Hepatitis C virus-associated cancer

Annual Review of Pathology: Mechanisms of Disease

Volumn 10, Issue , 2015, Pages 345-370

  Lin, Ming V ^a,b   King, Lindsay Y ^a,b   Chung, Raymond T ^a,b  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

cancer; cirrhosis; hepatocellular carcinoma; liver

Indexed keywords

ASUNAPREVIR; BOCEPREVIR; CORE PROTEIN; DASABUVIR; EPIDERMAL GROWTH FACTOR; GLYCOPROTEIN E2; GRAZOPREVIR; LEDIPASVIR PLUS SOFOSBUVIR; MICRORNA; MICRORNA 100; MICRORNA 122; MICRORNA 141; MICRORNA 145; NONSTRUCTURAL PROTEIN 3; NONSTRUCTURAL PROTEIN 5A; OMBITASVIR; PARITAPREVIR; PEGINTERFERON; PROTEIN P53; RIBAVIRIN; RITONAVIR; SOFOSBUVIR; SORAFENIB; TELAPREVIR;

ARTICLE; CELL DIFFERENTIATION; CELL ONCOGENE; CELL PROLIFERATION; CHEMOEMBOLIZATION; ENDOPLASMIC RETICULUM STRESS; EPIGENETICS; FIBROGENESIS; GENE EXPRESSION PROFILING; GENOMIC INSTABILITY; HEPATITIS B VIRUS; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; INTRACELLULAR SIGNALING; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; MALIGNANT TRANSFORMATION; METABOLIC DISORDER; MICROSATELLITE INSTABILITY; MOLECULAR PATHOLOGY; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR GENE; ANIMAL; EXPERIMENTAL LIVER NEOPLASM; HEPACIVIRUS; ISOLATION AND PURIFICATION; LIVER TUMOR; PATHOLOGY; VIROLOGY;

ANIMALS; CARCINOMA, HEPATOCELLULAR; HEPACIVIRUS; HEPATITIS C; HUMANS; LIVER NEOPLASMS; LIVER NEOPLASMS, EXPERIMENTAL;

EID: 84921912314     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev-pathol-012414-040323     Document Type: Article

References (195)

