MiR-183-96-182 cluster, prostatic zinc homeostasis and carcinogenesis

描述（由申请人提供）：锌是一种重要的微量营养素，在细胞中具有结构、催化和调节功能。鉴于锌的多样性和中心功能，生物体严格调节锌的体内平衡。前列腺独特的浓缩锌比其他器官高10倍。此外，与正常前列腺相比，前列腺癌病变是锌缺乏的。锌水平与侵袭性疾病呈负相关，低锌饮食增加前列腺癌风险，支持锌在前列腺中的保护作用。高水平的锌是维持前列腺正常分化状态所必需的，低水平的锌可能会增加去分化并导致前列腺肿瘤的发展或生长。前列腺细胞中的锌缺乏会引起代谢变化，从而增加细胞呼吸和细胞增殖。因此，前列腺癌中锌的减少可能与癌症病因有关，是该疾病的一种可行的选择性生物标志物。利用患者标本和原代前列腺细胞培养物，我们最近发现了miR-183、miR-96和miR-182这些microRNAs，它们作为miR-183家族簇一起表达，通过调节几种锌转运蛋白来调节前列腺中的锌稳态。MicroRNAs （miR）是一种小的非编码调控rna，通过与3'UTR结合来抑制其靶mrna的表达。与锌缺失一致，与来自同一患者的良性上皮相比，前列腺肿瘤中存在更高水平的miR-183簇。其他研究表明，miRs-183、96和182在前列腺癌和其他几种癌症中单独或作为一个集群过度表达。miR簇，如miR-183家族，作为单一的多胞核糖核酸共同表达，然后加工成成熟的miR。miR簇被认为是一种比单个miR更有效地协调复杂细胞过程的机制。总之，我们的初步数据表明miR-183簇是前列腺细胞内锌浓度的调节剂。据我们所知，这些数据是首次报道靶向金属转运蛋白家族的miRNA簇。此外，我们和其他人已经发现该miR簇在前列腺癌中过表达，有力地支持了该miR簇在癌变中的作用。目前的

DESCRIPTION (provided by applicant): Zinc is a vital micronutrient that has structural, catalytic and regulatory functions in cells. Given the diverse and central functions of zinc, organisms tightly regulate zinc homeostasis. The prostate uniquely concentrates zinc 10-fold higher than other organs. Furthermore, it is well established that prostate cancer lesions are zinc depleted compared to normal prostate. Zinc levels inversely associate with aggressive disease and low dietary zinc increases prostate cancer risk, supporting a protective role for zinc in the prostate. High levels of zinc are required to maintain the normal differentiated state of th prostate and lower zinc may increase dedifferentiation and lead to the development or outgrowth of prostate tumors. Zinc depletion in prostate cells causes metabolism changes that increase cellular respiration and cell proliferation. Thus, diminished zinc in prostate cancer may to contribute to the cancer etiology and is a viable selective biomarker for the disease. Using patient specimens and primary prostatic cell cultures we recently identified the microRNAs miR- 183, miR-96 and miR-182, which are expressed as together as the miR-183 family cluster, as regulators of zinc homeostasis in the prostate via regulation of several zinc transporters. MicroRNAs (miR) are small non- coding regulatory RNAs that suppress expression of their target mRNAs via binding to the 3'UTR. Consistent with zinc depletion, higher levels of the miR-183 cluster was present in prostate tumors compared to benign epithelium from the same patients. Others have shown that individually or as a cluster, miRs-183, 96 and 182 are overexpressed in prostate cancer and several other cancers. miR clusters, such as the miR-183 family, are co-expressed as a single polycystronic RNA then processed into the mature miR. miR clusters are thought to exist as a mechanism to more efficiently coordinate complex cell processes than regulation by a single miR can provide. In summary, our preliminary data show that the miR-183 cluster is a regulator of intracellular zinc concentrations in prostate cells. To our knowledge, these data are the first to report a miRNA cluster targeting a family of metal transport proteins. Furthermore, we and others have shown overexpression of this miR cluster in prostate cancer, strongly supporting a role for this miR-cluster in carcinogenesis. The present proposal is an extension of our recent data and will further analyze regulation of the miR- 183 cluster and its role in cell phenotype, zinc sequestration, prostate carcinogenesis and progression. The results of this project will have clear implications not only in prostate cancer, but also in other cancers in which the miR-183 cluster is highly expressed. Specifically we will examine the following hypotheses: 1) Sequestration of zinc in differentiated prostate epithelium is regulated by the coordinated expression of miRs-183, 96 and 182 as a cluster. 2) MiRs-183, 96 and 182 are oncomiRs that reduce zinc levels and promote dedifferentiation when over-expressed during prostate carcinogenesis.