PATHOGENESIS OF HEPATOCELLULAR CARCINOMA

Summary

Principal Investigator: N Fausto
Abstract: DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a common tumor worldwide. Its incidence has tripled in the USA during the last 25 years, and its prognosis is very poor. Although the main etiologic factors for HCC are well known, its pathogenesis is poorly understood. Thus, there is an urgent need for studies of the mechanisms of HCC development relevant to the human disease. HCC generally develops in cirrhotic livers in the presence of chronic inflammation, after a long phase consisting of hepatocyte proliferation and apoptosis. Oxidative stress generated in this environment can cause DMA damage that leads to chromosomal instability and disruption of cell cycle checkpoints. We have proposed that chromosomal instability, an almost universal finding in human HCC, may be caused by defects in the non-homologous end-joining (NHEJ) DMA repair pathway for double strand breaks (DSB). We have shown that the lack of the Ku70 component of NHEJ repair pathway accelerates HCC development in mice injected with diethylnitrosamine (DEN), and produces tumors with multiple numeric and structural chromosomal aberrations. A striking feature of tumorigenesis in Ku70-/- mice is the almost complete lack of p53 protein expression without alteration in p53 mRNA levels. We suggest that lack of p53 protein expression is caused by post-translational mechanisms that destabilize p53 through increased Mdm2 binding and proteasomal degradation. In contrast, mice that have a defect in ATM, a major transducer of DNA damage, are completely protected from DEN tumorigenesis for at least 12 months, and show large increases in p53 protein expression. We propose experiments designed to study the mechanisms of accelerated tumorigenesis in Ku70-/- mice, and HCC resistance in Atm-/- mice, and to determine: a) whether HCC development and chromosomal instability associated with Ku70 deficiency can be blocked by proteasome inhibitors and restoration of p53 activity through liver-specific inhibition of Mdm2 activity;b) whether HCC resistance in Atm-/- mice can be abolished by liver specific expression of mutant p53;c) whether human HCC and dysplastic lesions have altered expression of components of the NHEJ repair pathway, and d) whether molecular and karyotype homologies exist between human and Ku70-/- HCCs. The proposed experiments will increase our understanding of the mechanisms of hepatocellular carcinogenesis, and test therapeutic strategies that might be applied to human tumors.
Funding Period: ----------------1997 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients
    Maria W Smith
    Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195 8070, USA
    Gastroenterology 130:179-87. 2006
  2. pmc Responses of nontransformed human hepatocytes to conditional expression of full-length hepatitis C virus open reading frame
    Weiliang Tang
    Department of Pathology, University of Washington School of Medicine, K078 Health Sciences Building, Box 357705, Seattle, WA 98195 7705, USA
    Am J Pathol 171:1831-46. 2007
  3. ncbi Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis
    Jean S Campbell
    Department of Pathology, University of Washington School of Medicine, Box 357705, Seattle, WA 98195, USA
    Differentiation 75:843-52. 2007
  4. pmc Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3
    Kimberly J Riehle
    Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA
    J Exp Med 205:91-103. 2008
  5. ncbi Defective DNA strand break repair causes chromosomal instability and accelerates liver carcinogenesis in mice
    Narci C Teoh
    Australian National University Medical School, Canberra, Australia
    Hepatology 47:2078-88. 2008
  6. pmc Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2
    Vladimir Lesnikov
    Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1 100, P O Box 19024, Seattle, WA 98109 1024, USA
    Apoptosis 13:1005-12. 2008
