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

肝细胞癌是美国癌症相关死亡率上升最快的原因之一。 各州。发生肝细胞癌的最大风险因素是病毒感染(乙肝病毒和丙型肝炎病毒)。其他因素包括非 酒精性脂肪肝(NAFLD)、饮酒和肥胖/代谢综合征。遗传学也扮演着一个 在肝细胞癌的发生发展中起重要作用。值得注意的是，肝细胞癌的负担不成比例 在不同种族中表达；拉美裔的发病率和死亡率远远高于 在非西班牙裔白人(NHW)中，无论男女，特别是在南得克萨斯州，拉美裔美国人速度最快- 不断增长的人口。此外，感染丙型肝炎病毒(fi)的西班牙裔人的风险明显更高。 与患有丙型肝炎的新生儿相比，发生肝硬变和肝细胞癌的可能性更大。丙型肝炎病毒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与多种疾病有关 癌症类型，包括肝细胞癌。人类线粒体DNA单倍群是由独特的线粒体DNA集合定义的 多态，反映了由离散血统积累的突变。线粒体的分布 西班牙裔人口中的单倍群与NHW人口中的单倍群有很大不同，后者可能有一些 对拉美裔人更高的肝癌发病率的影响。基于这些事实和我们之前的研究，我们 试图确定线粒体单倍群、线粒体功能障碍和丙型肝炎病毒是否以及如何不同 感染(以及这些因素之间的相互作用)影响肝癌的发生和发展。这个 这里检验的假设是(1)西班牙裔特有的线粒体单倍群(S)和可能的相关 减少的OXPHOS提供了有利于肝癌进展的线粒体背景，以及(2) 丙型肝炎病毒蛋白和线粒体机制之间的相互作用损害OXPHOS和关键方面 线粒体途径，导致肝癌的发生。我们最近的突破包括：(1) 西班牙裔肝癌细胞系的建立和(2)可诱导的、剂量依赖的、非诱导性的 线粒体冲突表达系统，这将使我们能够检验最重要的假设。我们会 产生具有西班牙裔肝细胞癌核背景但不同线粒体单倍群和 研究这些线虫的线粒体功能和肿瘤发生。我们还将检验以下假设：(1) 线粒体功能降低会增加肝癌的发生，而OXPHOS活性的增强则会降低 肝细胞癌的发生和(2)西班牙裔的特定背景将使细胞对丙型肝炎病毒介导的肝细胞癌敏感 肿瘤发生学。最后，利用公共数据库中关于肝癌患者的大数据和我们独特的 访问我们研究所包含西班牙裔肝癌患者样本的大型肝脏生物库，我们将补充这些 分子研究与生物信息学和人类流行病学研究，以验证 线粒体遗传学、线粒体功能和丙型肝炎病毒感染在肝癌发生发展中的作用 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.