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.

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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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Seifried, Harold E
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Tulane University
Schools of Medicine
New Orleans
United States
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Kwon, Hyunjoo; Song, Kyoungsub; Han, Chang et al. (2016) Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease. Hepatology 63:1155-69
Chen, Weina; Han, Chang; Zhang, Jinqiang et al. (2015) Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1. Am J Pathol 185:1033-44
Chen, Weina; Han, Chang; Zhang, Jinqiang et al. (2015) miR-150 Deficiency Protects against FAS-Induced Acute Liver Injury in Mice through Regulation of AKT. PLoS One 10:e0132734
Yao, Lu; Han, Chang; Song, Kyoungsub et al. (2015) Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression. Cancer Res 75:1388-98
Zhu, Hanqing; Han, Chang; Lu, Dongdong et al. (2014) miR-17-92 cluster promotes cholangiocarcinoma growth: evidence for PTEN as downstream target and IL-6/Stat3 as upstream activator. Am J Pathol 184:2828-39
Lu, Lu; Byrnes, Kathleen; Han, Chang et al. (2014) miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth. Mol Cancer Res 12:890-900
Qadir, Ximena V; Han, Chang; Lu, Dongdong et al. (2014) miR-185 inhibits hepatocellular carcinoma growth by targeting the DNMT1/PTEN/Akt pathway. Am J Pathol 184:2355-64
Lu, D; Han, C; Wu, T (2014) 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPAR?-mediated activation of p21WAF1/Cip1. Oncogene 33:1101-12
Lu, Dongdong; Han, Chang; Wu, Tong (2013) 15-hydroxyprostaglandin dehydrogenase-derived 15-keto-prostaglandin E2 inhibits cholangiocarcinoma cell growth through interaction with peroxisome proliferator-activated receptor-?, SMAD2/3, and TAP63 proteins. J Biol Chem 288:19484-502
Song, Kyoungsub; Han, Chang; Zhang, Jinqiang et al. (2013) Epigenetic regulation of MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X protein in hepatocellular carcinoma cells. Hepatology 58:1681-92

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