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: 8658055
• 负责人: LARISA NONN
• 金额: $ 34.38万
• 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/8658055
• 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 risk; carcinogenesis; in vivo; knock-down; migration; overexpression; promoter; prostate cancer cell; 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.

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，生物体严格调节锌稳态。前列腺的锌浓度是其他器官的10倍。此外，众所周知，与正常前列腺相比，前列腺癌病变是锌耗尽的。锌水平与侵袭性疾病呈负相关，低饮食锌增加前列腺癌风险，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，而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导致代谢变化，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。 使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，它们作为miR-183家族簇一起表达，作为前列腺中锌稳态的调节剂，通过调节几种锌转运蛋白。微小RNA（miR）是小的非编码调节RNA，其通过结合至3 'UTR来抑制其靶mRNA的表达。与锌缺乏一致，与来自相同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。其他人已经表明，miR-183、96和182单独或作为簇在前列腺癌和几种其他癌症中过表达。miR簇，如miR-183家族，共表达为单个多半胱氨酸RNA，然后加工成成熟的miR。miR簇被认为是作为一种机制存在的，与单个miR的调节相比，它能更有效地协调复杂的细胞过程。总之，我们的初步数据表明，miR-183簇是前列腺细胞中细胞内锌浓度的调节剂。据我们所知，这些数据是第一个报告靶向金属转运蛋白家族的miRNA簇。此外，我们和其他人已经显示了该miR簇在前列腺癌中的过表达，强烈支持该miR簇在癌发生中的作用。 本 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意义，而且对miR-183簇高度表达的其他癌症也有明确的意义。具体来说，我们将检验以下假设：1）分化的前列腺上皮中锌的封存受到miRs-183、96和182作为簇的协调表达的调节。2)miR-183、96和182是在前列腺癌发生过程中过表达时降低锌水平并促进去分化的oncomiR。