Download PDF
Semin Liver Dis 2011; 31(4): 347-355
DOI: 10.1055/s-0031-1297924
© Thieme Medical Publishers

HCV and HCC: Clinical Update and a Review of HCC-Associated Viral Mutations in the Core Gene

Jawad Ahmad1 , Francis J. Eng1 , Andrea D. Branch1
  • 1Division of Liver Diseases, The Mount Sinai School of Medicine, New York, New York
Further Information

Publication History

Publication Date:
21 December 2011 (online)

   Permissions and Reprints
Preview

ABSTRACT

Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality. The worldwide incidence of HCC and the hepatitis C virus (HCV) has increased over several decades suggesting an etiologic link. Progress has been made recently in several fields related specifically to HCV and HCC. The epidemiology has been better characterized, surveillance and treatment programs have been instituted, and data have emerged detailing the effect of other risk factors for HCC in patients with HCV. Studies of HCV-related HCC suggest differences in oncogenic potential according to genotype and mutations in the viral sequence. These same mutations are associated with interferon treatment failure, insulin resistance, and expression of HCV minicore proteins. These viral mutations provide a focus for investigations into the molecular basis of HCV-related oncogenesis, which may lead to improved diagnostic tests for early (curable) HCC and to interventions to prevent, and/or greatly retard, the oncogenic process.

