microRNAs as Mediators of Zinc Homeostasis and Vitamin D Actions in the Prostate

Recent advancements in microRNA (miR) research have provided insight into their role as regulators of post-transcriptional gene expression. In the studies presented in this thesis, we sought to expand our understanding of miR function and regulation in prostate physiology and as potential contributors to prostate cancer (PCa). In Chapter II, we described the evolution and function of an oncomiRic miR cluster, the miR-183 family, which comprises of miRs-183, -96 and -182, in normal development and as a regulator of various diseases. We performed pathway analyses using reporter validated targets of the miR-183 family members, which enriched for specific pathways that included apoptosis, metabolism, DNA repair, circadian rhythm and immune function. In Chapter III, we focused on the specific role of the miR-183 family as a regulator of zinc homeostasis in the prostate and demonstrated that the overexpression of the miR-183 family reduces intracellular zinc in prostate epithelial cells. High levels of the miR-183 family increased the size of PCa cells xenografted in nude mice and reduced intracellular zinc levels in these tumors. Since PCa is characterized by a dramatic reduction in zinc levels compared to benign counterparts, these miRs may play a role in regulating prostate carcinogenesis by regulating zinc homeostasis. In Chapter IV, we continued to focus on prostate-specific miRs and discovered that vitamin D regulates miR expression in benign prostate stromal cells in vitro and in benign stromal tissue from vitamin D treated PCa patients. Network analyses using mRNA targets of vitamin D regulated miRs were enriched for genes involved in cancer growth, inflammation and chemokine regulation, consistent with vitamin D’s anti-proliferation and anti-inflammatory actions. Taken together, our findings support the concept that miRs are important mediators of prostate physiology in both the epithelium and the stroma.