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

肝细胞癌（HCC）是美国癌症相关死亡率上升最快的原因之一。 States.发生HCC的最大风险因素是病毒感染（HBV和HCV）。其他因素包括非 酒精性脂肪肝（NAFLD）、酒精使用和肥胖/代谢综合征。遗传学也起着 在HCC的发生和发展中起重要作用。值得注意的是，HCC负担不成比例 在不同的种族群体中表达;西班牙裔的发病率和死亡率远高于 在非西班牙裔白人（NHW）中，男女都是如此，特别是在西班牙裔最快的南德克萨斯州， 人口增长。此外，患有丙型肝炎病毒（HCV）感染的西班牙裔人的风险明显较高 与NHW合并HCV相比，HCV蛋白的一个主要靶点是 线粒体线粒体DNA（mtDNA）改变和线粒体功能障碍涉及多种疾病。 癌症类型，包括HCC。人类mtDNA单倍型群是由独特的mtDNA组定义的。 多态性，反映离散谱系积累的突变。线粒体的分布 西班牙裔人群中的单倍群与NHW人群中的单倍群有很大不同，NHW人群中的单倍群可能有一些 对西班牙裔肝癌发病率的影响。根据这些事实和我们以前的研究，我们 试图确定是否以及如何不同的线粒体单倍型群，线粒体功能障碍，HCV 感染（以及这些因素之间的相互作用）影响HCC肿瘤的发生和进展。的 这里检验的假设是：（1）西班牙人特有的线粒体单倍型群和可能的相关 减少的OXPHOS提供了有利于HCC进展的线粒体背景，以及（2）OXPHOS的减少提供了有利于HCC进展的线粒体背景， HCV蛋白和线粒体机制之间的相互作用损害了OXPHOS和 线粒体途径，导致HCC肿瘤发生。我们最近的突破包括：（1） 西班牙HCC细胞系的建立和（2）诱导的、剂量依赖性的、非- 语义冲突表达系统，这将使我们能够测试总体假设。我们将 产生具有西班牙HCC核背景但不同线粒体单倍型组的胞质杂交体， 研究这些胞质杂种的线粒体功能和肿瘤发生。我们还将测试假设（1） 线粒体功能降低会增加HCC肿瘤发生，而OXPHOS活性增强会降低 HCC肿瘤发生和（2）西班牙裔特异性背景将使细胞对HCV介导的HCC敏感 肿瘤发生最后，利用公共数据库中关于HCC患者的大数据和我们独特的 访问我们研究所的大型肝脏生物银行与西班牙裔HCC患者样本，我们将补充这些 生物信息学和人类流行病学研究的分子研究，以验证 肝细胞癌发生发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。

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.