1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, et al. 2013. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, Fr.: Int. Agency Res. Cancer. http://globocan.iarc.fr
2. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. 2006. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J. Hepatol. 45:529-38
3. Altekruse SF, McGlynn KA, Reichman ME. 2009. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J. Clin. Oncol. 27:1485-91
4. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. 2010. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127:2893-917
5. Parkin DM, Bray F, Ferlay J, Pisani P. 2001. Estimating the world cancer burden: Globocan 2000. Int. J. Cancer 94:153-56
6. El-Serag HB. 2007. Epidemiology of hepatocellular carcinoma inUSA. Hepatol. Res. 37(Suppl. 2):S88-94
7. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, et al., eds. 2014. SEER Cancer Statistics Review, 1975-2011. Bethesda, MD: Natl. Cancer Inst. http://seer.cancer.gov/csr/1975-2011/
8. Thein HH, Isaranuwatchai W, Campitelli MA, Feld JJ, Yoshida E, et al. 2013. Health care costs associated with hepatocellular carcinoma: a population-based study. Hepatology 58:1375-84
9. WHO (World Health Organ.). 2011. Hepatitis C. Rep. 164, WHO, Geneva. http://www.who. int/mediacentre/factsheets/fs164/en/
10. Hoofnagle JH. 2002. Course and outcome of hepatitis C. Hepatology 36:S21-29
11. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, et al. 2002. Protection against persistence of hepatitis C. Lancet 359:1478-83
12. Lagging LM, Westin J, Svensson E, Aires N, Dhillon AP, et al. 2002. Progression of fibrosis in untreated patients with hepatitis C virus infection. Liver 22:136-44
13. Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T, et al. 1990. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. PNAS 87:6547-49
14. El-Serag HB. 2002. Hepatocellular carcinoma and hepatitisCin theUnited States. Hepatology 36:S74-83
15. Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, et al. 2007. Sustained virological response to interferon-α is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 45:579-87
16. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, et al. 1995. Randomised trial of effects of interferon-α on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 346:1051-55
17. Valla DC, Chevallier M, Marcellin P, Payen JL, Trepo C, et al. 1999. Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment. Hepatology 29:1870-75
18. Mazzella G, Accogli E, Sottili S, Festi D, Orsini M, et al. 1996. Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. J. Hepatol. 24:141-47
19. Fattovich G, Stroffolini T, Zagni I, Donato F. 2004. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127:S35-50
20. Zender L, Villanueva A, Tovar V, Sia D, Chiang DY, Llovet JM. 2010. Cancer gene discovery in hepatocellular carcinoma. J. Hepatol. 52:921-29
21. Thorgeirsson SS, Grisham JW. 2002. Molecular pathogenesis of human hepatocellular carcinoma. Nat. Genet. 31:339-46
22. Takano S, Yokosuka O, Imazeki F, Tagawa M, Omata M. 1995. Incidence of hepatocellular carcinoma in chronic hepatitis B and C: a prospective study of 251 patients. Hepatology 21:650-55
23. Oka H, Kurioka N, Kim K, Kanno T, Kuroki T, et al. 1990. Prospective study of early detection of hepatocellular carcinoma in patients with cirrhosis. Hepatology 12:680-87
24. Seki S, Sakaguchi H, Kitada T, Tamori A, Takeda T, et al. 2000. Outcomes of dysplastic nodules in human cirrhotic liver: a clinicopathological study. Clin. Cancer Res. 6:3469-73
25. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Okazaki N, et al. 1990. Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet 336:1150-53
26. Brechot C. 1998. Molecular mechanisms of hepatitis B and C viruses related to liver carcinogenesis. Hepato-Gastroenterology 45(Suppl. 3):1189-96
27. Grisham JW. 2001. Molecular genetic alterations in primary hepatocellular neoplasms: hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma. In The Molecular Basis of Human Cancer, ed. WB Coleman, GJ Tsongalis, pp. 269-346. Totowa, NJ: Humana
28. Diao J, Garces R, Richardson CD. 2001. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev. 12:189-205
29. Kawakita N, Seki S, Sakaguchi H, Yanai A, Kuroki T, et al. 1992. Analysis of proliferating hepatocytes using a monoclonal antibody against proliferating cell nuclear antigen/cyclin in embedded tissues from various liver diseases fixed in formaldehyde. Am. J. Pathol. 140:513-20
30. Paradis V, Dargere D, Bonvoust F, Rubbia-Brandt L, Ba N, et al. 2000. Clonal analysis of micronodules in virus C-induced liver cirrhosis using laser capture microdissection (LCM) and HUMARA assay. Lab. Investig. 80:1553-59
