Mechanisms of obesity-induced hepatocarcinogenesis

肥胖诱发肝癌的机制

基本信息

批准号：
9065516
负责人：
FUNG-LUNG CHUNG
金额：
$ 36.43万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-08 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9065516
关键词：
4 hydroxynonenal Acetaldehyde Acrolein Adipose tissue Affect Aldehydes Antioxidants Base Excision Repairs Binding Biological Assay CTNNB1 gene Cells Chemopreventive Agent Chronic Country DNA DNA Adduction DNA Adducts DNA Damage DNA Repair DNA Repair Gene DNA Sequence Alteration Deoxyadenosines Deoxyguanosine Developing Countries Development Electrospray Ionization Epidemiologic Studies Exons Fatty Liver Genes Genetic Predisposition to Disease Health Hepatocarcinogenesis Hepatocyte High Fat Diet High Prevalence Hormones Human Incidence Induced Mutation Inflammation Kinetics Lesion Life Link Lipid Peroxidation Liquid Chromatography Liver Liver diseases Malignant neoplasm of liver Maps Mismatch Repair Modeling Mus Mutagenesis Mutate Mutation Mutation Spectra Nucleotide Excision Repair Obesity Oncogenes Polyphenon E Polyunsaturated Fatty Acids Population Predisposition Prevention Primary carcinoma of the liver cells Proteins Public Health Risk Role Single base substitution Source Staging Steatohepatitis TP53 gene Testing Thioctic Acid Time Tissues Ursidae Family Work adduct cancer type fatty acid oxidation feeding insight non-alcoholic non-alcoholic fatty liver oxidation oxidative DNA damage repaired tandem mass spectrometry tumor

项目摘要

DESCRIPTION (provided by applicant): Obesity is a major public health problem that impacts nearly a third of the US population. Evidence from epidemiological studies indicates that obesity is associated with the development of many types of cancer and its connection with liver cancer is particularly strong. In the US, obesity is associated with a high incidence of non-alcoholic-induced fatty liver disease (NAFLD) and liver cancer. The mechanisms underlying the increased risk of liver cancer in obese population are not fully understood. Because fatty tissues release hormones that promote inflammation, it is believed that chronic inflammation in fatty liver disease commonly seen in obese people is the culprit. In this two-PI project, we will focus on lipid peroxidation (LPO)-induced DNA damage and its effects on DNA repair and mutagenesis, and their roles in hepatocellular carcinoma (HCC) development. We propose that the formation of endogenous cyclic DNA adducts, including the propano Acr-dG and HNE-dG, the etheno of dA and dG, and the recently discovered DHH-etheno dA and DHH-etheno dG, from aldehydes generated by fatty acid oxidation as a result of chronic inflammation is increased in NAFLD; concomitantly, these aldehydes can also inhibit DNA repair mechanisms. We believe that these effects can induce mutations at driver genes for the promotion of hepatocarcinogenesis through non-alcoholic-induced steatohepatitis (NASH), a progressive form of NAFLD. We propose to use the genetically predisposed obese C57BL/6 (B-6) mice as a model, which are prone to develop NAFLD and HCC, in parallel with cultured mouse and human hepatocytes, to examine the hypothesis by carrying out the following aims: 1) to determine the formation of cyclic DNA adducts in livers of B-6 mice fed high fat diet during the course of HCC development; 2) to determine the mutational spectrum and map the distribution of bulky cyclic DNA adducts and oxidative-DNA damage (ODD) in two liver cancer driver genes, p53 and �-catenin (CTNNB1), in livers of B-6 mice during the NAFLD and HCC stages and in cultured hepatocytes treated with LPO aldehyde byproducts; 3) to determine the effects of LPO aldehydes on DNA repair capacity and mutational susceptibility; and 4) to examine the potential chemopreventive activities of lipoic acid and Polyphenon E for HCC development in obese B-6 mice.

描述（由申请人提供）：肥胖是一个主要的公共卫生问题，影响着近三分之一的美国人口。流行病学研究的证据表明，肥胖与多种癌症的发生有关，其中与肝癌的关系尤其密切。在美国，肥胖与非酒精性脂肪肝 (NAFLD) 和肝癌的高发病率有关。肥胖人群患肝癌风险增加的机制尚不完全清楚，因为脂肪组织会释放激素。据认为，肥胖人群中常见的脂肪肝疾病的慢性炎症是罪魁祸首。在这个 2-PI 项目中，我们将重点关注脂质过氧化 (LPO) 引起的 DNA 损伤及其对 DNA 修复和修复的影响。我们提出内源性环状 DNA 加合物的形成，包括丙醇 Acr-dG 和 HNE-dG、dA 的乙烯醇和dG，以及最近发现的 DHH-etheno dA 和 DHH-etheno dG，由慢性炎症导致的脂肪酸氧化产生的醛类在 NAFLD 中增加；同时，这些醛类也可以抑制 DNA 修复机制。可以诱导驱动基因突变，通过非酒精性脂肪性肝炎 (NASH) 促进肝癌发生，NASH 是一种进行性肝炎NAFLD。我们建议使用易患 NAFLD 和 HCC 的遗传性肥胖 C57BL/6 (B-6) 小鼠作为模型，与培养的小鼠和人类肝细胞平行，通过执行以下操作来检验该假设。目的：1) 确定在 HCC 发展过程中喂养高脂肪饮食的 B-6 小鼠肝脏中环状 DNA 加合物的形成；2) 确定突变谱并绘制大体积分布图； NAFLD 和 HCC 阶段 B-6 小鼠肝脏中以及用 LPO 醛副产物处理的培养肝细胞中两个肝癌驱动基因 p53 和 β-连环蛋白 (CTNNB1) 中的环状 DNA 加合物和氧化 DNA 损伤 (ODD)； 3) 确定 LPO 醛对 DNA 修复能力和突变易感性的影响；4) 检查潜在的化学预防活性；硫辛酸酸和 Polyphenon E 对肥胖 B-6 小鼠 HCC 发展的影响。