Hepatitis C Virus and Hepatocellular Carcinoma

Hepatitis C virus (HCV) is strongly linked with the development of hepatocellular carcinoma. However, cancer arises in only a subset of patients, and takes several years to develop. Thus, the role of HCV in the etiology of cancer has remained elusive. I summarize here the clinical and molecular virological connections between HCV and liver cancer.

[1]  M. Honda,et al.  Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. , 2002, Gastroenterology.

[2]  D. Lavanchy,et al.  The global burden of hepatitis C , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[3]  T. Umemura,et al.  Epidemiology of hepatocellular carcinoma in Japan , 2009, Journal of Gastroenterology.

[4]  H. Hotta,et al.  Complex formation of NS5B with NS3 and NS4A proteins of hepatitis C virus. , 1998, Biochemical and biophysical research communications.

[5]  S. Lemon,et al.  Production of infectious genotype 1a hepatitis C virus (Hutchinson strain) in cultured human hepatoma cells , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Samuel,et al.  Liver Cancer-Derived Hepatitis C Virus Core Proteins Shift TGF-Beta Responses from Tumor Suppression to Epithelial-Mesenchymal Transition , 2009, PloS one.

[7]  M. Lai,et al.  Hepatitis C Virus Causes Uncoupling of Mitotic Checkpoint and Chromosomal Polyploidy through the Rb Pathway , 2009, Journal of Virology.

[8]  Ali Azizi,et al.  Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2. , 2005, The Journal of general virology.

[9]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[10]  S. Lemon,et al.  Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer , 2011, Oncogene.

[11]  J. Esteban,et al.  Long interval between HCV infection and development of hepatocellular carcinoma. , 2008, Liver.

[12]  Sangeeta N. Bhatia,et al.  Persistent hepatitis C virus infection in microscale primary human hepatocyte cultures , 2010, Proceedings of the National Academy of Sciences.

[13]  M. Lai,et al.  Hepatitis C virus induces a mutator phenotype: Enhanced mutations of immunoglobulin and protooncogenes , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Toshiaki Maruyama,et al.  Complete Replication of Hepatitis C Virus in Cell Culture , 2005, Science.

[15]  R. Bartenschlager,et al.  Persistent and Transient Replication of Full-Length Hepatitis C Virus Genomes in Cell Culture , 2002, Journal of Virology.

[16]  Williams Jt,et al.  ROYAL COLLEGE OF PHYSICIANS. THE NEW BUILDING. , 1964, Lancet.

[17]  E. Schmidt,et al.  Transgenic expression of hepatitis C virus structural proteins in the mouse , 1997, Hepatology.

[18]  S Chevret,et al.  Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death , 2000, Gut.

[19]  H. Kwun,et al.  p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3. , 2001, The Journal of general virology.

[20]  M. Lai,et al.  Establishment of B-Cell Lymphoma Cell Lines Persistently Infected with Hepatitis C Virus In Vivo and In Vitro: the Apoptotic Effects of Virus Infection , 2003, Journal of Virology.

[21]  U. Gelatti,et al.  A case-control study on GB virus C/hepatitis G virus infection and hepatocellular carcinoma. Brescia HCC Study. , 1997, Hepatology.

[22]  J. Hoofnagle,et al.  THE TREATMENT OF CHRONIC VIRAL HEPATITIS , 1997 .

[23]  A. Siddiqui,et al.  Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-κB , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Y. Nagao,et al.  A cohort study of chronic liver disease in an HCV hyperendemic area of Japan: a prospective analysis for 12 years. , 2004, International journal of molecular medicine.

[25]  H. Yoshizawa.  Hepatocellular Carcinoma Associated with Hepatitis C Virus Infection in Japan: Projection to Other Countries in the Foreseeable Future , 2002, Oncology.

[26]  P. Boffetta,et al.  Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: A case‐control study in Italy , 1997 .

[27]  R. Jhaveri,et al.  Specific polymorphisms in hepatitis C virus genotype 3 core protein associated with intracellular lipid accumulation. , 2008, The Journal of infectious diseases.

