role of this miRNA in CaP.

They used LNCaP and cds1 cells cultured in androgen-depleted medium and transfected with synthetic miR-125b and antimiR-125b, respectively, and cell proliferation was assessed using the WST-1 assay. Chromatin immunoprecipitation (ChIP) assay was used to determine the loading of androgen receptor (AR) onto the 5'-DNA region of miR-125b. To test whether BAK1 mRNA is a direct target of miR-125b, a luciferase assay was performed in AR-negative DU145 cells to evaluate the effects of miR-125b on the 3'-untranslated region (3'-UTR) of the BAK1 gene.

The researchers report that synthetic miR-125b stimulated the growth of LNCaP cells in the absence of androgens. These cells retained typical morphological features. In contrast, in cds cells, inhibition of miR-125b activity using synthetic anti-miR-125b inhibited proliferation of these cells and this was accompanied by a reduction of cell size and increased neuroendocrine features. These data suggest that miR-125b stimulates the AI growth of LNCaP cells. Since the synthetic androgen R1881 upregulated the expression of miR-125b, we examined whether the AR is able to load to the 5'-DNA region of the miR-125b locus to serve as a transcriptional factor. Results from ChIP assays showed that treatment of LNCaP cells with R1881 induced a 4.5- to 6.5-fold increase in AR loading at the 5' region of miR-125b, suggesting that androgen-AR signaling regulates the expression of miR-125b in CaP cells. Since microarray assays demonstrated a > 2.0 fold downregulation of the BAK1 gene in miR-125b-treated LNCaP cells, and since the 3'-UTR of BAK1 gene contains a miR-125b binding site, luciferase assay of this 3'-UTR was performed. It was found that synthetic miR-125 induced a 50-60% reduction of the luciferase activity.

This data indicates that 1) miR-125b acts as an oncogene, contributing to the pathogenesis of CaP; 2) AR regulates the expression of miR-125b and 3) miR-125b targets the BAK1 gene.

Presented by Xu-Bao Shi, Lingru Xue, Joy Yang, Christopher P Evans, Ralph W deVere White at the Annual Meeting of the American Urological Association (AUA) - May 17 - 22, 2008. Orange County Convention Center - Orlando, Florida, USA.

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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