KEYWORDS

Hepatitis C virus - hepatocellular carcinoma - core protein - minicore

REFERENCES

  • 1 El-Serag H B, Mason A C. Rising incidence of hepatocellular carcinoma in the United States.  N Engl J Med. 1999;  340 (10) 745-750
    Search in Google Scholar
  • 2 Kew M C. Hepatitis B and C viruses and hepatocellular carcinoma.  Clin Lab Med. 1996;  16 (2) 395-406
    Search in Google Scholar
  • 3 Kim C M, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice.  Nature. 1991;  351 (6324) 317-320
    Search in Google Scholar
  • 4 Nishioka K, Watanabe J, Furuta S et al.. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan.  Cancer. 1991;  67 (2) 429-433
    Search in Google Scholar
  • 5 Bruix J, Barrera J M, Calvet X et al.. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis.  Lancet. 1989;  2 (8670) 1004-1006
    Search in Google Scholar
  • 6 Colombo M, Kuo G, Choo Q L et al.. Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma.  Lancet. 1989;  2 (8670) 1006-1008
    Search in Google Scholar
  • 7 Altekruse S F, McGlynn K A, Reichman M E. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.  J Clin Oncol. 2009;  27 (9) 1485-1491
    Search in Google Scholar
  • 8 Dominitz J A, Boyko E J, Koepsell T D et al.. Elevated prevalence of hepatitis C infection in users of United States veterans medical centers.  Hepatology. 2005;  41 (1) 88-96
    Search in Google Scholar
  • 9 Kanwal F, Hoang T, Kramer J R et al.. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection.  Gastroenterology. 2011;  140 (4) 1182-1188, e1
    Search in Google Scholar
  • 10 Sangiovanni A, Prati G M, Fasani P et al.. The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients.  Hepatology. 2006;  43 (6) 1303-1310
    Search in Google Scholar
  • 11 Tanaka Y, Kurbanov F, Mano S et al.. Molecular tracing of the global hepatitis C virus epidemic predicts regional patterns of hepatocellular carcinoma mortality.  Gastroenterology. 2006;  130 (3) 703-714
    Search in Google Scholar
  • 12 Tanaka H, Imai Y, Hiramatsu N et al.. Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990 to 2003.  Ann Intern Med. 2008;  148 (11) 820-826
    Search in Google Scholar
  • 13 Bruix J, Sherman M. American Association for the Study of Liver Diseases . Management of hepatocellular carcinoma: an update.  Hepatology. 2011;  53 (3) 1020-1022
    Search in Google Scholar
  • 14 Davila J A, Morgan R O, Richardson P A, Du X L, McGlynn K A, El-Serag H B. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States.  Hepatology. 2010;  52 (1) 132-141
    Search in Google Scholar
  • 15 Davila J A, Henderson L, Kramer J R et al.. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States.  Ann Intern Med. 2011;  154 (2) 85-93
    Search in Google Scholar
  • 16 Santi V, Trevisani F, Gramenzi A Italian Liver Cancer (ITA.LI.CA) Group et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival.  J Hepatol. 2010;  53 (2) 291-297
    Search in Google Scholar
  • 17 Lok A S, Sterling R K, Everhart J E HALT-C Trial Group et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma.  Gastroenterology. 2010;  138 (2) 493-502
    Search in Google Scholar
  • 18 Bruno S, Crosignani A, Maisonneuve P, Rossi S, Silini E, Mondelli M U. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study.  Hepatology. 2007;  46 (5) 1350-1356
    Search in Google Scholar
  • 19 Lee M H, Yang H I, Lu S N et al.. Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study.  J Clin Oncol. 2010;  28 (30) 4587-4593
    Search in Google Scholar
  • 20 Kumada T, Toyoda H, Kiriyama S et al.. Incidence of hepatocellular carcinoma in hepatitis C carriers with normal alanine aminotransferase levels.  J Hepatol. 2009;  50 (4) 729-735
    Search in Google Scholar
  • 21 Ishiguro S, Inoue M, Tanaka Y, Mizokami M, Iwasaki M, Tsugane S. JPHC Study Group . Serum aminotransferase level and the risk of hepatocellular carcinoma: a population-based cohort study in Japan.  Eur J Cancer Prev. 2009;  18 (1) 26-32
    Search in Google Scholar
  • 22 Maki A, Kono H, Gupta M et al.. Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma.  Ann Surg Oncol. 2007;  14 (3) 1182-1190
    Search in Google Scholar
  • 23 Suruki R Y, Mueller N, Hayashi K et al.. Host immune status and incidence of hepatocellular carcinoma among subjects infected with hepatitis C virus: a nested case-control study in Japan.  Cancer Epidemiol Biomarkers Prev. 2006;  15 (12) 2521-2525
