Viral hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Despite recent advances in the diagnosis and treatment of HCC, its prognosis remains dismal. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major risk factors for HCC. Although both are hepatotropic viral infections, there are important differences between the oncogenic mechanisms of these two viruses. In addition to the oncogenic potential of its viral proteins, HBV, as a DNA virus, can integrate into host DNA and directly transform hepatocytes. In contrast, HCV, an RNA virus, is unable to integrate into the host genome, and viral protein expression has a more critical function in hepatocarcinogenesis. Both HBV and HCV proteins have been implicated in disrupting cellular signal transduction pathways that lead to unchecked cell growth. Most HCC develops in the cirrhotic liver, but the linkage between cirrhosis and HCC is likely multifactorial. In this review, we summarize current knowledge regarding the pathogenetic mechanisms of viral HCC.

[1]  A. Lonardo,et al.  Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. , 2004, Gastroenterology.

[2]  F. Su,et al.  Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins , 1996, Journal of virology.

[3]  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.

[4]  A. Hevener,et al.  IKK-beta links inflammation to obesity-induced insulin resistance. , 2005, Nature medicine.

[5]  K. Flanders,et al.  Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis. , 1996, The Journal of clinical investigation.

[6]  Charles M. Rice,et al.  Unravelling hepatitis C virus replication from genome to function , 2005, Nature.

[7]  K. Koike Steatosis, liver injury, and hepatocarcinogenesis in hepatitis C viral infection , 2009, Journal of Gastroenterology.

[8]  J. Jacob,et al.  Hepatocellular carcinoma in the woodchuck model of hepatitis B virus infection. , 2004, Gastroenterology.

[9]  D. Häussinger,et al.  CD133+ hepatic stellate cells are progenitor cells. , 2007, Biochemical and biophysical research communications.

[10]  S. Schaefer Hepatitis B virus: significance of genotypes , 2005, Journal of viral hepatitis.

[11]  X. Gu,et al.  An intronic polymorphism in the corticotropin-releasing hormone receptor 2 gene increases susceptibility to HBV-related hepatocellular carcinoma in Chinese population , 2009, Human Genetics.

[12]  Jacques Ferlay,et al.  Estimates of the worldwide incidence of 25 major cancers in 1990 , 1999, International journal of cancer.

[13]  A. Franchitto,et al.  New insights into liver stem cells. , 2009, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[14]  A. Siddiqui,et al.  Hepatitis C Virus Subgenomic Replicons Induce Endoplasmic Reticulum Stress Activating an Intracellular Signaling Pathway , 2002, Journal of Virology.

[15]  I. Su,et al.  Enhanced expression of vascular endothelial growth factor‐A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis , 2009, Hepatology.

[16]  Chien-Jen Chen,et al.  Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma. , 2003, Journal of the National Cancer Institute.

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

[18]  R. Bartenschlager,et al.  Replication of hepatitis C virus. , 2000, The Journal of general virology.

[19]  Chien-Jen Chen,et al.  Hepatitis B virus DNA levels and outcomes in chronic hepatitis B , 2009, Hepatology.

[20]  H. Kwun,et al.  Dual effects of hepatitis C virus Core protein on the transcription of cyclin‐dependent kinase inhibitor p21 gene , 2003, Journal of viral hepatitis.

[21]  A. Kurimasa,et al.  Suppressive effects of retinoids on iron-induced oxidative stress in the liver. , 2009, Gastroenterology.

[22]  T. Furuya,et al.  Chromosomal imbalances detected by comparative genomic hybridization are associated with outcome of patients with hepatocellular carcinoma , 2002, Cancer.

[23]  Derek Y. Chiang,et al.  Genomics and signaling pathways in hepatocellular carcinoma. , 2007, Seminars in liver disease.

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

[25]  F. Chisari Unscrambling hepatitis C virus–host interactions , 2005, Nature.

[26]  K. Koike,et al.  Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator‐activated receptor α in transgenic mice: Implications for HCV‐associated hepatocarcinogenesis , 2008, International journal of cancer.

[27]  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.