  7. pmc Tissue-type plasminogen activator is not necessary for platelet-derived growth factor-c activation
    Kimberly J Riehle
    Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA Department of Surgery, University of Washington School of Medicine, Seattle, WA 98195, USA
    Biochim Biophys Acta 1842:318-25. 2014
  8. pmc Probing the mechanisms of electron capture dissociation mass spectrometry with nitrated peptides
    Andrew W Jones
    School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
    Phys Chem Chem Phys 12:13394-9. 2010
  9. ncbi Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration
    Yoko Obayashi
    Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA
    Biochem Biophys Res Commun 437:146-50. 2013
  10. pmc Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: evidence for stromal induction of hepatocellular carcinoma
    Jocelyn H Wright
    Department of Pathology, University of Washington, Seattle, WA
    Int J Cancer 134:778-88. 2014

Scientific Experts

  • Laia Caja
  • Michael G Katze
  • Jean Campbell
  • N Fausto
  • Laura Beretta
  • Michael A Joyce
  • Kimberly J Riehle
  • Jocelyn H Wright
  • Kathie Anne Walters
  • Matthew M Yeh
  • Maria W Smith
  • Sean Proll
  • Jill C Thompson
  • Catherine A Lazaro
  • Weiliang Tang
  • Sharon L Lederer
  • Yoko Obayashi
  • Joan Fernando
  • Keane K Y Lai
  • Narci Teoh
  • Andrew W Jones
  • Ji Yeon Baek
  • Jamil A Haque
  • Terrance J Kavanagh
  • Ryan S McMahan
  • Claudia Mitchell
  • Jiangning Li
  • Yansong Gu
  • Karen Swisshelm
  • James A Thompson
  • Yock Young Dan
  • Narci C Teoh
  • Vladimir Lesnikov
  • Theo K Bammler
  • Richard P Beyer
  • Bryan Paeper
  • Ronald S Y Cheung
  • David R Gretch
  • Matthew Fitzgibbon
  • Robert L Carithers
  • Chang Yeop Han
  • David L Thomas
  • D Lorne Tyrrell
  • Han K Ho
  • Margaret C Shuhart
  • Y Y Dan
  • Raymond S Yeung
  • Isabel Fabregat
  • Patricia Sancho
  • José L Lledó
  • Conrado M Fernández-Rodríguez
  • Garrett C Booth
  • Sufen Shang
  • Neha Lohia
  • Derek J Masse
  • Shelli M Morris
  • Jing Hou
  • Pawan Pyakurel
  • Masami Shimizu-Albergine
  • William M Grady
  • Angela M Wilson
  • Helen J Cooper
  • Dianne Botta
  • Geoffrey Farrell
  • Thomas J Montine
  • Jefferson Y Chan
  • Deborah L Diamond
  • David P Cox
  • Christopher C Franklin
  • Charles M Rice
  • Xuesong Yu
  • Andrew J Syder
  • Collin C White
  • Roger E Bumgarner
  • Jamil Haque
  • Howard Shulman
  • H Joachim Deeg
  • Emily Spaulding
  • Nicholas Gorden
  • Robert E Fleming
  • Stacey Lehman
  • Lawrence Corey
  • John T Brooling
  • Robert W Coombs
  • W Tony Parks
  • Ming Chang
  • Daniel G Sullivan
  • Melissa M Johnson
  • James P Kushner
  • C Lazaro

Detail Information

Publications36

  1. ncbi Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients
    Maria W Smith
    Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195 8070, USA
    Gastroenterology 130:179-87. 2006
    ..Our goals were to identify molecular processes influencing the liver disease progression and to find potential gene markers of early fibrosis...
  2. pmc Responses of nontransformed human hepatocytes to conditional expression of full-length hepatitis C virus open reading frame
    Weiliang Tang
    Department of Pathology, University of Washington School of Medicine, K078 Health Sciences Building, Box 357705, Seattle, WA 98195 7705, USA
    Am J Pathol 171:1831-46. 2007
    ..Expression of HCV ORF in host cells may contribute to HCV pathogenesis by producing oxidative stress and increasing the expression of genes related to the innate immune response and inflammation...
  3. ncbi Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis
    Jean S Campbell
    Department of Pathology, University of Washington School of Medicine, Box 357705, Seattle, WA 98195, USA
    Differentiation 75:843-52. 2007
    ..Our findings suggest that imatinib may be efficacious in the treatment of hepatocarcinogenesis, particularly when neovascularization is present...
