Omega-3 Fatty Acids and Hepatic Carcinogenesis

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（PUFAs）可以改善炎症性疾病并预防致癌。主要的效应分子被认为是二十二碳六烯酸(DHA, 22:6, ？-3)和二十碳五烯酸（EPA, 20:5, -3）。然而，DHA和EPA影响肝癌发生的确切机制尚未阐明。因此，本提案的总体目标是在机制水平上了解omega-3 PUFAs如何调节肝癌的发生。我们的总体假设是，膳食补充omega-3 PUFAs，单独或与其他标准治疗联合使用，是一种有效的无毒方法，可以阻断环氧化酶-2 （COX-2）衍生的前列腺素E2 （PGE2）和Wnt/¿-catenin信号通路，防止肝癌发生。本应用程序提出了三个具体目标来检验上述假设。目的1将检验我们的假设？-3 PUFAs抑制COX-2和¿-catenin信号系统，并通过在Fat-1转基因小鼠或膳食补充DHA和EPA的小鼠中使用化学诱导的肝肿瘤发展来预防肝癌的发生。目的2将评估omega-3 PUFAs对候选肝癌干细胞（称为“卵形细胞”）的影响。目的3将利用培养的肝癌细胞、肿瘤异种移植模型以及肝肿瘤诱导小鼠模型的互补方法来检验omega-3 PUFAs加阻断COX-2或¿-catenin的联合作用。拟议研究的结果将为利用omega-3 PUFAs进行人类肝细胞癌的化学预防和治疗提供重要的机制见解和治疗意义。公共卫生相关性：本应用旨在验证我们的假设，即膳食补充-3多不饱和脂肪酸（PUFAs）可能是一种有效的无毒方法，可以同时阻断环氧化酶-2 （COX-2）衍生的前列腺素E2 （PGE2）和Wnt/ -catenin信号通路，从而防止肝癌的发生。我们将进行一系列实验来验证上述假设。所提出的实验结果有望揭示？-3 PUFAs、COX-2和¿-catenin信号通路在肝癌发生中的作用，并为其化学预防和治疗提供重要的治疗意义。

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.