Omega-3 Fatty Acids and Hepatic Carcinogenesis

Summary

Principal Investigator: Tong Wu
Abstract: 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.
Funding Period: 2010-02-01 - 2014-01-31
more information: NIH RePORT

Top Publications

  1. pmc Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2
    Kyu Lim
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Mol Cancer Ther 8:3046-55. 2009
  2. pmc Cytosolic phospholipase A2alpha and peroxisome proliferator-activated receptor gamma signaling pathway counteracts transforming growth factor beta-mediated inhibition of primary and transformed hepatocyte growth
    Chang Han
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
    Hepatology 52:644-55. 2010
  3. pmc Microsomal prostaglandin E synthase-1 inhibits PTEN and promotes experimental cholangiocarcinogenesis and tumor progression
    Dongdong Lu
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
    Gastroenterology 140:2084-94. 2011
  4. pmc Cytosolic phospholipase A(2)α protects against Fas- but not LPS-induced liver injury
    Guiying Li
    Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130021, China
    J Hepatol 55:1281-90. 2011
  5. pmc MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin
    Jinqiang Zhang
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
    Gastroenterology 143:246-56.e8. 2012
  6. pmc 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1
    D Lu
    1 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA 2 Tongji University School of Life Science and Technology, Shanghai, China
    Oncogene 33:1101-12. 2014
  7. pmc miR-101 inhibits cholangiocarcinoma angiogenesis through targeting vascular endothelial growth factor (VEGF)
    Jinqiang Zhang
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
    Am J Pathol 182:1629-39. 2013
  8. pmc 15-hydroxyprostaglandin dehydrogenase-derived 15-keto-prostaglandin E2 inhibits cholangiocarcinoma cell growth through interaction with peroxisome proliferator-activated receptor-γ, SMAD2/3, and TAP63 proteins
    Dongdong Lu
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
    J Biol Chem 288:19484-502. 2013

Detail Information

Publications8

  1. pmc Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2
    Kyu Lim
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Mol Cancer Ther 8:3046-55. 2009
    ..These findings provide important preclinical evidence and molecular insight for utilization of omega-3 PUFAs for the chemoprevention and treatment of human HCC...
  2. pmc Cytosolic phospholipase A2alpha and peroxisome proliferator-activated receptor gamma signaling pathway counteracts transforming growth factor beta-mediated inhibition of primary and transformed hepatocyte growth
    Chang Han
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
    Hepatology 52:644-55. 2010
    ..The interplays between TGF-beta and cPLA(2)alpha signaling pathways were examined in rat primary hepatocytes, human hepatocellular carcinoma cells, and hepatocytes isolated from newly developed cPLA(2)alpha transgenic mice...
  3. pmc Microsomal prostaglandin E synthase-1 inhibits PTEN and promotes experimental cholangiocarcinogenesis and tumor progression
    Dongdong Lu
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
    Gastroenterology 140:2084-94. 2011
    ..Although COX-2 is involved in the development and progression of various human cancers, the role of mPGES-1 in carcinogenesis has not been determined. We investigated the role of mPGES-1 in human cholangiocarcinoma growth...
  4. pmc Cytosolic phospholipase A(2)α protects against Fas- but not LPS-induced liver injury
    Guiying Li
    Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130021, China
    J Hepatol 55:1281-90. 2011
    ..This study was designed to explore the role of hepatocyte cPLA(2)α in Fas-mediated liver injury, in vivo...
  5. pmc MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin
    Jinqiang Zhang
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
    Gastroenterology 143:246-56.e8. 2012
    ..MicroRNAs (miRNAs) have been implicated in the development and progression of human cancers. We investigated the roles and mechanisms of miR-26a in human cholangiocarcinoma...
  6. pmc 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPARγ-mediated activation of p21WAF1/Cip1
    D Lu
    1 Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA 2 Tongji University School of Life Science and Technology, Shanghai, China
    Oncogene 33:1101-12. 2014
    ..These results show a key 15-PGDH/15-keto-PGE2-mediated activation of PPARγ and p21(WAF1/Cip1) signaling cascade that regulates hepatocarcinogenesis and tumor progression. ..
  7. pmc miR-101 inhibits cholangiocarcinoma angiogenesis through targeting vascular endothelial growth factor (VEGF)
    Jinqiang Zhang
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
    Am J Pathol 182:1629-39. 2013
    ..This study established a novel tumor-suppressor role of miR-101 in cholangiocarcinoma and it suggests the possibility of targeting miR-101 and related signaling pathways for future therapy...
  8. pmc 15-hydroxyprostaglandin dehydrogenase-derived 15-keto-prostaglandin E2 inhibits cholangiocarcinoma cell growth through interaction with peroxisome proliferator-activated receptor-γ, SMAD2/3, and TAP63 proteins
    Dongdong Lu
    Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
    J Biol Chem 288:19484-502. 2013
    ..These findings disclose a novel 15-PGDH-mediated 15-keto-PGE2 signaling cascade that interacts with PPAR-γ, Smad2/3, and TAP63. ..

Research Grants30

  1. Novel Sulindac Derivatives for Colon Cancer Chemoprevention
    Robert C Reynolds; Fiscal Year: 2013
    ..This multidisciplinary research proposal may lead to a novel strategy for colon cancer chemoprevention. ..
  2. Role of Uhrf1 in Liver Development, Regeneration and Carciogenesis
    Chinweike Ukomadu; Fiscal Year: 2013
    ..We believe that we have discovered a gene called UHRF1 that is involved in all the three processes and will study how it plays a role in each situation. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page ..
  3. Functional Analysis of Cyclooxygenase-2
    Lawrence J Marnett; Fiscal Year: 2013
    ..These substrate-selective inhibitors may represent candidate cancer chemopreventive agents that lack the gastrointestinal and cardiovascular side effects of currently marketed NSAIDs. ..
  4. Role of microRNA-122 in hepatocarcinogenesis using conditional knock out mice
    Kalpana Ghoshal; Fiscal Year: 2013
    ..Thus, establishing role of miR-122 mimetic in an animal model (in preclinical trial) would be a major milestone in the treatment of this deadly disease in the near future. ..