MicroRNAs as Zinc Regulators in Cancer Cells and as Serum Markers of Aggressive Prostate Cancer
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This work examines the role of specific miRNAs in the molecular etiology of prostate cancer, their secretion from cells, and their application to blood-based biomarkers of aggressive prostate cancer. In Chapter II, we identified the miR-183 cluster in the regulation of zinc homeostasis in prostate cells. Zinc is normally accumulated to high levels in prostate tissue, yet is lost in prostate cancer. The miR-183 cluster was overexpressed in prostate cancer tissue and targets zinc transporters, reducing the cellular import and concentration of zinc. The secretion of the miR-183 cluster in cellular exosomes was investigated in Chapter III. Of the members of the miR-183 cluster, only miR-182 was secreted in exosomes from prostate and breast cancer cell lines. When miR-182 was overexpressed in breast cancer cells, it was packaged into exosomes at a higher level. Furthermore, these exosomes reduced zinc in recipient cells. In Chapter IV, we examined circulating miRNAs as potential prognostic biomarkers for prostate cancer. A signature of fourteen miRNAs was discovered that identified a subset of patients that have indolent, non-aggressive disease. Furthermore, eight of these miRNAs also identified patients that do not have biochemical recurrence after prostatectomy. We took a translational approach with this work, from discovering the miRNA-mediated basis of zinc loss to the application of miRNAs to a clinical need.