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）：长期目标是促进我们对甲基供体饮食缺乏在肝癌发生中基因表达的表观遗传调节中的作用的理解。在最后一个授予期间，我们表明编码蛋白酪氨酸磷酸酶O（PTPRO）的基因是甲基化的，并在大鼠模型中诱导的前肿瘤结节和原发性肝瘤中沉默。随后的研究表明，PTPRO是一种真正的肿瘤抑制剂。在本研究中，我们将检查其启动子甲基化是否可以用作特异性病因及其在肝脏功能的肝癌的生物标志物。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，探索肝癌发生营养基因相互作用的表观遗传调节。在人原发性肝肿瘤中经常丢失MAT1A导致SAM（所有甲基化反应的辅助因子）降低，并与肝细胞的去分化相关。 MAT1KO小鼠在喂养甲基缺陷饮食后表现出肝脏SAM水平降低，并增加了对肝损伤的敏感性。该提案的具体目的是：1）分析PTPRO CPG岛的甲基化谱系跨越启动子和Exon1的甲基化谱图使用epityper技术在大量不同病因的人类原发性HCC中，并确定HCC中PTPRO在HCC中是否与其表达不相反的甲基化。 2）确定PTPRO在调节HCC细胞的侵袭性中的潜在作用及其对药物的敏感性（阿霉素，5-氟尿嘧啶）诱导的凋亡，并通过底物捕获分析识别PTPRO的肝脏特异性底物（S），这将通过底物捕获分析揭示潜在的潜在治疗靶标的HCC。 3）与野生型小鼠相比，研究了MAT1KO小鼠对MAT1KO小鼠的肝脏生理学和易感性。 4）在CDAA饮食诱导的肝癌发生的早期阶段，比较了MAT1KO小鼠的肝脏基因组与野生型小鼠的甲基化谱，证实了候选基因的甲基化差异，并确定这些基因的甲基化状态是否与其表达不相反。希望这项研究能够为我们提供对PTPRO在肝肿瘤发生中的作用的新颖见解，（b）（b）饮食中甲基缺乏症与DNA甲基化的变化与肝癌的早期阶段的基因的变化与基因表达的变化，（c）在肝癌中的作用和SAM在肝癌中的作用以及肝脏诊断的其他阶段（c）诊断（c）诊断（c）的其他分数（c）的作用（c） HCC。该提案还非常符合最近宣布多家饮食，表观遗传事件和预防癌症的机构的计划。Liver癌症是世界上第五大流行的癌症，是与癌症相关死亡的第三大主要原因，年日期率超过500,000，并且在美国的频率和死亡率（尤其是男性）的增加。本研究将解决饮食中甲基缺乏症在肝肿瘤发生启动中的作用。具体而言，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的作用，以应对这种饮食缺乏，以及（b）鉴定肝癌早期诊断和表观遗传治疗的新型分子靶标。该提案还与最近关于饮食，表观遗传事件和预防癌症的多家机构的计划宣布非常吻合。