Omega-3 Fatty Acids and Hepatic Carcinogenesis

产品描述（由申请人提供）：流行病学和临床研究表明，鱼油中富含的ω-3多不饱和脂肪酸（PUFA）可以改善炎症性疾病并预防致癌作用。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 PUFA如何调节肝癌发生。我们的总体假设是，饮食补充omega-3 PUFA，单独或与其他标准治疗组合，代表了一种有效的无毒方法，阻断环氧化酶-2（考克斯-2）衍生的前列腺素E2（PGE 2）和Wnt/ω-连环蛋白信号通路，并预防肝癌发生。本申请提出了三个具体目标来检验上述假设。目标1将检验我们的假设，3多不饱和脂肪酸抑制考克斯-2和-连环蛋白信号系统，并通过化学诱导的Fat-1转基因小鼠或膳食补充DHA和EPA的小鼠的肝癌发生来预防肝癌的发生。目的2将评估ω-3多不饱和脂肪酸对被称为“卵圆细胞”的候选肝癌干细胞的作用。目的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ω-3 PUFA加上阻断考克斯-2或ω-连环蛋白的组合效应。从拟议的研究结果将提供重要的机制的见解和治疗的影响，利用omega-3 PUFA的化学预防和治疗人类肝细胞癌。公共卫生相关性：本申请旨在验证我们的假设，即膳食补充剂考克斯-2（COX-2）-衍生的前列腺素E2（PGE 2）和Wnt/-连环蛋白信号通路可能是一种有效的无毒方法，同时阻断，从而防止肝癌的发生。将进行一系列实验来评估上述假设。拟议的实验结果预计将揭示一个新的作用？- 3 PUFAs、考克斯-2和<$-catenin信号通路在肝癌发生发展中的作用，为肝癌的化学预防和治疗提供了重要的治疗意义。

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.