  4. pmc Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3
    Kimberly J Riehle
    Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA
    J Exp Med 205:91-103. 2008
    ..By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiological and neoplastic proliferative processes in the liver and may act as a tumor suppressor...
  5. ncbi Defective DNA strand break repair causes chromosomal instability and accelerates liver carcinogenesis in mice
    Narci C Teoh
    Australian National University Medical School, Canberra, Australia
    Hepatology 47:2078-88. 2008
    ....
  6. pmc Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2
    Vladimir Lesnikov
    Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1 100, P O Box 19024, Seattle, WA 98109 1024, USA
    Apoptosis 13:1005-12. 2008
    ..Both apoptotic Fas responses and cytoprotective effects of Tf were associated with significant shifts in plasma iron levels, which quantitatively differed between male and female mice...
  7. pmc Tissue-type plasminogen activator is not necessary for platelet-derived growth factor-c activation
    Kimberly J Riehle
    Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA Department of Surgery, University of Washington School of Medicine, Seattle, WA 98195, USA
    Biochim Biophys Acta 1842:318-25. 2014
    ..Our ELISA data suggest a difference between in vitro and in vivo activation of this growth factor, and our mouse model confirms that multiple proteases cleave and activate PDGF-C in vivo. ..
  8. pmc Probing the mechanisms of electron capture dissociation mass spectrometry with nitrated peptides
    Andrew W Jones
    School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
    Phys Chem Chem Phys 12:13394-9. 2010
    ....
  9. ncbi Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration
    Yoko Obayashi
    Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA
    Biochem Biophys Res Commun 437:146-50. 2013
    ..These effects may influence the role of mTORC1 on cell growth and proliferation. ..
  10. pmc Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: evidence for stromal induction of hepatocellular carcinoma
    Jocelyn H Wright
    Department of Pathology, University of Washington, Seattle, WA
    Int J Cancer 134:778-88. 2014
    ..PDGF-C transgenic mice provide a unique model for the in vivo study of tumor-stromal interactions in the liver. ..
  11. ncbi Interactions between MYC and transforming growth factor alpha alter the growth and tumorigenicity of liver progenitor cells
    Ronald S Y Cheung
    Department of Pathology, University of Washington, Seattle, WA 98195, USA
    Carcinogenesis 28:2624-31. 2007
    ..We conclude that the tumorigenic growth effects of MYC in TGFalpha-expressing liver progenitor cells are not solely dependent on its apoptotic activity...
  12. pmc Hepatitis C virus replication in transfected and serum-infected cultured human fetal hepatocytes
    Catherine A Lazaro
    Department of Pathology, University of Washington School of Medicine, K078 Health Sciences Building, Box 357705, Seattle, WA 98195 7705, USA
    Am J Pathol 170:478-89. 2007
    ..This culture system may be used to study the responses of nontransformed human hepatocytes to HCV infection, to analyze serum infectivity, and to clone novel HCVs from infected patients...
  13. ncbi Proinflammatory cytokine production in liver regeneration is Myd88-dependent, but independent of Cd14, Tlr2, and Tlr4
    Jean S Campbell
    Department of Pathology, University of Washington, 98195, USA
    J Immunol 176:2522-8. 2006
    ..In contrast, MyD88-dependent pathways appear to be responsible for TNF, IL-6, and their downstream signaling pathways...
  14. ncbi Cytosolic heat shock proteins and heme oxygenase-1 are preferentially induced in response to specific and localized intramitochondrial damage by tetrafluoroethylcysteine
    Han K Ho
    Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle, WA 98195, USA
    Biochem Pharmacol 72:80-90. 2006
    ..The cytoprotective effects of such HSP responses suggest a plausible role in modulating the progression of TFEC-induced cellular injury...
  15. ncbi Liver regeneration
    Nelson Fausto
    Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195 7470, USA
    Hepatology 43:S45-53. 2006
    ..Most of the new knowledge about the molecular and cellular mechanisms of liver regeneration is both conceptually important and directly relevant to clinical problems...
