Deregulation and editing of microRNAs in metastatic prostate cancer

Sammanfattning: Prostate cancer bone metastasis is still not fully understood, and increased knowledge could aid in the development of better treatment options for patients in the future. This thesis focuses on microRNAs (miRNAs), which modulate gene expression in healthy and tumour cells. Using cell culture, animal and patient studies, we investigated the biological role of microRNA-96 (miR-96) and microRNA-379 (miR-379) in prostate cancer bone metastasis. We also studied the role of A-to-I RNA editing in regulating miR-379 function.In Paper I, we showed that miR-96 can upregulate the mRNA and protein expression of adhesion proteins E-Cadherin and EpCAM through direct interaction with target sites in the mRNA coding sequence. We also showed that miR-96-transfected cells had increased cell-cell adhesion to both each other and osteoblasts, and an increased colony formation potential.In Paper II, we performed an in vivo anti-miRNA library screen, and identified miR-379 as a suppressor of prostate cancer bone metastasis. Downregulation of miR-379 enhanced incidence of bone metastasis in mice, increased colony formation potential in osteoblast-conditioned media, and increased cell growth. In bone metastasis samples from prostate cancer patients, miR-379 was frequently downregulated.In Paper III, we developed a two-tailed RT-qPCR method for the sensitive and specific quantification of A-to-I-edited miRNAs. Using this method, we could reveal that unedited, but not edited, miR-379 was frequently downregulated in prostate cancer patients with metastasis, treatment resistance, and shorter overall survival. The editing frequency of miR-379 was higher in prostate cancer tissues compared to benign tissues.In Paper IV, we compared the biological functions of unedited and edited miR-379 in prostate cancer cells. We found that unedited miR-379 increased cell growth in androgen-independent cell lines, but inhibited cell growth in androgen-sensitive cell lines. Both unedited and edited miR-379 also slightly enhanced colony formation and cell migration in all tested cell lines.Overall, this thesis reports multiple findings and tools that can help us better understand the process of prostate cancer bone metastasis and the role that miRNAs play in this process.