We had previously examined genome-wide expression of microRNAs and mRNAs in 60 primary human prostate tumors and 16 non-tumor prostate tissues in collaboration with Dr. Carlo Croce at Ohio State University. The analysis revealed that both key components of microRNA processing and numerous microRNAs were significantly altered in prostate tumors when compared with surrounding non-cancerous tissue. Tumor microRNAs were up- and down-regulated when compared with non-cancerous tissue and the expression profile of the tumors yielded a diagnostic microRNA signature. Notably, prostate tumors tended to express all members of the miR-106b-25 cluster at significantly higher levels than non-tumor prostate, which is consistent with the miR-106b-25 cluster having oncogenic properties in prostate tumor biology. The expression of miR-1 and miR-133 was consistently lower in tumors than in non-tumor prostate, indicating that these microRNAs may act as tumor suppressors. Both the miR-106b-25 cluster and the miR-1-133 cluster were extensively studied by us, and we showed how they signal in human prostate cancer cells and also revealed their association with disease recurrence. Beyond our interest in these two microRNA clusters, we also recognized that other microRNAs change their expression pattern at the transition of an organ-confined prostate tumor to a tumor with extraprostatic extension. Currently, we are exploring how these microRNAs may affect the metabolism in prostate cancer cells. Candidate microRNAs that are targeted by our research are those that are associated with disease recurrence. Top-ranked candidates will be assessed computationally to establish their candidate function in metabolic pathways. microRNAs that are predicted to influence specific metabolic pathways will then be experimentally evaluated using overexpression and knockout approaches to facilitate an integrated assessment of the cancer transcriptome and metabolome in response to microRNA expression changes. We are currently studying the function of two microRNAs, miR-484 and mir-769. In our previous studies, we identified mir-484 as being associated with extraprostatic extension and additional analyses showed that miR-484 significantly associates with reduced recurrence-free survival. Additional experiments showed that miR-484 expression increases migration of prostate cancer cells. There is not much known about the function of this microRNA. It is a regulator of mitochondrial biogenesis. A pathway analysis of TargetScan-predicted target genes indicated that this microRNA may regulate metabolism. We are currently pursuing the hypothesis that miR-484 reprograms metabolism and zinc homeostasis in prostate cancer cells. Alterations in zinc metabolism are a hallmark of prostate cancer. We are using miR-484 overexpression and knockdown approaches and are studying metabolic and gene expression patterns in relationship to miR-484 expression.
