Molecular mechanism of diet induced carcinogenesis

饮食致癌的分子机制

基本信息

批准号：
7750534
负责人：
Kalpana Ghoshal
金额：
$ 30.21万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750534
关键词：
Address Amino Acids Anabolism Animals Apoptosis Betaine Binding Proteins Biochemical Biological Assay Biological Markers Biological Models Biological Process C57BL/6 Mouse Cancer Etiology Candidate Disease Gene Cell Cycle Proteins Cells Cessation of life Characteristics Choline Cobra Colon Carcinoma Congenital Abnormality CpG Islands DNA Methylation DNA Methyltransferase DNA Modification Methylases Diagnosis Diet Doxorubicin Early Diagnosis Enzymes Epidemiologic Studies Epigenetic Process Etiology Event Exhibits Exons Fatty Liver Fluorouracil Folate Folic Acid Frequencies Functional disorder Funding Gene Expression Gene Expression Regulation Genes Genetic Polymorphism Genetic Predisposition to Disease Genome Grant Growth Hepatic Hepatocarcinogenesis Hepatocyte Homeostasis Human Hypermethylation Immunoprecipitation Injury Institutes Intake Knock-out Knockout Mice Link Liver Liver Cirrhosis Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Malnutrition Measures Mediating Metabolic Metabolic Pathway Methionine Methylation Micronutrients Modeling Molecular Molecular Profiling Molecular Target Mus Mutation NIH Program Announcements Nodule Nutrient Oncogene Proteins Oxidative Stress Pathogenesis Pharmaceutical Preparations Phenotype Predisposition Primary carcinoma of the liver cells Protein Tyrosine Phosphatase Proteins Rattus Reaction Regulation Regulator Genes Resistance Reverse Transcriptase Polymerase Chain Reaction Risk Role Staging Suppressor-Effector T-Lymphocytes Technology Time Tumor Suppressor Genes Tumor Suppressor Proteins United States Vitamin B 12 Weight Western Blotting Wild Type Mouse Zinc cancer prevention carcinogenesis cell transformation chemical carcinogen choline deficient diet cofactor feeding gene interaction insight liver cell proliferation men methionine methyl ester mortality new therapeutic target nonalcoholic steatohepatitis novel promoter response therapeutic target tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The long term objective is to advance our understanding of the role of dietary deficiency of the methyl donors in epigenetic regulation of gene expression in hepatocarcinogenesis. In the last granting period, we showed that the gene encoding protein tyrosine phosphatase O (PTPRO) is methylated and silenced in preneoplastic nodules and primary hepatomas induced in a rat model. Subsequent study established that PTPRO is a bona fide tumor suppressor. In the present study we will examine whether its promoter methylation can be used as biomarker for liver cancer of specific etiology and its function in liver. We will also explore epigenetic regulation of nutrient gene interaction in hepatocarcinogenesis using methionine adenosytransferase 1a (Mat1a) null (MAT1KO) mice and methyl deficient diet as a model system. Frequent loss of Mat1a in human primary liver tumors results in decreased SAM (cofactor for all methylation reactions) level and correlates with dedifferentiation of hepatocytes. MAT1KO mice exhibit reduced hepatic SAM level and increased susceptibility to hepatic injury upon feeding methyl-deficient diet. The specific aims of the proposal are: 1) to analyze methylation profile of PTPRO CpG island spanning the promoter and exon1 in a large number of human primary HCCs of different etiology using EpiTyper technology, and determine whether methylation of PTPRO in HCCs inversely correlates with its expression. 2) Determine the potential role of PTPRO in regulating invasiveness of HCC cells and their sensitization to drug (doxorubicin, 5-Fluorouracil)-induced apoptosis, and identify liver-specific substrate(s) of PTPRO by substrate-trapping assay that will unravel potential therapeutic targets for HCC. 3) Investigate liver pathophysiology and susceptibility to hepatocarcinogenesis of MAT1KO mice on CDAA diet compared to the wild type mice. 4) Compare methylation profile of the liver genome of MAT1KO mice with the wild type mice at early stages of CDAA diet-induced hepatocarcinogenesis, confirm differential methylation of the candidate genes and determine whether methylation status of these genes correlates inversely with their expression. It is hoped that this study will provide us with novel insights into (a) role of PTPRO in liver tumorigenesis, (b) relationship between dietary methyl deficiency and changes in DNA methylation and expression of genes at early stages of hepatocarcinogenesis, (c) role of Mat1a and SAM in induction of liver cancer by the deficient diet and (d) additional molecular targets for early stage diagnosis and epigenetic therapy of HCC. This proposal also fits well with the recent program announcement of multiple institutes on diet, epigenetic events and cancer prevention.Liver cancer is the fifth most prevalent cancer in the world and is the third leading cause of cancer-related death with annual date rate exceeding 500,000, and is increasing in frequency and mortality (particularly in men) in the United States. The present study will address the role of dietary methyl deficiency in the initiation of liver tumorigenesis. Specifically, this study is aimed at (a) elucidation of the role of specific genes that are methylated and silenced at early stages of liver cancer in response to this dietary deficiency and (b) identification of novel molecular targets for early diagnosis and epigenetic therapy of liver cancer. This proposal also fits well with the recent program announcement of multiple institutes on diet, epigenetic events and cancer prevention.