  16. ncbi Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes
    Chang Yeop Han
    Department of Medicine, University of Washington, Seattle, WA 98195 6426, USA
    Arterioscler Thromb Vasc Biol 26:1806-13. 2006
    ..Because cytokines stimulate the hepatic expression of inflammatory markers, we investigated their role in regulating SAA, apoA-I, and PON-1 expression...
  17. pmc Application of functional genomics to the chimeric mouse model of HCV infection: optimization of microarray protocols and genomics analysis
    Kathie Anne Walters
    Department of Microbiology, University of Washington, Seattle, WA, USA
    Virol J 3:37. 2006
    ..To identify genes affected by mouse liver mRNA hybridization, mRNA from identical human liver samples labeled with either Cy3 or Cy5 was compared in the presence and absence of known amounts of mouse liver mRNA labeled in only one dye...
  18. ncbi Identification of a specific gene expression pattern associated with HCV-induced pathogenesis in HCV- and HCV/HIV-infected individuals
    Kathie Anne Walters
    Department of Microbiology, School of Medicine, University of Washington, Box 358070, Seattle, WA 98195 8070, USA
    Virology 350:453-64. 2006
    ..Importantly, the pattern of gene expression observed in EGE (+) patients has similarities to patients who developed fibrosis within 1 year of receiving a liver transplant...
  19. pmc Distinct cellular responses differentiating alcohol- and hepatitis C virus-induced liver cirrhosis
    Sharon L Lederer
    Department of Microbiology, University of Washington, Seattle, WA, USA
    Virol J 3:98. 2006
    ..Global transcriptional profiling using oligonucleotide microarrays was therefore performed on liver biopsies from patients with cirrhosis caused by either chronic alcohol consumption or chronic hepatitis C virus (HCV)...
  20. pmc Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model: role of the innate antiviral immune response
    Kathie Anne Walters
    Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA
    PLoS Pathog 2:e59. 2006
    ..In summary, the nature of the initial interferon response to HCV infection may determine the extent of viral-mediated effects on host gene expression...
  21. pmc Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages
    Y Y Dan
    Department of Pathology, University of Washington, Seattle, WA 98115, USA
    Proc Natl Acad Sci U S A 103:9912-7. 2006
    ..hFLMPCs survive and differentiate into functional hepatocytes in vivo when transplanted into animal models of liver disease. hFLMPCs are a valuable tool for the study of human liver development, liver injury, and hepatic repopulation...
  22. ncbi The tyrphostin AG1478 inhibits proliferation and induces death of liver tumor cells through EGF receptor-dependent and independent mechanisms
    Laia Caja
    Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute IDIBELL, L Hospitalet de Llobregat, Barcelona, Spain
    Biochem Pharmacol 82:1583-92. 2011
    ..Interestingly, AG1478 preferentially acts on liver tumor cells, being untransformed cells much less responsive to its cytotoxic effects. In conclusion, AG1478 could be a potential therapeutic drug to be used in HCC...
  23. pmc Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli
    Joan Fernando
    Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute IDIBELL, L Hospitalet de Llobregat, Barcelona, Spain
    J Cell Physiol 227:1319-25. 2012
    ....
  24. pmc A random mutation capture assay to detect genomic point mutations in mouse tissue
    Jocelyn H Wright
    Department of Pathology, University of Washington and Department of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
    Nucleic Acids Res 39:e73. 2011
    ..This assay provides a versatile alternative to transgenic mouse models for the study of mutagenesis in vivo...
  25. pmc New concepts in liver regeneration
    Kimberly J Riehle
    Department of Surgery, University of Washington, Seattle, USA
    J Gastroenterol Hepatol 26:203-12. 2011
    ..This review traces the path that has been taken over the last few decades in the study of liver regeneration, highlights new concepts in the field, and discusses the challenges that still stand between us and clinical therapy...
