The role of exRNA in Health Disparity of Prostate Cancer

exRNA 在前列腺癌健康差异中的作用

• 批准号: 8877161
• 负责人: Zakaria Abd Elmageed
• 金额: $ 18.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877161
• 关键词: Address; Adipose tissue; African American; Androgens; Biological Markers; Castration; Cell Communication; Cell physiology; Cells; Clinical; Data; Development; Disease; Disease Progression; Enzymes; Exercise; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Human; In Vitro; Incidence; Investigation; LATS2 gene; Lead; Life Style; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Messenger RNA; Metastatic Prostate Cancer; MicroRNAs; Minority; Molecular; Neoplasm Metastasis; Normal Cell; Oncogenic; Other Genetics; Outcome; Outcome Study; Pathway interactions; Patients; Physiological; Principal Investigator; Process; Prognostic Marker; Prostatic Neoplasms; Proteins; RNA; Race; Recurrence; Research Personnel; Research Support; Resistance; Role; Specimen; Stem cells; Testing; Time; Tumor Suppressor Genes; Untranslated RNA; Vesicle; cancer cell; cancer health disparity; caucasian American; cellular targeting; clinical care; deprivation; expectation; extracellular; health disparity; human tissue; improved; innovation; men; mortality; neoplastic cell; programs; prostate cancer cell; prostate cancer cell line; public health relevance; racial disparity; receptor; selective expression; socioeconomics; therapeutic target; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): The mortality rate of PCa in African American (AA) is 2-3 times higher than Caucasian American (CA) men. A number of studies demonstrated that high incidence and mortality rates of PCa among AA men might originate from genetic, lifestyle or socioeconomic-related factors. Molecular mechanisms underlying these discrepancies are still under investigation. The process of tumor growth and metastasis mainly depends on the ability of cancer cells to communicate with each other and with neighboring cells. Microvesicles (MVs) are small cell-derived extracellular bodies secreted by normal and tumor cells and they promote cell-cell communication. The cargo of these vesicles carries microRNAs mRNAs and proteins to recipient cells. MicroRNAs (miRNAs) are small non-coding regulatory RNAs that negatively regulate gene expression at the post-transcriptional level. However, their real physiological function of extracellular RNA (exRNA) including miRNAs, in PCa racial disparities is still obscure. Our previous study demonstrates that MV-derived onco-miRNAs contribute to PCa progression through transformation of patient-derived adipose stem cells. Importantly, we identified selective expression of a subset of putative onco-miRNAs in prostate tumors. Thus, altered onco-miRNAs expression could be a determinant factor for high PCa progression and mortality rates among AA men. Thus, we hypothesize that "onco-miRNAs derived by prostate tumor microvesicles are critical to PC progression in AA men of PCa". This hypothesis will be tested by the following specific aims; 1) To investigate the expression levels of putative (miR-3613-3p and miR-3680-3p) and known (miR-125b, miR-130b and miR-155) onco-miRNAs in normal and PCa cells derived from AA and CA men as well as in human PCa specimens and 2) To examine the functional significance of these onco- miRNAs in mediating disease progression. This study is innovative, because it capitalizes on discovery of new functional roles for this putative onco-miRNAs and their relevant cellular target genes in PCa health disparity. Our expectation from this proposal is to understand the pleiotropic functions of these putative onco-miRNAs and clarify their implications in health disparity. Our preliminary results show that not only the expression of putative miRNAs (miR-3613-3p and miR-3680-3p) was higher in PCa cell lines versus normal cells but also in AA vs. CA patients. However, the expression of miRNA target genes (i.e. tumor suppressor genes; PDCD4 & LATS2) was low on in vitro and on human tissue level suggesting these miRNAs have an oncogenic activity. Our long-term goal is to explore the functional significance and potential clinical utilities of these putative miRNAs, as biomarkers or therapeutic targets, to improve the outcomes and quality of lives of patients suffering from this disease. The outcomes from this study will certainly benefit the PI by giving him the opportunity to acquire research support, exercise him to become independent investigator and inspire him to apply for independent research-supports (i.e. R01). In addition, scientific findings that will be obtained from this proposal may lead to discovery of new prognostic markers or therapeutic targets in PCa and definitely will address the reasons why African American men have more aggressive disease than other minorities.

 描述（由申请人提供）：非洲裔美国人 (AA) 的 PCa 死亡率比白人美国 (CA) 男性高 2-3 倍。多项研究表明，AA 男性中 PCa 的高发病率和死亡率可能源于此。这些差异背后的分子机制仍在研究中。肿瘤生长和转移的过程主要取决于癌细胞之间以及与邻近细胞的沟通能力。微泡 (MV) 是由正常细胞和肿瘤细胞分泌的小细胞源性胞外体，它们促进细胞间通讯，将 microRNA mRNA 和蛋白质携带到受体细胞。然而，我们之前的研究表明，包括 miRNA 在内的细胞外 RNA (exRNA) 的真正生理功能仍然不清楚。 MV 衍生的 onco-miRNA 通过转化患者来源的脂肪干细胞促进 PCa 进展。重要的是，我们发现了前列腺肿瘤中假定的 onco-miRNA 子集的选择性表达，因此，onco-miRNA 的表达可能是一个决定因素。因此，我们认为“前列腺肿瘤微泡衍生的癌基因对于 AA 男性的 PCa 进展至关重要”。通过以下具体目标进行测试；1) 研究正常中假定的（miR-3613-3p 和 miR-3680-3p）和已知的（miR-125b、miR-130b 和 miR-155）onco-miRNA 的表达水平和来自 AA 和 CA 男性以及人类 PCa 样本中的 PCa 细胞，以及 2) 检查这些致癌 miRNA 在介导疾病中的功能意义这项研究是创新的，因为它利用了这种假定的癌 miRNA 及其相关细胞靶基因在 PCa 健康差异中的新功能作用的发现，我们对这项提案的期望是了解这些假定的癌 miRNA 的多效性功能并阐明。我们的初步结果表明，不仅推定的 miRNA（miR-3613-3p 和 miR-3680-3p）的表达较高。 PCa 细胞系与正常细胞以及 AA 与 CA 患者的比较 然而，miRNA 靶基因（即肿瘤抑制基因；PDCD4 和 LATS2）在体外和人体组织水平上的表达较低，表明这些 miRNA 具有致癌活性。我们的长期目标是探索这些假定的 miRNA 作为生物标志物或治疗靶点的功能意义和潜在的临床用途，以改善患有这种疾病的患者的结果和生活质量。这项研究的结果肯定会有所改善。使PI有机会获得研究支持，锻炼他成为独立研究者并激励他申请独立研究支持（即R01），此外，从该提案中获得的科学发现可能会导致发现。 PCa 的新预后标志物或治疗靶点，肯定会解决非裔美国男性比其他少数族裔患有更具侵袭性疾病的原因。