The mitochondrial aspects of health disparity of hepatocellular carcinoma in Hispanic population

西班牙裔人群肝细胞癌健康差异的线粒体方面

• 批准号: 10729283
• 负责人: Yidong Bai
• 金额: $ 48.46万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729283
• 关键词: Alcohol consumption; Big Data; Bioinformatics; Biological Models; Cancer Etiology; Cell model; Cells; Cessation of life; Cirrhosis; Complement; Complex; Data; Databases; Development; Disease; Ethnic Origin; Ethnic Population; Exhibits; Functional disorder; Gender; Gene Expression; Generations; Genetic; Genetic Polymorphism; Genotype; Haplogroup; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; High Prevalence; Hispanic; Hispanic Populations; Human; Incidence; Inpatients; Investigation; Liver; Mediating; Metabolic Diseases; Metabolic syndrome; Mitochondria; Mitochondrial DNA; Molecular; Mutation; NADH dehydrogenase (ubiquinone); Neoplasm Metastasis; Not Hispanic or Latino; Nuclear; Obesity; Oxidative Stress; Pathologic; Pathway interactions; Patients; Physiological; Play; Population; Positioning Attribute; Prevention; Primary carcinoma of the liver cells; Procedures; Proteins; Regulation; Reporting; Research; Rest; Risk Factors; Role; Sampling; South Texas; System; Technology; Testing; Time; Tissue Sample; Tissues; United States; Viral Proteins; Virus Diseases; biobank; burden of illness; cancer type; dosage; epidemiology study; genetic risk factor; health disparity; hepatocellular carcinoma cell line; high risk; inducible gene expression; mitochondrial DNA alteration; mitochondrial dysfunction; mortality; non-alcoholic fatty liver disease; novel; protein expression; public database; success; transplant centers; tumorigenesis

Hepatocellular carcinoma (HCC) is one of the fastest-rising causes of cancer-related mortality in the United States. The biggest risk factor for developing HCC is viral infection (HBV and HCV). Other factors include non- alcoholic fatty liver disease (NAFLD), alcohol use, and obesity/metabolic syndromes. Genetics also plays an important role in the development and progression of HCC. Notably, HCC burden is disproportionately expressed among different ethnic groups; the incidence and mortality rates are much higher in Hispanics than in non-Hispanic whites (NHW) for both genders, particularly in South Texas where Hispanics are the fastest- growing population. Moreover, Hispanics with Hepatitis C Virus (HCV) infection are at a significantly higher risk of developing cirrhosis and HCC compared to NHW with HCV. One major target of HCV proteins is the mitochondria. Mitochondrial DNA (mtDNA) alterations and mitochondrial dysfunction are implicated in various types of cancer, including HCC. A human mtDNA haplogroup is defined by unique sets of mtDNA polymorphisms, reflecting mutations accumulated by a discrete lineage. The distribution of mitochondrial haplogroups in the Hispanic population differs greatly from that of the NHW population, which may have some influcence on the higher incidence of HCC in Hispanics. Based on these facts and our previous studies, we seek to determine whether and how distinct mitochondrial haplogroups, mitochondrial dysfunction, and HCV infection (as well as the interactions between these factors) impact HCC tumorigenesis and progresion. The hypothesis tested here is that (1) Hispanic-specific mitochondrial haplogroup(s) and possible associated reduced OXPHOS provide a mitochondrial background that favors HCC progresion and (2) that the interactions between HCV proteins and mitochondrial machinery compromise OXPHOS and critical aspects of mitochondrial pathways, leading to HCC tumorigenesis. Our recent breakthroughs include the following: (1) the establishment of Hispanic HCC cell lines and (2) the generation of an inducible, dosage-dependent, non- mitochondrial-conflicting expression system, which will enable us to test the overarching hypothesis. We will generate cybrids with a Hispanic HCC nuclear background but different mitochondrial haplogroups and investigate mitochondrial function and tumorigenesis in these cybrids. We will also test the hypotheses that (1) reduced mitochondrial function increases HCC tumorigenesis while enhanced OXPHOS activity will decrease HCC tumorigenesis and (2) a Hispanic-specific background will sensitize the cells to HCV-mediated HCC tumorigenesis. Finally, taking advantage of big data about HCC patients in public databases and our unique access to our institute’s large liver Biobank with Hispanic HCC patient samples, we will complement these molecular investigations with bioinformatics and human epidemiology studies to verify associations between mitochondrial genetics, mitochondrial function, and HCV infection in the development and progression of HCC in the Hispanic population.

肝细胞癌（HCC）是联合癌症相关死亡率最快的原因之一 国家。发展HCC的最大危险因素是病毒感染（HBV和HCV）。其他因素包括非 - 酒精脂肪肝病（NAFLD），酒精使用和肥胖/代谢综合征。遗传学也发挥了 在HCC的发展和发展中的重要作用。值得注意的是，HCC燃烧不成比例 在不同种族中表达；西班牙裔的事件和死亡率高于 在两种性别的非西班牙裔白人（NHW）中，尤其是在德克萨斯州南部的西班牙裔是最快的 - 人口增长。此外，乙型肝炎病毒（HCV）感染的西班牙裔人的风险明显更高 与HCV相比，与NHW相比，肝硬化和HCC的发展。 HCV蛋白的一个主要靶标是 线粒体。线粒体DNA（mtDNA）的改变和线粒体功能障碍在各种 癌症的类型，包括HCC。人类mtDNA单倍肌由独特的mtDNA集定义 多态性，反映了由离散谱系积累的突变。线粒体的分布 西班牙裔人口中的单次群与NHW人口的不同之处在于 对西班牙裔HCC较高事件的增长。基于这些事实和我们以前的研究，我们 寻求确定线粒体单倍元，线粒体功能障碍和HCV的不同以及如何不同 感染（以及这些因素之间的相互作用）会影响HCC肿瘤发生和编程。这 这里测试的假设是（1）西班牙裔特异性线粒体单倍群和可能相关的 减少的Oxphos提供了有利于HCC编程的线粒体背景，并且（2） HCV蛋白与线粒体机械之间的相互作用损害了Oxphos和关键方面 线粒体途径，导致HCC肿瘤发生。我们最近的突破包括以下内容：（1） 建立西班牙裔HCC细胞系，（2）产生诱导的剂量依赖性，非 - 线粒体冲突的表达系统，这将使我们能够检验总体假设。我们将 产生西班牙裔HCC核背景的周期，但线粒体单倍率不同， 研究这些囊肿中的线粒体功能和肿瘤发生。我们还将检验（1）的假设 线粒体功能降低会增加HCC肿瘤发生，而增强的OXPHOS活性将减少 HCC肿瘤发生和（2）西班牙裔特异性背景会将细胞感知到HCV介导的HCC 肿瘤发生。最后，利用有关公共数据库中HCC患者的大数据和我们独特的 使用西班牙裔HCC患者样品访问我们研究所的大肝生物库，我们将完成这些 生物信息学和人类流行病学研究的分子研究，以验证之间的关联 HCC的发育和进展中的线粒体遗传学，线粒体功能和HCV感染 在西班牙裔人口中。