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: 8508220
• 负责人: LARISA NONN
• 金额: $ 33.31万
• 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/8508220
• 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。鉴于锌的多样和中心功能，生物体严格调节锌稳态。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，前列腺癌病变已经耗尽锌。锌水平与侵袭性疾病和低饮食锌成反比，增加了前列腺癌的风险，支持锌在前列腺中的保护作用。需要高水平的锌来维持前列腺的正常分化状态，而较低的锌可能会增加去分化并导致前列腺肿瘤的发育或生长。前列腺细胞中的锌消​​耗会导致代谢变化，从而增加细胞呼吸和细胞增殖。因此，前列腺癌的锌减少可能为癌症的病因做出贡献，并且是该疾病的可行选择性生物标志物。 使用患者标本和原发性前列腺细胞培养物，我们最近确定了microRNAS miR-183，miR-96和miR-182，它们以miR-183家族簇形式表示为前列腺中锌稳态的调节剂，通过调节几个锌转运蛋白。 microRNA（miR）是小的非编码调节性RNA，通过与3'UTR结合抑制其靶标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。其他人则表明，MiRS-183、96和182在前列腺癌和其他几种癌症中过表达的miRS-183、96和182。 miR簇（例如miR-183家族）被共表达为单个多性肌酸RNA，然后加工到成熟的mir中。人们认为，与单​​个miR可以提供的调节相比，miR簇作为一种更有效地协调复杂细胞过程的机制。总而言之，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针对金属转运蛋白家族的miRNA簇。此外，我们和其他人在前列腺癌中表现出了这种miR簇的过表达，从而强烈支持这种miR簇在致癌中的作用。 现在 提案是我们最近数据的扩展，将进一步分析miR-183簇的调节及其在细胞表型，锌隔离，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具有明显的影响，而且还将在其他高度表达miR-183簇的癌症中具有明显的影响。具体而言，我们将检查以下假设：1）在分化的前列腺上皮中锌的固定受miRS-183、96和182作为簇的协调表达来调节。 2）miRS-183、96和182是oncomirs，在前列腺致癌过程中过度表达时，降低了锌水平并促进去分化。