Mitochondrial DNA and Prostate Cancer in African American

非裔美国人的线粒体 DNA 和前列腺癌

• 批准号: 8735897
• 负责人: KESHAV K SINGH
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735897
• 关键词: Address; African American; Age; American; Apoptosis; Basic Cancer Research; Biological Models; Cell Culture Techniques; Cell Proliferation; Cells; Code; Complex; DNA; DNA copy number; DNA polymerase gamma; Data; Development; Diagnosis; Ethnic Origin; European; Genes; Genetic; Genome; Gleason Grade for Prostate Cancer; Grant; Homeostasis; Human; In Vitro; Leukocytes; Malignant neoplasm of prostate; Measures; Mitochondria; Mitochondrial DNA; Mus; Mutation; Neoplasm Metastasis; Nuclear; Oxidative Phosphorylation; Play; Ploidies; Population; Predisposition; Production; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Subunits; Proteins; Role; Signal Transduction; Time; Tumorigenicity; Xenograft Model; base; cancer cell; cancer health disparity; carcinogenesis; caucasian American; design; men; mitochondrial genome; mortality; mutant; prostate carcinogenesis; public health relevance; tumor; tumorigenic

DESCRIPTION (provided by applicant): Mitochondria play a central role in cell proliferation, cell signaling and apoptosis. Mitochondria contain their own DNA (mtDNA). mtDNA serves as a determinant of human origin and ethnicity. Human mtDNA is a very small (16,569 bp) genome. The entire protein coding capacity of the mitochondrial genome is dedicated to the production of 13 protein subunits. These 13 proteins constitute various subunits that make up four oxidative phosphorylation (OXPHOS) complexes essential for energy (ATP) production and other mitochondrial function. African-American men (AAM) have the highest rate of prostate cancer, develop prostate cancer at an early age, present with a higher tumor grade at time of diagnosis, and have a higher rate of metastasis and mortality than Caucasian American men (CAM). The genetic mechanism(s) underlying this racial diversity in prostate cancer is not well understood. Our studies demonstrate that in AAM reduced mtDNA content plays an important role in prostate carcinogenesis. We measured the mtDNA copy number in white blood cells (WBC) and prostate tumor obtained from AAM and CAM. Our preliminary studies suggest that WBC of both AAM and CAM contained similar amount of mtDNA (copy number). However, when adjusted for age, Gleason grade and PSA (prostate specific antigen) the prostate tumors of AAM contained >6 times less mtDNA than CAM tumors. Our preliminary data suggest that mutations in nuclear gene encoding mitochondrial DNA polymerase gamma (POLG1) induce depletion of mtDNA and increase tumorigenic potential of cancer cells in vitro. These studies suggest that mtDNA homeostasis must play an important role in carcinogenesis. Based on these observations we hypothesize that reduced mtDNA content plays a critical role in prostate tumorigenesis in AAM by significantly altering the mitochondrial OXPHOS. AIM 1: Determine whether mutational spectrum of POLG1 in AAM prostate tumors differs from POLG1 mutational spectrum of CAM. Identify distinctive mutations in POLG1 gene in primary prostate tumors of AAM and determine its functional significance on mtDNA depletion, OXPHOS activity and apoptosis. AIM 2: Determine the consequences of mutant POLG1 induced depletion of mtDNA on prostate tumorigenesis in vitro and in mouse xenograft model. The proposed development of mtDNA depletion in prostate cells has the significant potential to enhance our understanding of prostate tumorigenesis in the African American population. This proposal addresses the two key objectives of the PAR-09-160 requesting exploratory grants in basic cancer research in cancer health disparities (R21). These objectives include: 1) the development of "new cell culture models/systems designed to investigate cancer disparities" and 2) explores the susceptibility to prostate cancer in African-American men due to "genetic differences" in mtDNA content.

描述（由申请人提供）：线粒体在细胞增殖，细胞信号传导和凋亡中起着核心作用。线粒体包含自己的DNA（mtDNA）。 mtDNA是人类起源和种族的决定因素。人mtDNA是一个很小的（16,569 bp）的基因组。线粒体基因组的整个蛋白质编码能力致力于产生13个蛋白质亚基。这13种蛋白质构成了各种亚基，构成了四个氧化磷酸化（OXPHOS）复合物对于能量（ATP）生产和其他线粒体功能所必需的。非裔美国人（AAM）的前列腺癌率最高，在诊断时患有前列腺癌，在诊断时具有更高的肿瘤级，并且比白种人男性（CAM）具有更高的转移和死亡率。在前列腺癌中这种种族多样性的遗传机制尚不清楚。我们的研究表明，在AAM中，降低mtDNA含量在前列腺癌发生中起重要作用。我们测量了白细胞（WBC）中的mtDNA拷贝数和从AAM和CAM获得的前列腺肿瘤。我们的初步研究表明，AAM和CAM的WBC都包含相似数量的mtDNA（拷贝数）。但是，当对年龄，格里森级和PSA（前列腺特异性抗原）进行调整时，AAM的前列腺肿瘤的含量比CAM肿瘤少6倍。我们的初步数据表明，编码线粒体DNA聚合酶γ（POLG1）的核基因突变会诱导mtDNA的耗竭并增加体外癌细胞的致瘤潜力。这些研究表明，mtDNA稳态必须在癌变中起重要作用。基于这些观察结果，我们假设减少mtDNA含量在AAM的前列腺肿瘤发生中起着至关重要的作用，它通过显着改变线粒体的oxphos。 AIM 1：确定AAM前列腺肿瘤中POLG1的突变光谱是否与CAM的POLG1突变谱有所不同。在AAM的原发性前列腺肿瘤中确定POLG1基因中的独特突变，并确定其在mtDNA耗竭，OXPHOS活性和凋亡中的功能意义。 AIM 2：确定突变体POLG1诱导的MTDNA耗竭在体外和小鼠异种移植模型中对前列腺肿瘤发生的影响。提议的前列腺细胞中mtDNA耗竭的发展具有增强我们对非裔美国人种群中前列腺肿瘤发生的理解的重要潜力。该提案旨在解决PAR-09-160的两个关键目标，要求在癌症健康差异基本癌症研究中探索性补助金（R21）。这些目标包括：1）开发“旨在研究癌症差异的新细胞培养模型/系统”和2）探索由于mtDNA含量中的“遗传差异”，探索了非裔美国人男性前列腺癌的敏感性。