Androgen signalling-modulatory microRNAs: roles in prostate cancer progression and therapy

Abstract

In the UK, prostate cancer is the most common cancer and the second most common cause of cancer related death amongst men. Prostate cancer is an androgen dependent malignancy that initially responds well to androgen ablation therapy. However, despite hormonal treatment, hormone unresponsive prostate cancer eventually emerges and may lead to death. Current diagnostic and therapeutic strategies have many limitations and it is imperative to identify new biomarkers and therapeutic targets for this condition. MicroRNAs have emerged over the years as potential biomarkers and therapeutic targets. MicroRNAs are small, non-coding RNAs that regulate gene silencing through the inhibition of translation and mRNA degradation, and function both as oncogenes, and as tumour suppressors. Circulating microRNAs potentially have a significant role as diagnostic, and prognostic markers and microRNAs and their inhibitors, in the form of antisense oligonucleotides, have therapeutic potential as regulators of gene expression. Work in this thesis has focused on the role of miR-1271-5p, an AR-modulatory microRNA, and miR-27a-3p in prostate cancer progression and therapy. I report that miR-1271-5p has androgenic potential, is implicated in disease progression and has therapeutic potential. In work described in this thesis, miR-27a-3p has been found to be an androgen receptor modulatory oncomiR in prostate cancer cell lines, and to have therapeutic potential in castrate resistant prostate cancer. The predicted targets of both miR-27a-3p and miR-1271-5p include genes with roles in growth arrest, apoptosis and DNA repair. It is hoped that the elucidation of the molecular and biological role of these microRNAs and their target genes in prostate cancer, will provide us with a better understanding of disease development and lay the foundation for further advances in the diagnosis and treatment of prostate cancer.