31. Okuda T, Wakasa K, Kubo S, Hamada T, Fujita M, et al. 2001. Clonal analysis of hepatocellular carcinoma and dysplastic nodule by methylation pattern of X-chromosome-linked human androgen receptor gene. Cancer Lett. 164:91-96
32. Toshikuni N, Nouso K, Higashi T, Nakatsukasa H, Onishi T, et al. 2000. Expression of telomeraseassociated protein 1 and telomerase reverse transcriptase in hepatocellular carcinoma. Br. J. Cancer 82:833-37
33. Ide T, Tahara H, Nakashio R, Kitamoto M, Nakanishi T, Kajiyama G. 1996. Telomerase in hepatocellular carcinogenesis. Hum. Cell 9:283-86
34. Karachristos A, Liloglou T, Field JK, Deligiorgi E, Kouskouni E, Spandidos DA. 1999. Microsatellite instability and p53 mutations in hepatocellular carcinoma. Mol. Cell Biol. Res. Commun. 2:155-61
35. Kawai H, Suda T, Aoyagi Y, Isokawa O, Mita Y, et al. 2000. Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology 31:1246-50
36. Roncalli M, Bianchi P, Grimaldi GC, Ricci D, Laghi L, et al. 2000. Fractional allelic loss in non-endstage cirrhosis: correlations with hepatocellular carcinoma development during follow-up. Hepatology 31:846-50
37. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. 2007. Genomics and signaling pathways in hepatocellular carcinoma. Semin. Liver Dis. 27:55-76
38. Blanc P, Etienne H, Daujat M, Fabre I, Zindy F, et al. 1992. Mitotic responsiveness of cultured adult human hepatocytes to epidermal growth factor, transforming growth factor α, and human serum. Gastroenterology 102:1340-50
39. Hoffmann B, Piasecki A, Paul D. 1989. Proliferation of fetal rat hepatocytes in response to growth factors and hormones in primary culture. J. Cell. Physiol. 139:654-62
40. Tonjes RR, Lohler J, O'Sullivan JF, Kay GF, Schmidt GH, et al. 1995. Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. Oncogene 10:765-68
41. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, et al. 2008. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359:1995-2004
42. Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, et al. 2008. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 299:53-60
43. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, et al. 2011. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat. Med. 17:589-95
44. Zona L, Lupberger J, Sidahmed-Adrar N, Thumann C, Harris HJ, et al. 2013. HRas signal transduction promotes hepatitis C virus cell entry by triggering assembly of the host tetraspanin receptor complex. Cell Host Microbe 13:302-13
45. Diao J, Pantua H, Ngu H, Komuves L, Diehl L, et al. 2012. Hepatitis C virus induces epidermal growth factor receptor activation via CD81 binding for viral internalization and entry. J. Virol. 86:10935-49
46. Fuchs BC, Hoshida Y, Fujii T, Wei L, Yamada S, et al. 2014. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology 59:1577-90
47. Pollak M. 2008. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer 8:915-28
48. Sachdev D, Yee D. 2007. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol. Cancer Ther. 6:1-12
49. Breuhahn K, Longerich T, Schirmacher P. 2006. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25:3787-800
50. Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, et al. 2010. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J. Hepatol. 52:550-59
51. Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, et al. 1997. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. PNAS 94:701-6
52. Vejchapipat P, Tangkijvanich P, Theamboonlers A, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. 2004. Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma. J. Gastroenterol. 39:1182-88
53. Lutterbach B, Zeng Q, Davis LJ, Hatch H, Hang G, et al. 2007. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res. 67:2081-88
54. Liu L, Cao Y, Chen C, Zhang X, McNabola A, et al. 2006. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66:11851-58
55. Zaret KS. 2008. Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat. Rev. Genet. 9:329-40
56. Zaret KS, Grompe M. 2008. Generation and regeneration of cells of the liver and pancreas. Science 322:1490-94
57. Thompson MD, Monga SP. 2007. WNT/β-catenin signaling in liver health and disease. Hepatology 45:1298-305
58. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, et al. 2008. Focal gains of VEGFA andmolecular classification of hepatocellular carcinoma. Cancer Res. 68:6779-88
59. Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, et al. 2007. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45:42-52
60. Sicklick JK, Li YX, Jayaraman A, Kannangai R, Qi Y, et al. 2006. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27:748-57
61. Tada M, Kanai F, Tanaka Y, Tateishi K, OhtaM, et al. 2008. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin. Cancer Res. 14:3768-76
62. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, et al. 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121-24
