Project 1: Disparities in Mitochondrial Peptidomics and Transcriptomics in Prostate Cancer

项目 1：前列腺癌线粒体肽组学和转录组学的差异

• 批准号: 10006099
• 负责人: Pinchas Cohen
• 金额: $ 0.14万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006099
• 关键词: Admixture; African; African American; Aging; Benign; Biogenesis; Biological; Biological Markers; Biopsy; Blood Circulation; California; Cancer Biology; Cancer Etiology; Cancer Patient; Cancer Prognosis; Cell physiology; Cessation of life; Counseling; DNA copy number; Data; Diagnosis; Disease; Education; Ethnic Origin; Ethnic group; Florida; Formalin; Future; Genetic; Genetic Polymorphism; Goals; Grant; Incidence; Intervention; Investigation; Latino; Lead; Life Style Modification; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; MicroRNAs; Minority; Minority Groups; Mitochondria; Mitochondrial DNA; Native Americans; Open Reading Frames; Outcome; Paraffin Embedding; Patients; Peptide Signal Sequences; Peptides; Plasma; Population; Predictive Value; Preventive Intervention; Prostate; Prostatic; Prostatic Neoplasms; RNA analysis; RNA, ribosomal, 12S; Race; Reporting; Research; Ribosomal RNA; Risk; Role; Sampling; Serum; Severities; Testing; Tissues; Transcript; anti-cancer; anticancer research; base; cancer diagnosis; cancer risk; caucasian American; cohort; diagnostic biomarker; diet and exercise; differential expression; ethnic difference; ethnic minority population; extracellular; health equity; humanin; large datasets; lifestyle factors; men; men' s group; mitochondrial dysfunction; mitochondrial genome; novel; prognostic; prostate biopsy; prostate cancer risk; rRNA Genes; racial difference; sample collection; transcriptome; transcriptome sequencing; transcriptomics; translational impact; tumor progression

Mitochondrial dysfunction and mtDNA polymorphisms have been associated with prostate cancer (PC) biology. We discovered a novel class of mitochondria-derived peptides (MDPs) that are transcribed from small open reading frames within the mtDNA. These include humanin, SHLP-2, and MOTS-c, which are circulating cytoprotective signaling peptides. Decreased MDP levels have been implicated in diseases of aging, and we recently found that Blacks have lower circulating levels of humanin and SHLP2 than Whites. We hypothesize that differences in MDP expression in minority men relative to Whites contribute to the elevated risk of PC. We seek to test the potential of plasma MDPs and their prostate expression levels as biomarkers for PC risk, both as pre-diagnostic biomarkers and as surrogate prognostic risk indicators in a group of men with and without PC including White, Latino, and Black men. We recently reported that in a small cohort of Black and White men undergoing prostate biopsy SHLP2 levels were significantly lower in men with PC vs. men without PC and that Black men had significantly lower levels than White men. A SHLP2 level >350 pg/ml had a negative predictive value of ≥95% for a negative biopsy regardless of race and may be an excellent biomarker to avoid biopsy. A larger dataset is needed to validate our results, and this grant will dramatically expand this research question and look at additional ethnic groups and their subpopulations. Our first goal for this project includes the analysis of the association between serum SHLP2 levels and PC risk in ethnic minorities. We will leverage two ongoing sample collection efforts at UF and USC to analyze 700 serum samples from White, Latino, and Black men (Aim 1). SHLP2 levels will be compared between men with and without PC and stratified by race. Our second goal is to determine the association between additional plasma MDPs and PC risk among men of different ethnicities. We will measure plasma levels of humanin, MOTS-c, SHLP2, and SHLP6 and determine the association between these MDPs, race, and cancer status (Aim 2). Using whole transcriptome RNAseq analysis of RNA from micro-dissected FFPE from prostate tumor patients who are Black, White, and Latino we will compare the prostate mito-transcriptome for divergent expression of MDP transcripts and their relation to cancer severity and ethnic origin (Aim 3). Finally, we will examine the contribution of mitochondrial DNA copy number in the circulation and in benign and malignant prostate tissues, to PC risk and severity. Our study will be the first comprehensive study of racial differences in mtDNAcn, mitochondrial-derived peptide expression and levels, and their effect on PC. If successful, MDP levels may serve as diagnostic biomarkers of PC, particularly in minority men. The expected finding, that MDP levels are regulated by interventions that may modify cancer risk (such as diet and exercise, which raise MDP levels) could lead to a simple approach where at-risk men get their level measured and are counseled to make a lifestyle modification and never get the disease in the first place.

线粒体功能障碍和mtDNA多态性与前列腺癌（PC）生物学相关。 我们发现了一类新的拟南芥衍生肽（MDP）， 阅读线粒体DNA中的框架。这些包括humanin，SHLP-2和MOTS-c，它们在循环中 细胞保护信号肽。MDP水平的降低与衰老疾病有关， 最近发现，黑人的循环水平低于白人的humanin和SHLP 2。我们假设 少数民族男性MDP表达相对于白人的差异导致PC风险升高。我们 试图测试血浆MDP及其前列腺表达水平作为PC风险生物标志物的潜力， 作为诊断前的生物标志物和作为一组有和没有PC的男性的替代预后风险指标 包括白色、拉丁美洲和黑人。我们最近报道，在一小群黑人和白色男性中， 接受前列腺活检的PC男性患者的SHLP 2水平显著低于无PC男性患者， 黑人男性的水平明显低于白色男性。SHLP 2水平>350 pg/ml具有阴性预测 无论种族如何，阴性活检的值≥95%，可能是避免活检的极好生物标志物。一 需要更大的数据集来验证我们的结果，而这笔赠款将大大扩展这一研究问题 看看其他的种族群体和他们的亚群。我们这个项目的第一个目标包括分析 少数民族血清SHLP 2水平与PC风险之间的关系。我们将利用两个正在进行的 在UF和南加州大学进行样本采集工作，分析来自白色、拉丁美洲人和黑人男性的700份血清样本（Aim 1）。将比较有和无PC的男性之间的SHLP 2水平，并按人种分层。我们的第二个目标是 以确定不同种族男性中额外血浆MDP与PC风险之间的关联。 我们将测量血浆humanin、MOTS-c、SHLP 2和SHLP 6的水平，并确定其与 这些MDP之间，种族，和癌症状态（目标2）。使用RNA的全转录组RNAseq分析 从来自黑人、白色和拉丁美洲人的前列腺肿瘤患者的显微解剖FFPE中，我们将比较 前列腺线粒体转录组的MDP转录本的不同表达及其与癌症严重程度的关系， 民族血统（目标3）。最后，我们将研究线粒体DNA拷贝数在细胞凋亡中的作用。 良性和恶性前列腺组织中，PC的风险和严重程度。我们的研究将是第一个 对mtDNAc n、脑源性肽表达和水平的种族差异的综合研究， 及其对PC的影响。如果成功，MDP水平可能作为PC的诊断生物标志物，特别是在 少数民族男子。预期的发现是，MDP水平受到可能改变癌症风险的干预措施的调节 (such饮食和运动，提高MDP水平）可能会导致一种简单的方法， 水平测量，并建议作出生活方式的改变，永远不会得到疾病摆在首位。