[28]  R. Palmiter,et al.  Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice , 1989, Cell.

[29]  Chien-Jen Chen,et al.  Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. , 2005, Journal of the National Cancer Institute.

[30]  Mohamed Hassan,et al.  Hepatitis C virus core protein triggers hepatic angiogenesis by a mechanism including multiple pathways , 2009, Hepatology.

[31]  Ding‐Shinn Chen,et al.  Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. , 2000, Gastroenterology.

[32]  I. Su,et al.  Hepatitis B virus pre‐S mutants, endoplasmic reticulum stress and hepatocarcinogenesis , 2006, Cancer science.

[33]  R. Chung,et al.  Treatment failure in hepatitis C: mechanisms of non-response. , 2009, Journal of hepatology.

[34]  Y. Jeng,et al.  Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma , 2007, International journal of cancer.

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

[36]  S. Thorgeirsson,et al.  Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China , 2002, Hepatology.

[37]  Ding‐Shinn Chen,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level , 2007 .

[38]  T. Niki,et al.  Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells , 1999, Hepatology.

[39]  S. Friedman,et al.  Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. , 1989, The Journal of clinical investigation.

[40]  V. Mazzaferro,et al.  Genome‐wide molecular profiles of HCV‐induced dysplasia and hepatocellular carcinoma , 2007, Hepatology.

[41]  M. Czaja,et al.  Cell signaling in oxidative stress-induced liver injury. , 2007, Seminars in liver disease.

[42]  M. Rattray,et al.  A tumor progression model for hepatocellular carcinoma: bioinformatic analysis of genomic data. , 2006, Gastroenterology.

[43]  K. Matsuzaki Modulation of TGF-beta signaling during progression of chronic liver diseases. , 2009, Frontiers in bioscience.

[44]  Y. Kwong,et al.  Pin1 interacts with a specific serine-proline motif of hepatitis B virus X-protein to enhance hepatocarcinogenesis. , 2007, Gastroenterology.

[45]  K. Meyer,et al.  Transcriptional Repression of p53 Promoter by Hepatitis C Virus Core Protein* , 1997, The Journal of Biological Chemistry.

[46]  M. Kew Hepatic iron overload and hepatocellular carcinoma. , 2009, Cancer letters.

[47]  J. Bruix,et al.  Molecular targeted therapies in hepatocellular carcinoma , 2008, Hepatology.

[48]  I. Gareen,et al.  National Institutes of Health consensus development conference statement: Management of hepatitis B , 2009, Hepatology.

[49]  Christine Pourcel,et al.  Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma , 1980, Nature.

[50]  S. Lemon,et al.  Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. , 2006, Gastroenterology.

[51]  N. Iizuka,et al.  Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. , 2002, Cancer research.

[52]  K. Horimoto,et al.  Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma , 2009, Hepatology.

[53]  O. Hino,et al.  Hepatitis C Virus Core Protein Interacts with 14-3-3 Protein and Activates the Kinase Raf-1 , 2000, Journal of Virology.

[54]  M. Gambardella,et al.  Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity , 2001, Hepatology.

[55]  P. Hofschneider,et al.  Integrated hepatitis B virus X and 3' truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. , 1994, Oncogene.

[56]  H. Sumimoto,et al.  Regulation of novel superoxide-producing NAD(P)H oxidases. , 2006, Antioxidants & redox signaling.

[57]  A. Clouston,et al.  Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis , 1999, Hepatology.

[58]  R. Bartenschlager,et al.  Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion , 2005, Oncogene.

[59]  R. Ray,et al.  Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling , 2008, Journal of Virology.

[60]  C. Harris,et al.  Hepatitis B virus X protein inhibits nucleotide excision repair , 1999, International journal of cancer.

[61]  V. Mazzaferro,et al.  A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. , 2006, Gastroenterology.

[62]  H. Herbst,et al.  Expression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesis. , 1996, The American journal of pathology.

[63]  Ding‐Shinn Chen,et al.  Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. , 2003, Gastroenterology.

[64]  S. Murakami,et al.  Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. , 1999, Journal of hepatology.