63. Elsharkawy AM, Mann DA. 2007. Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46:590-97
64. Li XM, Tang ZY, Zhou G, Lui YK, Ye SL. 1998. Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 17:13-17
65. Poon RT, Ho JW, Tong CS, Lau C, Ng IO, Fan ST. 2004. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br. J. Surg. 91:1354-60
66. Imura S, Miyake H, Izumi K, Tashiro S, Uehara H. 2004. Correlation of vascular endothelial cell proliferation with microvessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in hepatocellular carcinoma. J. Med. Investig. 51:202-9
67. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, et al. 2002. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 35:834-42
68. Campbell JS, Johnson MM, Bauer RL, Hudkins KL, Gilbertson DG, et al. 2007. Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis. Differentiation 75:843-52
69. Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, et al. 2005. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. PNAS 102:3389-94
70. Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, et al. 2009. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J. Clin. Investig. 119:465-77
71. Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P. 1994. Geographic variation of p53 mutational profile in nonmalignant human liver. Science 264:1317-19
72. Kim CW, Chang KM. 2013. Hepatitis C virus: virology and life cycle. Clin. Mol. Hepatol. 19:17-25
73. Pawlotsky JM. 2003. Hepatitis C virus genetic variability: pathogenic and clinical implications. Clin. Liver Dis. 7:45-66
74. Schaefer EA, Chung RT. 2012. Anti-hepatitis C virus drugs in development. Gastroenterology 142:1340-50.e1
75. Fusco DN, Chung RT. 2012. Novel therapies for hepatitis C: insights from the structure of the virus. Annu. Rev. Med. 63:373-87
76. Pawlotsky JM, Chevaliez S, McHutchison JG. 2007. The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 132:1979-98
77. Hundt J, Li Z, Liu Q. 2013. Post-Translational modifications of hepatitis C viral proteins and their biological significance. World J. Gastroenterol. 19:8929-39
78. Khaliq S, Jahan S, Hassan S. 2011. Hepatitis C virus p7: molecular function and importance in hepatitis C virus life cycle and potential antiviral target. Liver Int. 31:606-17
79. Welbourn S, Pause A. 2006. HCV NS2/3 protease. In Hepatitis C Viruses: Genomes and Molecular Biology, ed. SL Tan, pp. 151-62. Norfolk, UK: Horiz. Biosci.
80. Pang PS, Jankowsky E, Planet PJ, Pyle AM. 2002. The hepatitis C viral NS3 protein is a processive DNA helicase with cofactor enhanced RNA unwinding. EMBO J. 21:1168-76
81. De Francesco R, Steinkuhler C. 2000. Structure and function of the hepatitis C virus NS3-NS4A serine proteinase. Curr. Top. Microbiol. Immunol. 242:149-69
82. Gouttenoire J, Castet V, Montserret R, Arora N, Raussens V, et al. 2009. Identification of a novel determinant for membrane association in hepatitis C virus nonstructural protein 4B. J. Virol. 83:6257-68
83. Shirota Y, Luo H, Qin W, Kaneko S, Yamashita T, et al. 2002. Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity. J. Biol. Chem. 277:11149-55
84. Reyes GR. 2002. The nonstructural NS5A protein of hepatitis C virus: an expanding, multifunctional role in enhancing hepatitis C virus pathogenesis. J. Biomed. Sci. 9:187-97
85. DeMarini DJ, Johnston VK, Konduri M, Gutshall LL, Sarisky RT. 2003. Intracellular hepatitis C virus RNA-dependent RNA polymerase activity. J. Virol. Methods 113:65-68
86. Kiyosawa K, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K, et al. 2004. Hepatocellular carcinoma: recent trends in Japan. Gastroenterology 127:S17-26
87. Bosch FX, Ribes J, Cleries R, Diaz M. 2005. Epidemiology of hepatocellular carcinoma. Clin. Liver Dis. 9:191-211
88. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, et al. 2002. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am. J. Epidemiol. 155:323-31
89. Imazeki F, Yokosuka O, Fukai K, Saisho H. 2003. Favorable prognosis of chronic hepatitis C after interferon therapy by long-Term cohort study. Hepatology 38:493-502
90. Zoulim F, Chevallier M, Maynard M, Trepo C. 2003. Clinical consequences of hepatitisCvirus infection. Rev. Med. Virol. 13:57-68
91. Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, et al. 2009. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 136:138-48
92. Hino K, Okita K. 2004. Interferon therapy as chemoprevention of hepatocarcinogenesis in patients with chronic hepatitis C. J. Antimicrob. Chemother. 53:19-22
93. Kang SM, Kim SJ, Kim JH, Lee W, Kim GW, et al. 2009. Interaction of hepatitis C virus core protein with Hsp60 triggers the production of reactive oxygen species and enhances TNF-α-mediated apoptosis. Cancer Lett. 279:230-37