[28]  A. Valleron,et al.  Correlation between hepatitis C virus prevalence and hepatocellular carcinoma mortality in Europe , 1999, Journal of viral hepatitis.

[29]  M. Lai,et al.  Hepatitis C Virus Core Protein Binds to the Cytoplasmic Domain of Tumor Necrosis Factor (TNF) Receptor 1 and Enhances TNF-Induced Apoptosis , 1998, Journal of Virology.

[30]  P Boffetta,et al.  A meta‐analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma , 1998, International journal of cancer.

[31]  O. Yokosuka,et al.  HCV-core protein accelerates recovery from the insensitivity of liver cells to Fas-mediated apoptosis induced by an injection of anti-Fas antibody in mice. , 2000, Journal of hepatology.

[32]  Céline Hernandez,et al.  Production of infectious hepatitis C virus in primary cultures of human adult hepatocytes. , 2010, Gastroenterology.

[33]  Christopher T. Jones,et al.  Cell culture–produced hepatitis C virus does not infect peripheral blood mononuclear cells , 2008, Hepatology.

[34]  M. Kieny,et al.  HCV core, NS3, NS5A and NS5B proteins modulate cell proliferation independently from p53 expression in hepatocarcinoma cell lines , 2004, Archives of Virology.

[35]  T. Gojobori,et al.  A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  I. Jacobson,et al.  New and experimental therapies for HCV , 2009, Nature Reviews Gastroenterology &Hepatology.

[37]  R. Ray,et al.  Expression of hepatitis C virus non‐structural 5A protein in the liver of transgenic mice , 2003, FEBS letters.

[38]  J. Bruix,et al.  PREVALENCE OF ANTIBODIES TO HEPATITIS C VIRUS IN SPANISH PATIENTS WITH HEPATOCELLULAR CARCINOMA AND HEPATIC CIRRHOSIS , 1989, The Lancet.

[39]  J. Silver,et al.  Replication of Subgenomic Hepatitis C Virus Rnas in a Hepatoma Cell Line , 1999 .

[40]  F. Chisari,et al.  Hepatitis C virus core and E2 protein expression in transgenic mice , 1997, Hepatology.

[41]  Shinn-Jang Hwang,et al.  HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis , 2002, Oncogene.

[42]  C. Rice,et al.  Efficient initiation of HCV RNA replication in cell culture. , 2000, Science.

[43]  N. Kato,et al.  NS3 protein of Hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner. , 2006, The Journal of general virology.

[44]  M. Yanagi,et al.  Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[45]  E. Schiff,et al.  Viral pathogenesis of hepatocellular carcinoma in the United States , 1993, Hepatology.

[46]  M. Houghton,et al.  Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. , 1989, Science.

[47]  P. Pontisso,et al.  HCV-associated liver cancer without cirrhosis , 1995, The Lancet.

[48]  E. Schmidt,et al.  Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis , 2005, Hepatology.

[49]  Andrew Macdonald,et al.  Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular β-Catenin and Stimulation of β-Catenin-Responsive Transcription , 2005, Journal of Virology.

[50]  F. Chisari,et al.  Lack of detection of negative-strand hepatitis C virus RNA in peripheral blood mononuclear cells and other extrahepatic tissues by the highly strand-specific rTth reverse transcriptase PCR , 1995, Journal of virology.

[51]  K. Meyer,et al.  Hepatitis C virus core protein represses p21WAF1/Cip1/Sid1 promoter activity. , 1998, Gene.

[52]  Y. Shiratori,et al.  Hepatitis C Virus Core Protein Enhances p53 Function through Augmentation of DNA Binding Affinity and Transcriptional Ability* , 2000, The Journal of Biological Chemistry.

[53]  Charles M. Rice,et al.  Highly Permissive Cell Lines for Subgenomic and Genomic Hepatitis C Virus RNA Replication , 2002, Journal of Virology.