描述（由申请人提供）：长期目标是加深我们对甲基供体饮食缺乏在肝癌发生中基因表达表观遗传调控中的作用的理解。在最后的资助期间，我们发现编码蛋白酪氨酸磷酸酶 O (PTPRO) 的基因在大鼠模型中诱导的癌前结节和原发性肝癌中被甲基化和沉默。随后的研究证实 PTPRO 是一种真正的肿瘤抑制剂。在本研究中，我们将探讨其启动子甲基化是否可以作为特定病因肝癌的生物标志物及其在肝脏中的功能。我们还将使用蛋氨酸腺苷转移酶 1a (Mat1a) null (MAT1KO) 小鼠和甲基缺乏饮食作为模型系统，探索肝癌发生中营养基因相互作用的表观遗传调控。人类原发性肝肿瘤中 Mat1a 的频繁缺失会导致 SAM（所有甲基化反应的辅助因子）水平降低，并与肝细胞去分化相关。 MAT1KO 小鼠在喂食缺乏甲基的饮食后表现出肝脏 SAM 水平降低和肝损伤的易感性增加。该提案的具体目标是：1）利用EpiTyper技术分析大量不同病因的人类原发性HCC中跨越启动子和外显子1的PTPRO CpG岛的甲基化谱，并确定HCC中PTPRO的甲基化是否与其呈负相关。表达。 2) 确定 PTPRO 在调节 HCC 细胞侵袭性及其对药物（阿霉素、5-氟尿嘧啶）诱导的细胞凋亡的敏感性中的潜在作用，并通过底物捕获测定鉴定 PTPRO 的肝脏特异性底物，从而揭示其潜力HCC 的治疗靶点。 3) 与野生型小鼠相比，研究采用 CDAA 饮食的 MAT1KO 小鼠的肝脏病理生理学和对肝癌发生的易感性。 4)比较CDAA饮食诱发肝癌早期MAT1KO小鼠与野生型小鼠肝脏基因组的甲基化谱，确认候选基因的差异甲基化，并确定这些基因的甲基化状态是否与其表达负相关。希望这项研究能够为我们提供新的见解：(a) PTPRO 在肝脏肿瘤发生中的作用，(b) 饮食甲基缺乏与肝癌早期阶段 DNA 甲基化和基因表达变化之间的关系，(c) 作用Mat1a 和 SAM 在饮食不足诱导肝癌中的作用以及 (d) 用于 HCC 早期诊断和表观遗传学治疗的其他分子靶点。这一提议也与近期多个机构在饮食、表观遗传事件和癌症预防方面宣布的计划相契合。肝癌是世界上第五大流行癌症，也是癌症相关死亡的第三大原因，年发病率超过50万例，并且在美国，其频率和死亡率（尤其是男性）正在增加。本研究将探讨膳食甲基缺乏在肝脏肿瘤发生中的作用。具体来说，这项研究的目的是（a）阐明在肝癌早期甲基化和沉默的特定基因针对这种饮食缺陷的作用，以及（b）鉴定用于肝癌早期诊断和表观遗传治疗的新分子靶点。肝癌。该提议也与多个机构最近宣布的有关饮食、表观遗传事件和癌症预防的计划非常吻合。