The role of prohibitin and miR-27a in prostate cancer progression and therapy response
Creators: name: Sita-Lumsden, Ailsa
Publisher: name: Imperial College London
Year: 2016

description: Introduction: Prostate cancer is the most commonly diagnosed male cancer in the Western world, with more than 40,000 cases in the UK diagnosed annually. The androgen receptor (AR) is required for the survival and proliferation of the prostate cancer cell and is key to prostate cancer treatment. The levels of both AR itself and its cofactors are in turn modulated by specific microRNAs, hence manipulating key microRNAs that affect androgen signaling is a potential therapeutic strategy for prostate cancer. One such key microRNA is miR-27a, which has a confirmed oncogenic role in gastric cancer and we previously showed to target the AR corepressor Prohibitin. In addition, circulating microRNAs (miRNAs) have been a source of hope as potential new biomarkers for cancer. Results: There is evidence that prohibitin is decreased in the more aggressive prostate cancer cell lines and also in metastatic deposits in clinical cases of prostate cancer. Conversely miR-27a is increased in the more aggressive cell lines and in the metastatic deposits in clinical cases of prostate cancer. Treatment of LNCaP cells with an anti-sense oligomiR inhibitor of miR-27a (ASO-27a) resulted in a decrease in miR-27a levels, an increase in prohibitin levels, and a decrease in cell growth. Conversely when LNCaP cells were induced to express high levels of miR-27a (via stable transfection with a doxycycline-inducible miR-27a expression vector) there was a significant increase in growth. These findings, suggestive of tumour-promoting properties of miR-27a, were supported in an in vivo xenograft model. Mice bearing human prostate tumours and treated systemically with ASO-27a had significantly less tumour growth when compared to those treated with control oligomiR. Surprisingly, we did not observe a direct effect on prohibitin levels in the treated tumours. The genes showing significant differential expression following treatment with ASO-27a were compared with published data sets of gene expression at different clinical stages of prostate cancer tissue. Multiple genes of interest were identified, that were both significantly raised following treatment with ASO-27a and expressed at significantly lower levels in cases of metastatic prostate cancer. In the circulation of men with metastatic prostate cancer I found that miR-27a is generally higher when compared to men with healthy prostates. A targeted panel of miRs was screened in this context, and a subset consisting of miR-21, miR-10b, miR-126, miR-150, miR-378 and miR-93 could differentiate benign from metastatic disease; it would be interesting to explore this 6 miR signature further as potential diagnostic or predictive biomarker test. Conclusion: We have shown that using an anti-sense oligomiR to miR-27a reduces prostate cancer growth both in vitro and in vivo, at least in part via increasing apoptosis, and thus warrants further investigation as a potential future therapy. In addition circulating levels of miRNAs, including miR-27a, may provide clinically useful biomarker information regarding diagnosis, prognosis, or prediction of response to treatment.