    Search in Google Scholar
  • 24 Dienstag J L, Ghany M G, Morgan T R HALT-C Trial Group et al. A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C.  Hepatology. 2011;  54 (2) 396-405
    Search in Google Scholar
  • 25 Hoefs J C, Shiffman M L, Goodman Z D, Kleiner D E, Dienstag J L, Stoddard A M. HALT-C Trial Group . Rate of progression of hepatic fibrosis in patients with chronic hepatitis C: results from the HALT-C trial.  Gastroenterology. 2011;  141 (3) 900-908 e1-e2
    Search in Google Scholar
  • 26 Asahina Y, Tsuchiya K, Tamaki N et al.. Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection.  Hepatology. 2010;  52 (2) 518-527
    Search in Google Scholar
  • 27 Hassan M M, Spitz M R, Thomas M B et al.. The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States.  J Hepatol. 2009;  50 (2) 334-341
    Search in Google Scholar
  • 28 Lok A S, Everhart J E, Di Bisceglie A M, Kim H Y, Hussain M, Morgan T R. HALT-C Trial Group . Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C.  Hepatology. 2011;  54 (2) 434-442
    Search in Google Scholar
  • 29 Ikeda K, Marusawa H, Osaki Y et al.. Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: a prospective study.  Ann Intern Med. 2007;  146 (9) 649-656
    Search in Google Scholar
  • 30 Gelatti U, Covolo L, Franceschini M Brescia HCC Study Group et al. Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.  J Hepatol. 2005;  42 (4) 528-534
    Search in Google Scholar
  • 31 Inoue M, Yoshimi I, Sobue T, Tsugane S. JPHC Study Group . Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan.  J Natl Cancer Inst. 2005;  97 (4) 293-300
    Search in Google Scholar
  • 32 Lambrecht R W, Sterling R K, Naishadham D HALT-C Trial Group et al. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C.  Gastroenterology. 2011;  140 (5) 1490-1500, e3
    Search in Google Scholar
  • 33 Nahon P, Sutton A, Rufat P et al.. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis.  Gastroenterology. 2008;  134 (1) 102-110
    Search in Google Scholar
  • 34 Kurahashi N, Inoue M, Iwasaki M, Tanaka Y, Mizokami M, Tsugane S. JPHC Study Group . Isoflavone consumption and subsequent risk of hepatocellular carcinoma in a population-based prospective cohort of Japanese men and women.  Int J Cancer. 2009;  124 (7) 1644-1649
    Search in Google Scholar
  • 35 Lai M S, Hsieh M S, Chiu Y H, Chen T H. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.  Hepatology. 2006;  43 (6) 1295-1302
    Search in Google Scholar
  • 36 N'Kontchou G, Paries J, Htar M T et al.. Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis.  Clin Gastroenterol Hepatol. 2006;  4 (8) 1062-1068
    Search in Google Scholar
  • 37 Veldt B J, Chen W, Heathcote E J et al.. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus.  Hepatology. 2008;  47 (6) 1856-1862
    Search in Google Scholar
  • 38 Ohishi W, Fujiwara S, Cologne J B et al.. Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study.  Cancer Epidemiol Biomarkers Prev. 2008;  17 (4) 846-854
    Search in Google Scholar
  • 39 Ohki T, Tateishi R, Sato T et al.. Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.  Clin Gastroenterol Hepatol. 2008;  6 (4) 459-464
    Search in Google Scholar
  • 40 Chen C L, Yang H I, Yang W S et al.. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan.  Gastroenterology. 2008;  135 (1) 111-121
    Search in Google Scholar
  • 41 Inoue M, Kurahashi N, Iwasaki M Japan Public Health Center-based Prospective Study Group et al. Metabolic factors and subsequent risk of hepatocellular carcinoma by hepatitis virus infection status: a large-scale population-based cohort study of Japanese men and women (JPHC Study Cohort II).  Cancer Causes Control. 2009;  20 (5) 741-750
    Search in Google Scholar
  • 42 Rossi M, Lipworth L, Maso L D et al.. Dietary glycemic load and hepatocellular carcinoma with or without chronic hepatitis infection.  Ann Oncol. 2009;  20 (10) 1736-1740
    Search in Google Scholar
  • 43 Nkontchou G, Bastard J P, Ziol M et al.. Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis.  J Hepatol. 2010;  53 (5) 827-833
    Search in Google Scholar
