Mechanisms of obesity-induced hepatocarcinogenesis

肥胖诱发肝癌的机制

• 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
• 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

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，影响近三分之一的美国人口。流行病学研究的证据表明，肥胖与许多类型癌症的发展有关，与肝癌的联系尤其密切。在美国，肥胖与非酒精性脂肪肝（NAFLD）和肝癌的高发病率相关。肥胖人群中肝癌风险增加的潜在机制尚未完全了解。由于脂肪组织会释放促进炎症的激素，因此人们认为肥胖人群中常见的脂肪肝疾病中的慢性炎症是罪魁祸首。在这两个PI项目中，我们将专注于脂质过氧化（LPO）诱导的DNA损伤及其对DNA修复和突变的影响，以及它们在肝细胞癌（HCC）发展中的作用。我们提出，内源性环状DNA加合物的形成，包括丙Acr-dG和HNE-dG，dA和dG的乙烯基，以及最近发现的DHH-乙烯基dA和DHH-乙烯基dG，由脂肪酸氧化产生的醛作为慢性炎症的结果在NAFLD中增加;同时，这些醛也可以抑制DNA修复机制。我们认为，这些作用可以诱导驱动基因突变，通过非酒精性脂肪性肝炎（NASH）（NAFLD的一种进行性形式）促进肝癌发生。本研究拟以肥胖的C57 BL/6（B-6）小鼠为模型，与培养的小鼠和人肝细胞平行，通过以下目的来验证这一假说：1）确定高脂饮食喂养的B-6小鼠在肝癌发生过程中肝脏中环状DNA加合物的形成; 2）在B-6小鼠的NAFLD和HCC阶段的肝脏中以及在用LPO醛副产物处理的培养的肝细胞中，确定突变谱并绘制两个肝癌驱动基因p53和β-连环蛋白（CTNNB 1）中大环DNA加合物和氧化DNA损伤（ODD）的分布; 3）确定LPO醛对DNA修复能力和突变敏感性的影响; 4）检测硫辛酸的潜在化学预防活性， 酸和Polyphenon E对肥胖B-6小鼠HCC发展的影响。