  26. ncbi The transforming growth factor-beta (TGF-β) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells
    Laia Caja
    Biological Clues of Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute IDIBELL, Barcelona, Spain
    J Cell Physiol 226:1214-23. 2011
    ....
  27. pmc Extracellular matrix dynamics in hepatocarcinogenesis: a comparative proteomics study of PDGFC transgenic and Pten null mouse models
    Keane K Y Lai
    Molecular Diagnostics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
    PLoS Genet 7:e1002147. 2011
    ....
  28. pmc Inactivation of p38 MAPK during liver regeneration
    Jean S Campbell
    Department of Pathology, University of Washington, School of Medicine, Seattle, WA 98195, USA
    Int J Biochem Cell Biol 43:180-8. 2011
    ..Our results suggest that p38 MAPK inactivation plays a permissible role in DNA replication during liver regeneration and is consistent with a role for p38 MAPK in the maintenance of hepatocyte cell cycle arrest in adult liver...
  29. pmc Attenuated progression of diet-induced steatohepatitis in glutathione-deficient mice
    Jamil A Haque
    Department of Pathology, University of Washington, Seattle, WA 98195 7470, USA
    Lab Invest 90:1704-17. 2010
    ..Thus, metabolic adaptations resulting from severe GSH deficiency seem to protect against the development of steatohepatitis...
  30. ncbi Mouse models of hepatocellular carcinoma
    Nelson Fausto
    Department of Pathology, University of Washington, Seattle, Washington 98195, USA
    Semin Liver Dis 30:87-98. 2010
    ..for the analysis of the development of these tumors, we still lack precise knowledge about pathogenesis of hepatocellular carcinoma (HCC)...
  31. pmc TGF-beta inactivation and TGF-alpha overexpression cooperate in an in vivo mouse model to induce hepatocellular carcinoma that recapitulates molecular features of human liver cancer
    Ji Yeon Baek
    Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
    Int J Cancer 127:1060-71. 2010
    ..Thus, TGF-beta signaling inactivation appears to cooperate with TGF-alpha in vivo to promote the formation of liver cancer that recapitulates molecular features of human HCC...
  32. ncbi Induction of p53 renders ATM-deficient mice refractory to hepatocarcinogenesis
    Narci Teoh
    Australian National University Medical School at The Canberra Hospital, Canberra, Australia
    Gastroenterology 138:1155-65.e1-2. 2010
    ..Ataxia Telangiectasia Mutated (ATM) kinase senses DNA strand breaks and induces p53. Our aims were to establish whether ATM deficiency alters the carcinogenic response of hepatocytes to diethylnitrosamine (DEN)...
  33. pmc Relationships between deficits in tissue mass and transcriptional programs after partial hepatectomy in mice
    Jiangning Li
    Department of Pathology, School of Medicine, University of Washington, Seattle, WA 98195, USA
    Am J Pathol 175:947-57. 2009
    ..We suggest that the changes in gene expression during the first 4 to 6 hours after 2/3 PH may induce chromatin remodeling and facilitate the binding of new sets of transcription factors required for DNA replication...
  34. pmc Distinct Nrf1/2-independent mechanisms mediate As 3+-induced glutamate-cysteine ligase subunit gene expression in murine hepatocytes
    James A Thompson
    Department of Pathology, University of Washington, Seattle, WA 98195, USA
    Free Radic Biol Med 46:1614-25. 2009
    ....
  35. pmc Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes
    Kathie Anne Walters
    Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, United States of America
    PLoS Pathog 5:e1000269. 2009
    ..This in vitro system could be utilized to further define the cellular mechanism of this perturbation...
  36. pmc HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice
    Michael A Joyce
    Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
    PLoS Pathog 5:e1000291. 2009
    ..We conclude that HCV contributes to hepatocyte damage and apoptosis by inducing stress and pro-apoptotic BAX while preventing the induction of anti-apoptotic NF-kappaB and BCL-xL, thus sensitizing hepatocytes to apoptosis...