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

MiR-183-96-182簇、前列腺锌稳态和致癌作用

• 批准号: 8399569
• 负责人: LARISA NONN
• 金额: $ 34.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399569
• 关键词: 3' Untranslated Regions; Anaplasia; Apoptosis; Automobile Driving; Benign; Binding; Biological; Biological Markers; Cancer Etiology; Carrier Proteins; Cell Culture Techniques; Cell Proliferation; Cell Respiration; Cell physiology; Cells; Characteristics; Chemoprotective Agent; Citrates; Complex; DNA Damage; Data; Development; Diagnosis; Dietary Zinc; Disease; Epithelium; Family; Family member; Functional RNA; Gleason Grade for Prostate Cancer; Homeostasis; Human; In Vitro; Incidence; Individual; Inflammatory; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Metabolism; Metals; Methylation; MicroRNAs; Micronutrients; Organ; Organism; Patients; Phenotype; Physiological; Play; Process; Prognostic Marker; Prostate; Prostatic; Prostatic Neoplasms; RNA; Regulation; Reporting; Research; Rodent Model; Role; Signal Transduction; Site; Specimen; Sum; Therapeutic Intervention; Tissues; Zinc; Zinc deficiency; base; cancer cell; cancer risk; carcinogenesis; in vivo; knock-down; migration; overexpression; promoter; prostate cancer prevention; prostate carcinogenesis; therapeutic target; treatment strategy; uptake; zinc-binding protein

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. PUBLIC HEALTH RELEVANCE: Zinc is a vital micronutrient that has structural, catalytic and regulatory functions in cells. The prostate gland uniquely concentrates zinc and zinc depletion is a hallmark of prostate cancer. This proposal investigates how dysregulation of a microRNA cluster contributes to prostate carcinogenesis by regulation of zinc homeostasis. MicroRNAs have become attractive therapeutic targets and therefore, it is imperative to understand the regulation and physiological role of specific microRNAs.

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。鉴于锌的多样化和核心功能，生物体严格调节锌的稳态。前列腺的锌浓度独特，比其他器官高 10 倍。此外，众所周知，与正常前列腺相比，前列腺癌病变的锌含量较低。锌水平与侵袭性疾病呈负相关，低膳食锌会增加前列腺癌风险，支持锌在前列腺中的保护作用。维持前列腺的正常分化状态需要高水平的锌，而较低的锌可能会增加去分化并导致前列腺肿瘤的发展或生长。前列腺细胞中的锌耗尽会导致新陈代谢变化，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有助于癌症病因学，并且是该疾病的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，我们最近鉴定了 microRNA miR-183、miR-96 和 miR-182，它们与 miR-183 家族簇一起表达，通过调节几种锌转运蛋白作为前列腺中锌稳态的调节剂。 MicroRNA (miR) 是小型非编码调节 RNA，可通过与 3'UTR 结合来抑制其靶 mRNA 的表达。与锌消耗一致，与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，miR-183、96 和 182 单独或作为簇在前列腺癌和其他几种癌症中过度表达。 miR 簇，例如 miR-183 家族，共表达为单个多环反子 RNA，然后加工成成熟的 miR。 miR 簇被认为是一种比单个 miR 的调节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因子。据我们所知，这些数据是第一个报告针对金属转运蛋白家族的 miRNA 簇的数据。此外，我们和其他人已经证明该 miR 簇在前列腺癌中过度表达，有力地支持了该 miR 簇在癌发生中的作用。 现在的 该提案是我们最近数据的延伸，将进一步分析 miR-183 簇的调控及其在细胞表型、锌螯合、前列腺癌发生和进展中的作用。该项目的结果不仅对前列腺癌有明确的影响，而且对 miR-183 簇高表达的其他癌症也有明确的影响。具体来说，我们将检查以下假设：1) 分化的前列腺上皮中锌的封存受到 miR-183、96 和 182 作为簇的协调表达的调节。 2) MiRs-183、96和182是oncomiRs，当在前列腺癌发生过程中过度表达时，它们会降低锌水平并促进去分化。 公众健康相关性：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。前列腺独特地浓缩了锌，锌缺乏是前列腺癌的一个标志。该提案研究了 microRNA 簇的失调如何通过调节锌稳态而导致前列腺癌的发生。 MicroRNA 已成为有吸引力的治疗靶点，因此，了解特定 microRNA 的调节和生理作用势在必行。