[65]  J. Chang,et al.  HCV core protein modulates Rb pathway through pRb down-regulation and E2F-1 up-regulation. , 2001, Biochimica et biophysica acta.

[66]  G. Yamada,et al.  Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C. , 2004, Antioxidants & redox signaling.

[67]  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.

[68]  H. El‐Serag,et al.  Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. , 2007, Gastroenterology.

[69]  G. Fontemaggi,et al.  Physical and functional interaction between HCV core protein and the different p73 isoforms , 2003, Oncogene.

[70]  T. Takegami,et al.  Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells , 1995, Journal of virology.

[71]  S. Friedman,et al.  Experimental models of hepatocellular carcinoma. , 2008, Journal of hepatology.

[72]  P. Arora,et al.  Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. , 2008, Cancer letters.

[73]  In-Kyung Kim,et al.  Activation of calcium signaling by hepatitis B virus-X protein in liver cells , 2003, Experimental & Molecular Medicine.

[74]  W. Gerlich,et al.  Hypermodification and immune escape of an internally deleted middle-envelope (M) protein of frequent and predominant hepatitis B virus variants. , 2002, Virology.

[75]  Mohamed Hassan,et al.  Activation of c-Jun NH2-terminal kinase (JNK) signaling pathway is essential for the stimulation of hepatitis C virus (HCV) non-structural protein 3 (NS3)-mediated cell growth. , 2005, Virology.

[76]  Hiroyoshi Taniguchi,et al.  Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. , 2004, Journal of medical virology.

[77]  C. J. Chen,et al.  Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. , 1999, American journal of epidemiology.

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

[79]  H. Ren,et al.  Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors. , 2005, Experimental cell research.

[80]  S. Weinman,et al.  Causes and consequences of mitochondrial reactive oxygen species generation in hepatitis C , 2006, Journal of gastroenterology and hepatology.

[81]  H. M. Reis,et al.  Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease. , 2009, Cancer letters.

[82]  T. Kodama,et al.  Subcellular localization of HCV core protein regulates its ability for p53 activation and p21 suppression. , 2002, Biochemical and biophysical research communications.

[83]  K. Eguchi,et al.  Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection , 2003, Cancer.

[84]  J. Woodgett,et al.  X Protein of Hepatitis B Virus Inhibits Fas-mediated Apoptosis and Is Associated with Up-regulation of the SAPK/JNK Pathway* , 2001, The Journal of Biological Chemistry.

[85]  Yoon-Koo Kang,et al.  Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. , 2009, The Lancet. Oncology.

[86]  L. Roberts,et al.  The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. , 2005, Journal of hepatology.

[87]  S. Thorgeirsson,et al.  Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[88]  S. Nuti,et al.  Inhibition of Natural Killer Cells through Engagement of CD81 by the Major Hepatitis C Virus Envelope Protein , 2002, The Journal of experimental medicine.

[89]  E. Yu,et al.  Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. , 2007, Gastroenterology.

[90]  L. Wang,et al.  Calcium signaling by HBx protein in hepatitis B virus DNA replication. , 2001, Science.

[91]  D. Häussinger,et al.  Hepatitis C virus core protein induces cell proliferation and activates ERK, JNK, and p38 MAP kinases together with the MAP kinase phosphatase MKP-1 in a HepG2 Tet-Off cell line. , 2002, Virology.

[92]  C. Boland,et al.  Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma , 2008, Hepatology.

[93]  J. Pekow,et al.  Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C‐related cirrhosis , 2007, Cancer.

[94]  Soo-Ho Choi,et al.  Modulation of the Transforming Growth Factor-β Signal Transduction Pathway by Hepatitis C Virus Nonstructural 5A Protein* , 2006, Journal of Biological Chemistry.

[95]  S. Kaneko,et al.  Molecular functions and biological roles of hepatitis B virus x protein , 2006, Cancer science.

[96]  Ding‐Shinn Chen,et al.  Therapeutic implications of hepatitis B virus genotypes , 2005, Liver international : official journal of the International Association for the Study of the Liver.

[97]  Christopher J. Parsons,et al.  Molecular mechanisms of hepatic fibrogenesis , 2007, Journal of gastroenterology and hepatology.