  • 44 Lok A S, Seeff L B, Morgan T R HALT-C Trial Group et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.  Gastroenterology. 2009;  136 (1) 138-148
    Search in Google Scholar
  • 45 Lok A S, Everhart J E, Wright E C HALT-C Trial Group et al. Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C.  Gastroenterology. 2011;  140 (3) 840-849, quiz e12
    Search in Google Scholar
  • 46 Shiffman M L, Morishima C, Dienstag J L HALT-C Trial Group et al. Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial.  Gastroenterology. 2009;  137 (6) 1986-1994
    Search in Google Scholar
  • 47 Morgan T R, Ghany M G, Kim H Y HALT-C Trial Group et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C.  Hepatology. 2010;  52 (3) 833-844
    Search in Google Scholar
  • 48 Cardoso A C, Moucari R, Figueiredo-Mendes C et al.. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis.  J Hepatol. 2010;  52 (5) 652-657
    Search in Google Scholar
  • 49 Bruix J, Poynard T, Colombo M EPIC3 Study Group et al. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C.  Gastroenterology. 2011;  140 (7) 1990-1999
    Search in Google Scholar
  • 50 Tanimoto Y, Tashiro H, Aikata H et al.. Impact of pegylated interferon therapy on outcomes of patients with hepatitis C virus-related hepatocellular carcinoma after curative hepatic resection.  Ann Surg Oncol. 2011;  Epub ahead of print
    Search in Google Scholar
  • 51 Burd E M. Human papillomavirus and cervical cancer.  Clin Microbiol Rev. 2003;  16 (1) 1-17
    Search in Google Scholar
  • 52 Raimondi S, Bruno S, Mondelli M U, Maisonneuve P. Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis.  J Hepatol. 2009;  50 (6) 1142-1154
    Search in Google Scholar
  • 53 Ray R B, Meyer K, Ray R. Hepatitis C virus core protein promotes immortalization of primary human hepatocytes.  Virology. 2000;  271 (1) 197-204
    Search in Google Scholar
  • 54 Shan Y, Chen X G, Huang B, Hu A B, Xiao D, Guo Z M. Malignant transformation of the cultured human hepatocytes induced by hepatitis C virus core protein.  Liver Int. 2005;  25 (1) 141-147
    Search in Google Scholar
  • 55 Moriya K, Fujie H, Shintani Y et al.. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice.  Nat Med. 1998;  4 (9) 1065-1067
    Search in Google Scholar
  • 56 Naas T, Ghorbani M, Alvarez-Maya I et al.. Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2.  J Gen Virol. 2005;  86 (Pt 8) 2185-2196
    Search in Google Scholar
  • 57 Li Z H, Tang Q B, Wang J et al.. Hepatitis C virus core protein induces malignant transformation of biliary epithelial cells by activating nuclear factor-kappaB pathway.  J Gastroenterol Hepatol. 2010;  25 (7) 1315-1320
    Search in Google Scholar
  • 58 Chen R F, Li Z H, Liu R Y, Kong X H, Tang Q B, Wang J. Malignant transformation of the cultured human normal biliary tract epithelial cells induced by hepatitis C virus core protein.  Oncol Rep. 2007;  17 (1) 105-110
    Search in Google Scholar
  • 59 Jin D Y, Wang H L, Zhou Y et al.. Hepatitis C virus core protein-induced loss of LZIP function correlates with cellular transformation.  EMBO J. 2000;  19 (4) 729-740
    Search in Google Scholar
  • 60 Smirnova I S, Aksenov N D, Kashuba E V et al.. Hepatitis C virus core protein transforms murine fibroblasts by promoting genomic instability.  Cell Oncol. 2006;  28 (4) 177-190
    Search in Google Scholar
  • 61 El-Serag H B, Rudolph K L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.  Gastroenterology. 2007;  132 (7) 2557-2576
    Search in Google Scholar
  • 62 Bartosch B, Thimme R, Blum H E, Zoulim F. Hepatitis C virus-induced hepatocarcinogenesis.  J Hepatol. 2009;  51 (4) 810-820
    Search in Google Scholar
  • 63 Fishman S L, Factor S H, Balestrieri C et al.. Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma.  Clin Cancer Res. 2009;  15 (9) 3205-3213
    Search in Google Scholar
  • 64 Ogata S, Nagano-Fujii M, Ku Y, Yoon S, Hotta H. Comparative sequence analysis of the core protein and its frameshift product, the F protein, of hepatitis C virus subtype 1b strains obtained from patients with and without hepatocellular carcinoma.  J Clin Microbiol. 2002;  40 (10) 3625-3630
    Search in Google Scholar
  • 65 Rüster B, Zeuzem S, Krump-Konvalinkova V et al.. Comparative sequence analysis of the core- and NS5-region of hepatitis C virus from tumor and adjacent non-tumor tissue.  J Med Virol. 2001;  63 (2) 128-134
