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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

基本信息

批准号：
10006117
负责人：
Pinchas Cohen
金额：
$ 29.71万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/10006117
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&apos 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

项目摘要

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线粒体衍生肽（MDP），它们是从小开放转录的线粒体 DNA 内的阅读框。其中包括护脑素、SHLP-2 和 MOTS-c，这些药物正在循环使用细胞保护信号肽。 MDP 水平下降与衰老疾病有关，我们最近发现黑人的护脑素和 SHLP2 循环水平低于白人。我们假设少数族裔男性相对于白人的 MDP 表达差异导致 PC 风险升高。我们寻求测试血浆 MDP 及其前列腺表达水平作为 PC 风险生物标志物的潜力，两者作为一组患有和不患有 PC 的男性的预诊断生物标志物和替代预后风险指标包括白人、拉丁裔和黑人。我们最近报道称，在一小群黑人和白人中接受前列腺活检的 SHLP2 水平在患有 PC 的男性中显着低于未患有 PC 的男性，并且黑人男性的水平明显低于白人男性。 SHLP2 水平 >350 pg/ml 具有阴性预测无论种族如何，活检阴性的值≥95%，可能是避免活检的绝佳生物标志物。一个需要更大的数据集来验证我们的结果，这笔资助将极大地扩展这个研究问题并关注其他族裔群体及其亚人群。我们这个项目的第一个目标包括分析少数民族血清 SHLP2 水平与 PC 风险之间的关联。我们将利用两个正在进行的佛罗里达大学和南加州大学的样本收集工作分析了来自白人、拉丁裔和黑人男性的 700 份血清样本（目标 1）。将比较患有和未患有 PC 的男性之间的 SHLP2 水平，并按种族进行分层。我们的第二个目标是确定不同种族男性中额外血浆 MDP 与 PC 风险之间的关联。我们将测量护脑素、MOTS-c、SHLP2 和 SHLP6 的血浆水平并确定关联性这些 MDP、种族和癌症状况之间的关系（目标 2）。使用 RNA 的全转录组 RNAseq 分析来自黑人、白人和拉丁裔前列腺肿瘤患者的显微解剖 FFPE，我们将比较前列腺线粒体转录组用于 MDP 转录物的不同表达及其与癌症严重程度和癌症的关系种族血统（目标 3）。最后，我们将检查线粒体 DNA 拷贝数在循环以及良性和恶性前列腺组织中的 PC 风险和严重程度。我们的研究将是第一个 mtDNAcn、线粒体衍生肽表达和水平的种族差异的综合研究，以及它们对 PC 的影响。如果成功，MDP 水平可以作为 PC 的诊断生物标志物，特别是在少数族裔男性。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（例如饮食和运动，这会提高 MDP 水平）可能会导致一种简单的方法，让高危男性得到他们的测量水平并建议改变生活方式，从一开始就永远不会患上这种疾病。