[98]  M. Lai,et al.  Hepatitis C Virus Triggers Mitochondrial Permeability Transition with Production of Reactive Oxygen Species, Leading to DNA Damage and STAT3 Activation , 2006, Journal of Virology.

[99]  K. Koike,et al.  High‐level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice , 1994, Hepatology.

[100]  A. Kurimasa,et al.  Retinoic acid receptor α dominant negative form causes steatohepatitis and liver tumors in transgenic mice , 2004, Hepatology.

[101]  J. Wands,et al.  Hepatitis C virus core protein stimulates hepatocyte growth: Correlation with upregulation of wnt‐1 expression , 2005, Hepatology.

[102]  Y. Shin,et al.  Liver X receptor mediates hepatitis B virus X protein–induced lipogenesis in hepatitis B virus–associated hepatocellular carcinoma , 2009, Hepatology.

[103]  Kook Hwan Kim,et al.  Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRalpha. , 2008, The Biochemical journal.

[104]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. , 2005, Nature medicine.

[105]  I. Ng,et al.  Molecular Pathogenesis of Hepatocellular Carcinoma , 2016, Liver Cancer.

[106]  T. Liang,et al.  Mouse models for the study of HCV infection and virus–host interactions , 2008, Journal of Hepatology.

[107]  M. Honda,et al.  Different signaling pathways in the livers of patients with chronic hepatitis B or chronic hepatitis C , 2006, Hepatology.

[108]  B. Bacon,et al.  Effects of iron loading on pathogenicity in hepatitis C virus–infected chimpanzees , 1999, Hepatology.

[109]  N. Savaraj,et al.  Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers , 2006, Molecular carcinogenesis.

[110]  J. Sicklick,et al.  Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. , 2008, Journal of hepatology.

[111]  J. Wands,et al.  Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma , 2006, Hepatology.

[112]  R. Schneider,et al.  Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[113]  Chien-Jen Chen,et al.  Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. , 2006, Gastroenterology.

[114]  J. Vinel,et al.  Nonstructural 3 protein of hepatitis C virus triggers an oxidative burst in human monocytes via activation of NADPH oxidase. , 2001, The Journal of biological chemistry.

[115]  D. Shafritz,et al.  Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens. , 1981, The New England journal of medicine.

[116]  K. Koike,et al.  Multiple integration site of hepatitis B virus DNA in hepatocellular carcinoma and chronic active hepatitis tissues from children , 1987, Journal of virology.

[117]  Ze-Guang Han,et al.  Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. , 2009, Journal of hepatology.

[118]  M. Manns,et al.  Telomeres and telomerase: A dual role in hepatocarcinogenesis , 2004, Hepatology.

[119]  N. Holbrook,et al.  Cellular response to oxidative stress: Signaling for suicide and survival * , 2002, Journal of cellular physiology.

[120]  M. Lai,et al.  Hepatitis C Virus Core Protein Interacts with Heterogeneous Nuclear Ribonucleoprotein K* , 1998, The Journal of Biological Chemistry.

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

[122]  P. Schirmacher,et al.  Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade – results of an explorative CGH meta-analysis , 2005, British Journal of Cancer.

[123]  Jacques Ferlay,et al.  Estimating the world cancer burden: Globocan 2000 , 2001, International journal of cancer.

[124]  C. Sabin,et al.  HBV A1762T, G1764A Mutations Are a Valuable Biomarker for Identifying a Subset of Male HBsAg Carriers at Extremely High Risk of Hepatocellular Carcinoma: A Prospective Study , 2008, The American Journal of Gastroenterology.

[125]  T. Braciale,et al.  Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. , 2000, The Journal of clinical investigation.

[126]  M. Feitelson,et al.  Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. , 2007, Cancer letters.

[127]  A. Lok,et al.  Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. , 2002, Gastroenterology.

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

[129]  Y. Liaw,et al.  Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma , 2007, Gut.

[130]  B. Bell,et al.  The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. , 2006, Journal of hepatology.