94. Kao CF, Chen SY, Chen JY, Wu Lee YH. 2004. Modulation of p53 transcription regulatory activity and post-Translational modification by hepatitis C virus core protein. Oncogene 23:2472-83
95. Yoshida I, Oka K, Hidajat R, Nagano-Fujii M, Ishido S, Hotta H. 2001. Inhibition of p21/Waf1/Cip1/Sdi1 expression by hepatitis C virus core protein. Microbiol. Immunol. 45:689-97
96. Alisi A, Giambartolomei S, Cupelli F, Merlo P, Fontemaggi G, et al. 2003. Physical and functional interaction between HCV core protein and the different p73 isoforms. Oncogene 22:2573-80
97. Cho J, Baek W, Yang S, Chang J, Sung YC, Suh M. 2001. HCV core protein modulates Rb pathway through pRb down-regulation and E2F-1 up-regulation. Biochim. Biophys. Acta 1538:59-66
98. Aoki H, Hayashi J, Moriyama M, Arakawa Y, Hino O. 2000. Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. J. Virol. 74:1736-41
99. Hayashi J, Aoki H, Kajino K, Moriyama M, Arakawa Y, Hino O. 2000. 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 α. Hepatology 32:958-61
100. Joo M, Hahn YS, Kwon M, Sadikot RT, Blackwell TS, Christman JW. 2005. Hepatitis C virus core protein suppresses NF-κB activation and cyclooxygenase-2 expression by direct interaction with IκB kinase β. J. Virol. 79:7648-57
101. Fukutomi T, Zhou Y, Kawai S, Eguchi H, Wands JR, Li J. 2005. HepatitisCvirus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology 41:1096-105
102. Peifer M, Polakis P. 2000. Wnt signaling in oncogenesis and embryogenesis-A look outside the nucleus. Science 287:1606-9
103. Terris B, Pineau P, Bregeaud L, Valla D, Belghiti J, et al. 1999. Close correlation between β-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 18:6583-88
104. Jeng YM, Wu MZ, Mao TL, Chang MH, Hsu HC. 2000. Somatic mutations of β-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma. Cancer Lett. 152:45-51
105. Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ. 2000. WISP-1 is a Wnt-1-And β-cateninresponsive oncogene. Genes Dev. 14:585-95
106. Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, et al. 2001. A novel variant ofWISP1 lacking a VonWillebrand type C module overexpressed in scirrhous gastric carcinoma. Oncogene 20:5525-32
107. Tanaka S, Sugimachi K, Kameyama T, Maehara S, Shirabe K, et al. 2003. HumanWISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma. Hepatology 37:1122-29
108. Shi Y, Massague J. 2003. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685-700
109. Massague J, Blain SW, Lo RS. 2000. TGFβsignaling in growth control, cancer, and heritable disorders. Cell 103:295-309
110. Nelson DR, Gonzalez-Peralta RP, Qian K, Xu Y, Marousis CG, et al. 1997. Transforming growth factor-β1 in chronic hepatitis C. J. Viral Hepat. 4:29-35
111. Pavio N, Battaglia S, Boucreux D, Arnulf B, Sobesky R, et al. 2005. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-Tumor tissue interact with Smad3 and inhibit the TGF-βpathway. Oncogene 24:6119-32
112. Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S, et al. 2002. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J. Exp. Med. 195:35-41
113. Tseng CT, Klimpel GR. 2002. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J. Exp. Med. 195:43-49
114. Zhao LJ, Wang L, Ren H, Cao J, Li L, et al. 2005. Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors. Exp. Cell Res. 305:23-32
115. Zemel R, Gerechet S, Greif H, Bachmatove L, Birk Y, et al. 2001. Cell transformation induced by hepatitis C virus NS3 serine protease. J. Viral Hepat. 8:96-102
116. Deng L, Nagano-Fujii M, Tanaka M, Nomura-TakigawaY, Ikeda M, et al. 2006. NS3 protein of hepatitis Cvirus associates with the tumour suppressor p53 and inhibits its function in anNS3 sequence-dependent manner. J. Gen. Virol. 87:1703-13
117. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. 2005. Hepatitis C virus proteaseNS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. PNAS 102:17717-22
118. Lan KH, Sheu ML, Hwang SJ, Yen SH, Chen SY, et al. 2002.HCVNS5A interacts with p53 and inhibits p53-mediated apoptosis. Oncogene 21:4801-11
119. Majumder M, Ghosh AK, Steele R, Ray R, Ray RB. 2001. Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J. Virol. 75:1401-7
120. Ghosh AK, Majumder M, Steele R, Meyer K, Ray R, Ray RB. 2000. Hepatitis C virus NS5A protein protects against TNF-Alpha mediated apoptotic cell death. Virus Res. 67:173-78
121. Liao QJ, Ye LB, Timani KA, She YL, Yang XJ, et al. 2005. HepatitisCvirus non-structural 5Aprotein can enhance full-length core protein-induced nuclear factor-κB activation. World J. Gastroenterol. 11:6433-39
122. Arima N, Kao CY, Licht T, Padmanabhan R, Sasaguri Y. 2001. Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A. J. Biol. Chem. 276:12675-84
123. Street A, Macdonald A, Crowder K, Harris M. 2004. The hepatitis C virus NS5A protein activates a phosphoinositide 3-kinase-dependent survival signaling cascade. J. Biol. Chem. 279:12232-41