    Search in Google Scholar
  • 66 Delhem N, Sabile A, Gajardo R et al.. Activation of the interferon-inducible protein kinase PKR by hepatocellular carcinoma derived-hepatitis C virus core protein.  Oncogene. 2001;  20 (41) 5836-5845
    Search in Google Scholar
  • 67 Horie C, Iwahana H, Horie T et al.. Detection of different quasispecies of hepatitis C virus core region in cancerous and noncancerous lesions.  Biochem Biophys Res Commun. 1996;  218 (3) 674-681
    Search in Google Scholar
  • 68 Alam S S, Nakamura T, Naganuma A et al.. Hepatitis C virus quasispecies in cancerous and noncancerous hepatic lesions: the core protein-encoding region.  Acta Med Okayama. 2002;  56 (3) 141-147
    Search in Google Scholar
  • 69 Takahashi K, Iwata K, Matsumoto M et al.. Hepatitis C virus (HCV) genotype 1b sequences from fifteen patients with hepatocellular carcinoma: the ‘progression score’ revisited.  Hepatol Res. 2001;  20 (2) 161-171
    Search in Google Scholar
  • 70 Hung C H, Chen C H, Lee C M et al.. Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma.  J Viral Hepat. 2008;  15 (1) 58-65
    Search in Google Scholar
  • 71 Akuta N, Suzuki F, Kawamura Y et al.. Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis.  Hepatology. 2007;  46 (5) 1357-1364
    Search in Google Scholar
  • 72 Nakamoto S, Imazeki F, Fukai K et al.. Association between mutations in the core region of hepatitis C virus genotype 1 and hepatocellular carcinoma development.  J Hepatol. 2010;  52 (1) 72-78
    Search in Google Scholar
  • 73 Kobayashi M, Akuta N, Suzuki F et al.. Influence of amino-acid polymorphism in the core protein on progression of liver disease in patients infected with hepatitis C virus genotype 1b.  J Med Virol. 2010;  82 (1) 41-48
    Search in Google Scholar
  • 74 Donlin M J, Cannon N A, Yao E Virahep-C Study Group et al. Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy.  J Virol. 2007;  81 (15) 8211-8224
    Search in Google Scholar
  • 75 Enomoto N, Maekawa S. HCV genetic elements determining the early response to peginterferon and ribavirin therapy.  Intervirology. 2010;  53 (1) 66-69
    Search in Google Scholar
  • 76 Okanoue T, Itoh Y, Hashimoto H et al.. Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study.  J Gastroenterol. 2009;  44 (9) 952-963
    Search in Google Scholar
  • 77 Akuta N, Suzuki F, Kawamura Y et al.. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels.  J Hepatol. 2007;  46 (3) 403-410
    Search in Google Scholar
  • 78 Mori N, Imamura M, Kawakami Y Hiroshima Liver Study Group et al. Randomized trial of high-dose interferon-alpha-2b combined with ribavirin in patients with chronic hepatitis C: Correlation between amino acid substitutions in the core/NS5A region and virological response to interferon therapy.  J Med Virol. 2009;  81 (4) 640-649
    Search in Google Scholar
  • 79 Akuta N, Suzuki F, Hirakawa M et al.. A matched case-controlled study of 48 and 72 weeks of peginterferon plus ribavirin combination therapy in patients infected with HCV genotype 1b in Japan: amino acid substitutions in HCV core region as predictor of sustained virological response.  J Med Virol. 2009;  81 (3) 452-458
    Search in Google Scholar
  • 80 Akuta N, Suzuki F, Kawamura Y et al.. Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b.  J Med Virol. 2007;  79 (11) 1686-1695
    Search in Google Scholar
  • 81 Akuta N, Suzuki F, Kawamura Y et al.. Prediction of response to pegylated interferon and ribavirin in hepatitis C by polymorphisms in the viral core protein and very early dynamics of viremia.  Intervirology. 2007;  50 (5) 361-368
    Search in Google Scholar
  • 82 Akuta N, Suzuki F, Sezaki H et al.. Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load.  J Med Virol. 2006;  78 (1) 83-90
    Search in Google Scholar
  • 83 Akuta N, Suzuki F, Hirakawa M et al.. Amino acid substitutions in the hepatitis C virus core region of genotype 1b are the important predictor of severe insulin resistance in patients without cirrhosis and diabetes mellitus.  J Med Virol. 2009;  81 (6) 1032-1039
    Search in Google Scholar
  • 84 Funaoka Y, Sakamoto N, Suda G et al.. Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91.  J Virol. 2011;  85 (12) 5986-5994
    Search in Google Scholar
