Omega-3 Fatty Acids and Hepatic Carcinogenesis

Omega-3 脂肪酸与肝癌发生

基本信息

批准号：
8449722
负责人：
Tong Wu
金额：
$ 28.47万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449722
关键词：
Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Bees C3H/He Mouse Cancerous Carcinogens Chemicals Chemoprevention Chemopreventive Agent Chronic Hepatitis Cirrhosis Clinical Research Cytosolic Phospholipase A2 Development Diet Dietary Intervention Diethylnitrosamine Dinoprostone Disease Docosahexaenoic Acids Eicosapentaenoic Acid Enzymes Epidemiologic Studies Essential Fatty Acids Fatty acid glycerol esters Fish Oils Goals Growth Hepatic Hepatocarcinogenesis Hepatocyte Human Inflammation Inflammatory Knockout Mice Laboratories Liver diseases Liver neoplasms Malignant Epithelial Cell Malignant neoplasm of liver Metabolism Mus Natural regeneration Neoplasms Omega-3 Fatty Acids Pathway interactions Phenobarbital Play Polyunsaturated Fatty Acids Premalignant Primary carcinoma of the liver cells Process Production Prostaglandins Publishing Role Series Signal Pathway Signal Transduction Staging Stem cells System Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Transgenic Mice Xenograft Model beta catenin cancer cell cancer stem cell carcinogenesis cyclooxygenase 1 cyclooxygenase 2 dietary supplements effective therapy insight mortality mouse model neoplastic cell novel offspring oval cell prevent public health relevance research study tumor tumor xenograft tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Epidemiological and clinical studies have demonstrated that omega-3 polyunsaturated fatty acids (PUFAs) rich in fish oil may ameliorate inflammatory diseases and prevent carcinogenesis. The primary effector molecules are thought to be docosahexaenoic acid (DHA, 22:6, omega-3) and eicosapentaenoic acid (EPA, 20:5, omega-3). However, the precise mechanisms by which DHA and EPA influence hepatic carcinogenesis have not been elucidated. Therefore, the overall goal of this proposal is to understand, at a mechanistic level, how omega-3 PUFAs modulate hepatic carcinogenesis. Our overall hypothesis is that dietary supplement of omega-3 PUFAs, either alone or in combination with other standard therapy, represents an effective nontoxic approach that blocks the cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and Wnt/beta-catenin signaling pathways and prevents hepatic carcinogenesis. This application proposes three specific aims to examine the above hypotheses. Aim 1 will examine our hypothesis that omega-3 PUFAs inhibit COX-2 and beta-catenin signaling system and prevent hepatocarcinogenesis by using chemical-induced liver tumor development in Fat-1 transgenic mice or mice with dietary supplement of DHA and EPA. Aim 2 will evaluate the effect of omega-3 PUFAs on the candidate hepatic cancer stem cells, termed "oval cells". Aim 3 will utilize complementary approaches of cultured hepatocellular cancer cells, tumor xenograft models, as well as mice models of hepatic tumor induction to examine the combinational effect of omega-3 PUFAs plus blocking COX-2 or beta-catenin. Results from the proposed studies will provide important mechanistic insight and therapeutic implications for utilizing omega-3 PUFAs for the chemoprevention and treatment of human hepatocellular carcinoma.

描述（由申请人提供）：流行病学和临床研究表明，富含鱼油的omega-3多不饱和脂肪酸（PUFA）可能会改善炎症性疾病并预防致癌性。主要的效应分子被认为是二十二碳六烯酸（DHA，22：6，Omega-3）和eicosapentaenoic酸（EPA，20：5，Omega-3）。然而，尚未阐明DHA和EPA影响肝癌发生的确切机制。因此，该提案的总体目标是在机械水平上了解Omega-3 Pufas如何调节肝癌的作用。我们的总体假设是，单独或与其他标准疗法结合使用的Omega-3 Pufas的饮食补充是一种有效的无毒方法，可以阻止环氧酶-2（COX-2）衍生的前列腺素E2（PGE2）（PGE2）（PGE2）和Wnt/beta/beta/beta/beta/beta/beta/beta/beta/beta-catenin信号通路和预科。该申请提出了三个特定的目的，以检查上述假设。 AIM 1将研究我们的假设，即Omega-3 PUFA抑制COX-2和β-catenin信号系统，并通过使用化学诱导的脂肪转基因小鼠或DHA和EPA饮食中的脂肪转基因小鼠或小鼠中化学诱导的肝肿瘤发育来预防肝癌发生。 AIM 2将评估omega-3 Pufas对候选肝癌干细胞的影响，称为“椭圆细胞”。 AIM 3将利用培养的肝细胞癌细胞，肿瘤异种移植模型以及肝肿瘤诱导的小鼠模型的互补方法来检查Omega-3 PUFAS以及阻断COX-2或β-catenin的组合作用。拟议的研究的结果将为利用omega-3 PUFAS的化学预防和治疗人肝细胞癌提供重要的机械洞察力和治疗意义。