[131]  Yong Poovorawan,et al.  Interleukin-1beta gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection. , 2006, World journal of gastroenterology.

[132]  K. Okita,et al.  Genetic aberrations detected by comparative genomic hybridization in hepatocellular carcinomas: Their relationship to clinicopathological features , 1999, Hepatology.

[133]  J. Dubuisson,et al.  Positive effect of the hepatitis C virus nonstructural 5A protein on viral multiplication , 2004, Archives of Virology.

[134]  K. Koike,et al.  Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)‐β signaling from tumor suppression to oncogenesis in early chronic hepatitis B , 2009, Hepatology.

[135]  S. Paggi,et al.  Sorafenib in Advanced Hepatocellular Carcinoma , 2008 .

[136]  John D. Groopman,et al.  Prospective Evaluation of Hepatitis B 1762T/1764A Mutations on Hepatocellular Carcinoma Development in Shanghai, China , 2009, Cancer Epidemiology Biomarkers & Prevention.

[137]  T. Tsunoda,et al.  Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. , 2001, Cancer research.

[138]  R. Fisher,et al.  Genes Involved in Viral Carcinogenesis and Tumor Initiation in Hepatitis C Virus-Induced Hepatocellular Carcinoma , 2009, Molecular medicine.

[139]  K. Jeang,et al.  Hepatitis C virus core protein‐induced loss of LZIP function correlates with cellular transformation , 2000, The EMBO journal.

[140]  S. Sarin,et al.  Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent , 2002, Journal of gastroenterology and hepatology.

[141]  Alexander Bürkle,et al.  Increase in de novo HBV DNA integrations in response to oxidative DNA damage or inhibition of poly(ADP‐ribosyl)ation , 2002, Hepatology.

[142]  K. Koike,et al.  Interaction of hepatitis C virus core protein with retinoid X receptor α modulates its transcriptional activity , 2002, Hepatology.

[143]  M. Ostrowski,et al.  Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. , 2008, Gastroenterology.

[144]  Chien-Jen Chen,et al.  Long-term tracking of hepatitis B viral load and the relationship with risk for hepatocellular carcinoma in men. , 2008, Carcinogenesis.

[145]  T. Roskams,et al.  HBx or HCV core gene expression in HepG2 human liver cells results in a survival benefit against oxidative stress with possible implications for HCC development. , 2007, Chemico-biological interactions.

[146]  S. Hirohashi,et al.  Genetic profile of hepatocellular carcinoma revealed by array-based comparative genomic hybridization: identification of genetic indicators to predict patient outcome. , 2005, Journal of hepatology.

[147]  G. Jay,et al.  HBx gene of hepatitis B virus induces liver cancer in transgenic mice , 1991, Nature.

[148]  M. Anzola Hepatocellular carcinoma: role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis , 2004, Journal of viral hepatitis.

[149]  T. Okanoue,et al.  Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas , 2005, Gut.

[150]  S. Kojima,et al.  Retinoids in liver fibrosis and cancer. , 2002, Frontiers in bioscience : a journal and virtual library.

[151]  Guan-Tarn Huang,et al.  Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. , 2006, JAMA.

[152]  S. Satoh,et al.  Comprehensive allelotype study of hepatocellular carcinoma: Potential differences in pathways to hepatocellular carcinoma between hepatitis B virus–positive and –negative tumors , 2000, Hepatology.

[153]  Peter Schirmacher,et al.  MicroRNA gene expression profile of hepatitis C virus–associated hepatocellular carcinoma , 2007, Hepatology.

[154]  C. W. Kim,et al.  HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-β1 , 2005, Experimental & Molecular Medicine.

[155]  M. Mizokami,et al.  Hepatitis B Virus Genotypes and Hepatocellular Carcinoma in Japan , 2003, Intervirology.

[156]  H. Fukuda,et al.  Metal Contents in the Liver of Patients with Chronic Liver Disease Caused by Hepatitis C Virus , 2003, Oncology.

[157]  P. Hofschneider,et al.  Hepatoma-derived integrated HBV DNA causes multi-stage transformation in vitro. , 1996, Oncogene.

