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.

Public Health Relevance Statement 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.