[54]  R. Bartenschlager,et al.  Production of infectious hepatitis C virus in tissue culture from a cloned viral genome , 2005, Nature Medicine.

[55]  N. Kato,et al.  The DNA Damage Sensors Ataxia-Telangiectasia Mutated Kinase and Checkpoint Kinase 2 Are Required for Hepatitis C Virus RNA Replication , 2008, Journal of Virology.

[56]  N. Tanaka,et al.  Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis , 1996, Journal of Gastroenterology.

[57]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[58]  R. Bartenschlager,et al.  The lipid droplet is an important organelle for hepatitis C virus production , 2007, Nature Cell Biology.

[59]  T. Liang,et al.  Pathogenesis of hepatitis C-associated hepatocellular carcinoma. , 2004, Gastroenterology.

[60]  K Koike,et al.  Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. , 1997, The Journal of general virology.

[61]  Soo-Ho Choi,et al.  Nonstructural 5A protein activates beta-catenin signaling cascades: implication of hepatitis C virus-induced liver pathogenesis. , 2009, Journal of hepatology.

[62]  N. Seki,et al.  Antiapoptotic regulation by hepatitis C virus core protein through up-regulation of inhibitor of caspase-activated DNase. , 2003, Virology.

[63]  J. Kaldor,et al.  Estimating progression to cirrhosis in chronic hepatitis C virus infection , 2001, Hepatology.

[64]  Francis Simon,et al.  Hepatitis C virus NS5A protein binds TBP and p53, inhibiting their DNA binding and p53 interactions with TBP and ERCC3. , 2002, Biochimica et biophysica acta.

[65]  Lin Deng,et al.  Single-point mutations of hepatitis C virus NS3 that impair p53 interaction and anti-apoptotic activity of NS3. , 2006, Biochemical and biophysical research communications.

[66]  Tuya Shilagard,et al.  Visualizing hepatitis C virus infections in human liver by two-photon microscopy. , 2009, Gastroenterology.

[67]  S. Kitazawa,et al.  Non-structural protein 4A of Hepatitis C virus accumulates on mitochondria and renders the cells prone to undergoing mitochondria-mediated apoptosis. , 2006, The Journal of general virology.

[68]  Yoshiharu Matsuura,et al.  The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice , 1998, Nature Medicine.

[69]  Yuqiong Liang,et al.  Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[70]  O. Chazouilleres,et al.  Determinants of outcome of compensated hepatitis C virus‐related cirrhosis , 1998, Hepatology.

[71]  Yuqiong Liang,et al.  Hepatitis C Virus Induces E6AP-Dependent Degradation of the Retinoblastoma Protein , 2007, PLoS pathogens.

[72]  S. Weinman,et al.  Hepatitis C Virus Core Protein Inhibits Mitochondrial Electron Transport and Increases Reactive Oxygen Species (ROS) Production* , 2005, Journal of Biological Chemistry.

[73]  C. Englert,et al.  Characterization of cell lines allowing tightly regulated expression of hepatitis C virus core protein. , 1996, Virology.

[74]  H. El‐Serag.  Hepatocellular carcinoma and hepatitis C in the United States , 2002, Hepatology.

[75]  Soo-Ho Choi,et al.  Non‐structural 5A protein of hepatitis C virus induces a range of liver pathology in transgenic mice , 2009, The Journal of pathology.

[76]  V. Pazienza,et al.  An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. , 2005, Journal of hepatology.

[77]  M L Yarmush,et al.  Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[78]  S. Gordon,et al.  Clinical outcome of hepatitis C as a function of mode of transmission , 1998, Hepatology.

[79]  C. Rice,et al.  Flying under the radar: the immunobiology of hepatitis C. , 2007, Annual review of immunology.

[80]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[81]  William M. Lee,et al.  Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. , 2009, Gastroenterology.

[82]  S. Lemon,et al.  Impaired Replication of Hepatitis C Virus Containing Mutations in a Conserved NS5B Retinoblastoma Protein-Binding Motif , 2009, Journal of Virology.

