Omega-3 Fatty Acids and Hepatic Carcinogenesis

Omega-3 脂肪酸与肝癌发生

• 批准号: 8096663
• 负责人: Tong Wu
• 金额: $ 30.29万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 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/8096663
• 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; Health; 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; 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

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, ?-3) and eicosapentaenoic acid (EPA, 20:5, ?-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/¿-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 ?-3 PUFAs inhibit COX-2 and ¿-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 ¿-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. PUBLIC HEALTH RELEVANCE: This application is proposed to test our hypothesis that dietary supplement of ¿-3 polyunsaturated fatty acids (PUFAs) may represent an effective nontoxic approach that blocks the cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and Wnt/¿-catenin signaling pathways simultaneously and thus prevents hepatic carcinogenesis. A series of experiments will be performed to evaluate the above hypothesis. Results of the proposed experiments are expected to reveal a novel role of ?-3 PUFAs, COX-2 and ¿-catenin signaling pathways in liver carcinogenesis and provide important therapeutic implications for its chemoprevention and treatment.

描述（由应用提供）：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（PUFAS）可能会改善炎症性疾病并预防致癌性。原发性效应分子被认为是二十二碳六烯酸（DHA，22：6，？-3）和eicosapentaenoic酸（EPA，20：5，？-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如何调节肝癌的发生。我们的总体假设是，单独或与其他标准疗法结合使用Omega-3 Pufas的饮食补充是一种有效的无毒方法，它阻止了环氧酶-2（COX-2）衍生的前列腺素E2（PGE2）（PGE2）（PGE2）和Wnt/wnt/？？？¿-catenin信号pathways和-Catenin信号pathways and toresiss Hepatitic Carcarcatiens carccarcineogenogenencorsenogenencensogensogensogensogensogensogensogensogensogensogensogenseption。该申请提出了三个特定旨在检查上述假设的特定旨在。 AIM 1将检查我们的假设：-3 PUFA抑制COX-2和�-catenin信号传导系统，并通过使用化学诱导的脂肪1转基因小鼠或饮食补充DHA和EPA中的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对候选肝细胞癌细胞的影响，称为“椭圆形细胞”。 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完整方法来检查Omega-3 PUFAS以及阻断Cox-2或 - catenin的组合作用。拟议研究的结果将为使用omega-3 PUFAS进行化学预防和治疗人肝细胞癌的重要机理洞察力和治疗意义。公共卫生相关性：提出了这一应用来检验我们的假设：-3多不饱和脂肪酸（PUFAS）可能代表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）（pge2）和wnt/wnt/= -catenin pathloese confatientic caregen。将进行一系列实验以评估上述假设。提出的实验的结果有望揭示肝癌中的PUFAS，COX-2和 - 卡丁蛋白信号通路的新作用，并为其化学预防和治疗提供了重要的治疗意义。