Significance of Vitamin D-Regulated MicroRNAs in Prostate Cancer Prevention

描述(由申请者提供)：这是由伊利诺伊大学芝加哥分校病理学助理教授拉里萨·农恩博士提出的NCI过渡职业发展奖(K22)提案。她拥有药理学/癌症生物学博士学位，前列腺癌预防博士后培训，刚刚过渡到她的第一个独立职位。为了确保这项提议和她的职业生涯的成功，农恩博士把自己置于一个支持性的研究环境中，那里有丰富的资深癌症预防研究人员。 这项建议将识别和表征正常前列腺中受维生素D调节的microRNAs。现在，调节性小分子非编码微RNA(MiRNAs)在癌症发病机制中的作用是显而易见的。与蛋白质编码基因类似，致癌miRNAs和肿瘤抑制基因miRNAs已经被确定。我们推测，化学预防药物，如维生素D，会改变miRNA的表达，其方式与癌症相关的miRNA改变相反。流行病学和实验室研究支持维生素D在前列腺癌中的化学预防作用。到目前为止，维生素D或任何化学预防药物对miRNAs的调节还没有被调查过。 我们的总体假设是，维生素D的前列腺癌预防活性涉及肿瘤抑制基因miRNAs的上调和/或潜在致癌miRNAs的下调。为了支持我们的假设，我们提供了来自366个miRNA表达阵列的初步数据，表明维生素D调节几个前列腺癌相关miRNAs的表达。这个建议将在这些令人兴奋的初步发现基础上进行扩展，并测试以下特定假设：1)原代培养的正常人类前列腺上皮细胞经维生素D处理后，前列腺癌相关miRNAs的表达发生变化，2)维生素D调节的miRNAs在前列腺细胞中发挥抗癌活性，以及3)维生素D调节的miRNAs的表达与前列腺组织中维生素D代谢物的浓度有关。该提案的结果将为基于已确定的维生素D调节的miRNAs的后续研究奠定基础。

DESCRIPTION (provided by applicant): 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.