[83]  C. Rice,et al.  Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. , 1997, Science.

[84]  R. Koff,et al.  Hepatitis C-related hepatocellular carcinoma. Prevalence and significance. , 1993, Archives of internal medicine.

[85]  R. Bartenschlager,et al.  Production of Infectious Genotype 1b Virus Particles in Cell Culture and Impairment by Replication Enhancing Mutations , 2009, PLoS pathogens.

[86]  M. Honda,et al.  Hepatitis C virus core protein induces apoptosis and impairs cell‐cycle regulation in stably transformed chinese hamster ovary cells , 2000, Hepatology.

[87]  Charles M. Rice,et al.  Flaviviridae :T he Viruses and Their Replication , 2007 .

[88]  S. Lemon,et al.  Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells , 2002, Hepatology.

[89]  S. Seki,et al.  Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis , 1995, The Lancet.

[90]  M. Tong,et al.  Clinical outcomes after transfusion-associated hepatitis C. , 1995, The New England journal of medicine.

[91]  Zhijian J. Chen,et al.  Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[92]  P. Marcellin,et al.  Treatment of hepatitis C virus–related cirrhosis: A randomized, controlled trial of interferon alfa‐2b versus no treatment , 1999, Hepatology.

[93]  A. Shavinskaya,et al.  Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[94]  M. Katze,et al.  Antiapoptotic and Oncogenic Potentials of Hepatitis C Virus Are Linked to Interferon Resistance by Viral Repression of the PKR Protein Kinase , 1999, Journal of Virology.

[95]  Stanley M Lemon,et al.  Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[96]  C. Bréchot,et al.  Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-β pathway , 2005, Oncogene.

[97]  S. Porru,et al.  Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. , 2002, American journal of epidemiology.

[98]  P. Hsu,et al.  Hepatitis C Virus Core Protein Modulates TRAIL-Mediated Apoptosis by Enhancing Bid Cleavage and Activation of Mitochondria Apoptosis Signaling Pathway1 , 2005, The Journal of Immunology.

[99]  M. Mondelli,et al.  Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: A prospective study , 1997, Hepatology.

[100]  M. Chen,et al.  Activation of p53 tumor suppressor by hepatitis C virus core protein. , 1999, Virology.

[101]  Ralf Bartenschlager,et al.  Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus , 2005, Nature.

[102]  Yan-Hwa Wu Lee,et al.  Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation , 2004, Oncogene.

[103]  C-F Kao,et al.  Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein , 2004, Oncogene.

[104]  A. Pezzoli,et al.  Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. , 1996, Journal of hepatology.

[105]  Frank Scholle,et al.  Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. , 2002, Gastroenterology.

[106]  M. Lai,et al.  Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation. , 2008, Virology.

[107]  R. Ray,et al.  Hepatitis C Virus NS5A Physically Associates with p53 and Regulates p21/waf1 Gene Expression in a p53-Dependent Manner , 2001, Journal of Virology.

[108]  Kenneth Koury,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[109]  J. Mankouri,et al.  Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion. , 2010, The Journal of general virology.

[110]  P. Thompson,et al.  The NS3 protein of hepatitis C virus induces caspase-8-mediated apoptosis independent of its protease or helicase activities. , 2004, Virology.

[111]  Andrew Macdonald,et al.  The Hepatitis C Virus NS5A Protein Activates a Phosphoinositide 3-Kinase-dependent Survival Signaling Cascade* , 2004, Journal of Biological Chemistry.

[112]  William M. Lee,et al.  Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. , 2008, The New England journal of medicine.

[113]  M. Houghton,et al.  PREVALENCE OF ANTIBODIES TO HEPATITIS C VIRUS IN ITALIAN PATIENTS WITH HEPATOCELLULAR CARCINOMA , 1989, The Lancet.

[114]  K. Meyer,et al.  Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. , 1999, The Journal of general virology.

[115]  D. Burton,et al.  Robust hepatitis C virus infection in vitro. , 2005, Proceedings of the National Academy of Sciences of the United States of America.