This is a NCI Transition Career Development Award (K22) proposal by Dr. Larisa Nonn, an Assistant Professor of Pathology at the University of Illinois at Chicago. She has a doctoral degree in Pharmacology/Cancer Biology, postdoctoral training in prostate cancer prevention and has just transitioned into her first independent position. To ensure success with this proposal and her career, Dr. Nonn has placed herself in a supportive research environment, rich in senior cancer prevention investigators. This proposal will identify and characterize vitamin D-regulated microRNAs in normal prostate. The role of regulatory small non-coding microRNAs (miRNAs) in the pathogenesis of cancer is now evident. Similarly to protein-coding genes, oncogenic miRNAs and tumor suppressor miRNAs have been identified. We postulate that chemopreventive agents, such as vitamin D, alter miRNA expression in a manner opposing to the cancer-associated miRNA changes. Epidemiologic and laboratory studies support a chemopreventive role for vitamin D in prostate. To date, regulation of miRNAs by vitamin D, or any chemopreventive agent, have not yet been investigated. Our overall hypothesis is that the prostate cancer preventive activities of vitamin D involve up-regulation of tumor suppressor miRNAs and/or down-regulation of potentially oncogenic miRNAs. In support of our hypothesis, we present preliminary data from a 366 miRNA expression array, showing that vitamin D regulates the expression of several prostate cancer-related miRNAs This proposal will expand on these exciting preliminary findings and test the following specific hypotheses;1) vitamin D treatment of primary cultures of normal human prostatic epithelial cells alters the expression of prostate cancer-related miRNAs, 2) vitamin D-regulated miRNAs exert anti-cancer activity in prostate cells, and 3) the expression of vitamin D-regulated miRNAs correlate with the concentration of vitamin D metabolites in prostate tissue. The results of this proposal will lay the foundation for subsequent studies based on the identified vitamin D-regulated miRNAs.
