Omega-3 Fatty Acids and Hepatic Carcinogenesis

描述(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)可以缓解炎症性疾病，防止癌症发生。主要的效应分子被认为是二十二碳六烯酸(DHA，22：6，omega-3)和二十碳五烯酸(EPA，20：5，omega-3)。然而，DHA和EPA影响肝癌发生的确切机制尚未阐明。因此，这项提议的总体目标是在机制水平上了解omega-3多不饱和脂肪酸是如何调控肝癌发生的。我们的总体假设是，膳食补充omega-3 PUFAs，无论是单独还是与其他标准治疗相结合，都是一种有效的无毒方法，可以阻断环氧合酶-2(COX-2)衍生的前列腺素E2(PGE2)和Wnt/β-catenin信号通路，防止肝癌的发生。本申请提出了三个具体目标来检验上述假设。目的1验证我们的假设，即omega-3多不饱和脂肪酸抑制COX-2和β-catenin信号系统，并通过在Fat-1转基因小鼠或饮食中补充DHA和EPA的小鼠中使用化学诱导的肝癌发生来防止肝癌的发生。目的2评价omega-3多不饱和脂肪酸对候选肝癌干细胞--卵圆细胞的作用。目的3将利用培养的肝癌细胞、肿瘤异种移植模型以及小鼠肝肿瘤诱导模型的互补方法来检验omega-3多不饱和脂肪酸与阻断COX-2或β-catenin的联合作用。这项研究的结果将为利用omega-3多不饱和脂肪酸化学预防和治疗人肝细胞癌提供重要的机制见解和治疗启示。

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.