Down regulation of RARγ in Prostate Cancer and the Potential control of its Expression via microRNA-96
Russell, James A., Jr.
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Background: Knockout of Rarγ leads to prostate neoplasia. Similarly stem cell research has identified RARγ as the main nuclear receptor for ATRA signaling. Although the RARγ is eminently druggable, clinical trials have been equivocal. We reasoned that micro-RNA that target RARγ may have utility as serum-bourne biomarkers of patients that are amenable to ATRA-based therapy. Methods: We analyzed human primary prostate cancer tissue data from the cBioPortal database to find RARγ transcript expression and the expression of miR-96. Non-malignnat and malignant prostate cell lines were also queried for transcript and protein expression of RARγ and miR-96, an established miRNA targeting RARγ. We also used a miR-96 antagomir to knockdown the miRNA and measure responsiveness to ATRA. Results: We used cBioPortal to evaluate the transcriptional expression from primary prostate cancer tissue and observed that RARγ was down-regulated in 59.18% of patients. In addition to finding the expression of RARγ to be commonly down-regulated, we also examined the expression of miRNA predicted to target the receptor's transcript and found the miR-183-96-182 cluster to be over expressed in this primary prostate cancer tissue. Of the miRNA in this cluster that were predicted to target RARγ, miR-182 had been validated to target the RARγ transcript and miR-96 had not been validated. Matched tissue expression of the RARγ and miR-96 and 182 revealed that 72% of patients with RARγ down-regulation had parallel increase in targeting miRNA. In prostate cancer cell lines we identified down regulation of RARγ and increased miR-96. When treating C42 and PC3 cells with a miR-96 antagomir there is a 25% and 50% decrease in cell growth respectively. Finally, use of miR-96 antagomirs up-regulated RARγ transcript in LNCAP-C42 cells. We were unable to elicit a negative effect on cell proliferation using ATRA for cells induced to have higher RARγ transcript. Conclusions: Given the central role of RARγ in normal prostate biology, and the very significant interactions in prostate cancer cells, as revealed by TCGA, it is worthy to study miR-96 as a method to develop a new targeted therapy for selected patients that are expressing high levels of miR-96.