  • 85 Fraser C S, Doudna J A. Structural and mechanistic insights into hepatitis C viral translation initiation.  Nat Rev Microbiol. 2007;  5 (1) 29-38
    Search in Google Scholar
  • 86 Fukushi S, Katayama K, Kurihara C et al.. Complete 5′ noncoding region is necessary for the efficient internal initiation of hepatitis C virus RNA.  Biochem Biophys Res Commun. 1994;  199 (2) 425-432
    Search in Google Scholar
  • 87 Hellen C U, Sarnow P. Internal ribosome entry sites in eukaryotic mRNA molecules.  Genes Dev. 2001;  15 (13) 1593-1612
    Search in Google Scholar
  • 88 Honda M, Ping L H, Rijnbrand R C et al.. Structural requirements for initiation of translation by internal ribosome entry within genome-length hepatitis C virus RNA.  Virology. 1996;  222 (1) 31-42
    Search in Google Scholar
  • 89 Kieft J S, Zhou K, Jubin R, Doudna J A. Mechanism of ribosome recruitment by hepatitis C IRES RNA.  RNA. 2001;  7 (2) 194-206
    Search in Google Scholar
  • 90 Otto G A, Puglisi J D. The pathway of HCV IRES-mediated translation initiation.  Cell. 2004;  119 (3) 369-380
    Search in Google Scholar
  • 91 Wang C, Sarnow P, Siddiqui A. Translation of human hepatitis C virus RNA in cultured cells is mediated by an internal ribosome-binding mechanism.  J Virol. 1993;  67 (6) 3338-3344
    Search in Google Scholar
  • 92 McMullan L K, Grakoui A, Evans M J et al.. Evidence for a functional RNA element in the hepatitis C virus core gene.  Proc Natl Acad Sci U S A. 2007;  104 (8) 2879-2884
    Search in Google Scholar
  • 93 Vassilaki N, Friebe P, Meuleman P et al.. Role of the hepatitis C virus core + 1 open reading frame and core cis-acting RNA elements in viral RNA translation and replication.  J Virol. 2008;  82 (23) 11503-11515
    Search in Google Scholar
  • 94 Tuplin A, Evans D J, Simmonds P. Detailed mapping of RNA secondary structures in core and NS5B-encoding region sequences of hepatitis C virus by RNase cleavage and novel bioinformatic prediction methods.  J Gen Virol. 2004;  85 (Pt 10) 3037-3047
    Search in Google Scholar
  • 95 Walewski J L, Gutierrez J A, Branch-Elliman W et al.. Mutation Master: profiles of substitutions in hepatitis C virus RNA of the core, alternate reading frame, and NS2 coding regions.  RNA. 2002;  8 (5) 557-571
    Search in Google Scholar
  • 96 Branch A D, Stump D D, Gutierrez J A, Eng F, Walewski J L. The hepatitis C virus alternate reading frame (ARF) and its family of novel products: the alternate reading frame protein/F-protein, the double-frameshift protein, and others.  Semin Liver Dis. 2005;  25 (1) 105-117
    Search in Google Scholar
  • 97 Eng F J, Walewski J L, Klepper A L et al.. Internal initiation stimulates production of p8 minicore, a member of a newly discovered family of hepatitis C virus core protein isoforms.  J Virol. 2009;  83 (7) 3104-3114
    Search in Google Scholar
  • 98 Ogura S, Akuta N, Hirakawa M et al.. Virological and biochemical features in elderly HCV patients with hepatocellular carcinoma: amino acid substitutions in HCV core region as predictor of mortality after first treatment.  Intervirology. 2009;  52 (4) 179-188
    Search in Google Scholar
  • 99 Eng F J, Yusuke Y, Kopp M et al.. Viral mutations that predict treatment failure and liver cancer control expression of the newly-discovered HCV minicore proteins.  Paper presented at: 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 29–November 2, 2010; Boston, MA
  • 100 Chen H M, Tanaka N, Mitani Y et al.. Critical role for constitutive type I interferon signaling in the prevention of cellular transformation.  Cancer Sci. 2009;  100 (3) 449-456
    Search in Google Scholar
  • 101 Fridman A L, Tainsky M A. Critical pathways in cellular senescence and immortalization revealed by gene expression profiling.  Oncogene. 2008;  27 (46) 5975-5987
    Search in Google Scholar
  • 102 Lindkvist A, Ivarsson K, Jernberg-Wiklund H, Paulsson-Karlsson Y. Interferon-induced sensitization to apoptosis is associated with repressed transcriptional activity of the hTERT promoter in multiple myeloma.  Biochem Biophys Res Commun. 2006;  341 (4) 1141-1148
    Search in Google Scholar

Jawad AhmadM.D. F.R.C.P. 

Division of Liver Diseases, The Mount Sinai School of Medicine

Box 1104, One Gustave L. Levy Place, New York, NY 10029

Email: jawad.ahmad@mountsinai.org