[158]  K. Koike Pathogenesis of HCV‐associated HCC: Dual‐pass carcinogenesis through activation of oxidative stress and intracellular signaling , 2007, Hepatology research : the official journal of the Japan Society of Hepatology.

[159]  M. Sheu,et al.  Hepatitis C virus NS5A as a potential viral Bcl‐2 homologue interacts with Bax and inhibits apoptosis in hepatocellular carcinoma , 2003, International journal of cancer.

[160]  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.

[161]  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.

[162]  C. J. Chen,et al.  Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men. , 2001, Journal of the National Cancer Institute.

[163]  Giuseppe Vasapollo,et al.  Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma , 2008, Molecular Cancer Therapeutics.

[164]  Victor V. Keasler,et al.  Enhancement of Hepatitis B Virus Replication by the Regulatory X Protein In Vitro and In Vivo , 2006, Journal of Virology.

[165]  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.

[166]  Bao-zong Li,et al.  Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response. , 2007, Virus research.

[167]  O. Hino,et al.  Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha. , 2000, Hepatology.

[168]  A. Fukushima,et al.  Clinical Significance of Evaluation of Serum Zinc Concentrations in C-Viral Chronic Liver Disease , 2006, Digestive Diseases and Sciences.

[169]  T. Wakita,et al.  Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response , 2008, Hepatology.

[170]  G. Gwak,et al.  Wnt signaling enhances the activation and survival of human hepatic stellate cells , 2007, FEBS Letters.

[171]  M. Yeh,et al.  Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[172]  A. Kidd,et al.  Genetic variability in hepatitis B viruses. , 2002, The Journal of general virology.

[173]  M. Strubin,et al.  Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1 , 2008, Hepatology.

[174]  Ji Hyun Jung,et al.  Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. , 2003, Human molecular genetics.

[175]  J. Barrett,et al.  cis-Activation of the human telomerase gene (hTERT) by the hepatitis B virus genome. , 2001, Journal of the National Cancer Institute.

[176]  Chien-Jen Chen,et al.  Associations Between Hepatitis B Virus Genotype and Mutants and the Risk of Hepatocellular Carcinoma , 2008, Journal of the National Cancer Institute.

[177]  Jun Qin,et al.  Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. , 2005, Molecular cell.

[178]  Mohamed Hassan,et al.  Induction of high-molecular-weight (HMW) tumor necrosis factor(TNF) alpha by hepatitis C virus (HCV) non-structural protein 3 (NS3) in liver cells is AP-1 and NF-kappaB-dependent activation. , 2007, Cellular signalling.

[179]  Seok-Geun Lee,et al.  Transcriptional repression of the human p53 gene by hepatitis B viral X protein , 2000, Oncogene.

[180]  Y. Berdichevsky,et al.  Cell transformation induced by hepatitis C virus NS3 serine protease , 2001, Journal of viral hepatitis.

[181]  L. Boscá,et al.  Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins , 2004, Gut.

[182]  G. Fattovich Natural History and Prognosis of Hepatitis B , 2003, Seminars in liver disease.

[183]  J. Wands,et al.  Overexpression of insulin receptor substrate‐1 and hepatitis Bx genes causes premalignant alterations in the liver , 2009, Hepatology.

[184]  J. Sheu,et al.  Chromosomal abnormality in hepatocellular carcinoma by comparative genomic hybridisation in Taiwan. , 1999, European journal of cancer.

[185]  K. Koike,et al.  Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. , 2001, Cancer research.

[186]  P. Hofschneider,et al.  The PreS2 activator MHBst of hepatitis B virus activates c‐raf‐1/Erk2 signaling in transgenic mice , 2002, The EMBO journal.

[187]  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.

[188]  Lifen Gao,et al.  In vitro transfection of the hepatitis B virus PreS2 gene into the human hepatocarcinoma cell line HepG2 induces upregulation of human telomerase reverse transcriptase. , 2007, Biochemical and biophysical research communications.

[189]  Jian-Min Yuan,et al.  Prediagnostic level of serum retinol in relation to reduced risk of hepatocellular carcinoma. , 2006, Journal of the National Cancer Institute.

[190]  M. Baptista,et al.  High prevalence of 1762T 1764A mutations in the basic core promoter of hepatitis B virus isolated from black africans with hepatocellular carcinoma compared with asymptomatic carriers , 1999, Hepatology.

[191]  S. Locarnini,et al.  The hepatitis B virus and common mutants. , 2003, Seminars in liver disease.

[192]  H. Nakamura,et al.  Serum thioredoxin levels as an indicator of oxidative stress in patients with hepatitis C virus infection. , 2000, Journal of hepatology.

[193]  J. Ou,et al.  Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[194]  I. B. Borel Rinkes,et al.  Mouse models in liver cancer research: a review of current literature. , 2008, World journal of gastroenterology.

[195]  Mu-jun Zhao,et al.  Hepatitis B virus X protein sensitizes cells to starvation‐induced autophagy via up‐regulation of beclin 1 expression , 2009, Hepatology.

[196]  J. Schaack,et al.  Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: role of JNK, p38 MAPK and AP-1. , 2004, The Biochemical journal.

[197]  Hung-Yi Wu,et al.  Hepatitis C Virus NS5A Protein Down-regulates the Expression of Spindle Gene Aspm through PKR-p38 Signaling Pathway* , 2008, Journal of Biological Chemistry.

[198]  T. Roskams Different types of liver progenitor cells and their niches. , 2006, Journal of hepatology.

[199]  V. Wong,et al.  Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma , 2004, Gut.

[200]  Chi-Hung Lin,et al.  Hepatitis C Virus Core Protein Interacts with Cellular Putative RNA Helicase , 1999, Journal of Virology.

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

[202]  Rajagopal N. Aravalli,et al.  Molecular mechanisms of hepatocellular carcinoma , 2008, Hepatology.

[203]  E. Lara-Pezzi,et al.  The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells , 2008, Hepatology.

[204]  Sheng-Nan Lu,et al.  Aflatoxin exposure and hepatitis C virus in advanced liver disease in a hepatitis C virus endemic area in Taiwan. , 2007, The American journal of tropical medicine and hygiene.

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

[206]  Katsunori Yoshida,et al.  Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma , 2007, Hepatology.

[207]  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.

[208]  C. Bréchot,et al.  Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis , 2006, Oncogene.

[209]  M. Katze,et al.  Subversion of Cell Signaling Pathways by Hepatitis C Virus Nonstructural 5A Protein via Interaction with Grb2 and P85 Phosphatidylinositol 3-Kinase , 2002, Journal of Virology.

[210]  A. Siddiqui,et al.  Hepatitis B Virus X Protein Stimulates the Mitochondrial Translocation of Raf-1 via Oxidative Stress , 2007, Journal of Virology.

[211]  E. Peles,et al.  Protein tyrosine kinase PYK2 involved in Ca2+-induced regulation of ion channel and MAP kinase functions , 1995, Nature.

[212]  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.

[213]  J. Bartolomé,et al.  Hepatitis C virus core protein transactivates the inducible nitric oxide synthase promoter via NF-kappaB activation. , 2003, Antiviral research.

[214]  V. Desmet,et al.  Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. , 2001, Hepatology.

[215]  P. Paterlini-Bréchot,et al.  Cytobiological consequences of calcium-signaling alterations induced by human viral proteins. , 2006, Biochimica et biophysica acta.

[216]  P. Tangkijvanich,et al.  Association of HLA‐DRB1*13 and TNF‐α gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population , 2007, Journal of viral hepatitis.

[217]  B. McMahon,et al.  Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. , 2007, The Journal of infectious diseases.

[218]  V. Wong,et al.  High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[219]  Y. Takei,et al.  Iron, hepatitis C virus, and hepatocellular carcinoma: iron reduction preaches the gospel for chronic hepatitis C , 2007, Journal of Gastroenterology.

[220]  S. Caldwell,et al.  The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology , 2009, Journal of Gastroenterology.

[221]  S. Douc-Rasy,et al.  TP53 family members and human cancers , 2003, Human mutation.