124. Street A, Macdonald A, McCormick C, Harris M. 2005. Hepatitis C virus NS5A-mediated activation of phosphoinositide 3-kinase results in stabilization of cellular β-catenin and stimulation of β-cateninresponsive transcription. J. Virol. 79:5006-16
125. Gavert N, Ben-Ze'ev A. 2007. β-Catenin signaling in biological control and cancer. J. Cell. Biochem. 102:820-28
126. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, et al. 1998. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. PNAS 95:8847-51
127. Choi SH, Hwang SB. 2006. Modulation of the transforming growth factor-βsignal transduction pathway by hepatitis C virus nonstructural 5A protein. J. Biol. Chem. 281:7468-78
128. Wakefield JG, Bonaccorsi S, Gatti M. 2001. The Drosophila protein Asp is involved in microtubule organization during spindle formation and cytokinesis. J. Cell Biol. 153:637-48
129. Wu SC, Chang SC, WuHY, Liao PJ, Chang MF. 2008. Hepatitis C virusNS5A protein down-regulates the expression of spindle gene Aspm through PKR-p38 signaling pathway. J. Biol. Chem. 283:29396-404
130. Tardif KD, Mori K, Siddiqui A. 2002. Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J. Virol. 76:7453-59
131. Lefkowitch JH, Schiff ER, Davis GL, Perrillo RP, Lindsay K, et al. 1993. Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group. Gastroenterology 104:595-603
132. Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, et al. 1997. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J. Gen. Virol. 78(Pt. 7):1527-31
133. Bach N, Thung SN, Schaffner F. 1992. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis. Hepatology 15:572-77
134. Barba G, Harper F, Harada T, Kohara M, Goulinet S, et al. 1997. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. PNAS 94:1200-5
135. Koike K, Moriya K. 2005. Metabolic aspects of hepatitis C viral infection: steatohepatitis resembling but distinct from NASH. J. Gastroenterol. 40:329-36
136. Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, et al. 2004. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 126:840-48
137. Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, et al. 2002. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 16:185-94
138. Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, et al. 2002. Interaction of hepatitis C virus core protein with retinoid X receptor αmodulates its transcriptional activity. Hepatology 35:937-46
139. Koike K. 2009. Steatosis, liver injury, and hepatocarcinogenesis in hepatitis C viral infection. J. Gastroenterol. 44(Suppl. 19):82-88
140. Okuda M, Li K, Beard MR, Showalter LA, Scholle F, et al. 2002. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitisCvirus core protein. Gastroenterology 122:366-75
141. Bataller R, Paik YH, Lindquist JN, Lemasters JJ, Brenner DA. 2004. Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 126:529-40
142. Schuppan D, Krebs A, Bauer M, Hahn EG. 2003. Hepatitis C and liver fibrosis. Cell Death Differ. 10(Suppl. 1):S59-67
143. Mazzocca A, Sciammetta SC, Carloni V, Cosmi L, Annunziato F, et al. 2005. Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells. J. Biol. Chem. 280:11329-39
144. Marra F. 1999. Hepatic stellate cells and the regulation of liver inflammation. J. Hepatol. 31:1120-30
145. Lalor PF, Shields P, Grant A, Adams DH. 2002. Recruitment of lymphocytes to the human liver. Immunol. Cell Biol. 80:52-64
146. Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, et al. 2007. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 46:48-57
147. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. 2005. Laminin-5 with transforming growth factor-β1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129:1375-83
148. Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA, et al. 2002. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359:397-401
149. Abu Dayyeh BK, Yang M, Fuchs BC, Karl DL, Yamada S, et al. 2011. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology 141:141-49
150. Yang Z, Wu Q, Shi Y, Nie Y, Wu K, Fan D. 2012. Epidermal growth factor 61A>G polymorphism is associated with risk of hepatocellular carcinoma: a meta-Analysis. Genet. Test. Mol. Biomark. 16:1086-91
151. Zhong JH, You XM, Gong WF, Ma L, Zhang Y, et al. 2012. Epidermal growth factor gene polymorphism and risk of hepatocellular carcinoma: a meta-Analysis. PLOS ONE 7:e32159
152. Trepo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E, et al. 2011. Impact of patatin-like phospholipase-3 (rs738409C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 54:60-69
153. Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, et al. 2011. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 53:791-99
154. Corradini SG, Burza MA, Molinaro A, Romeo S. 2011. Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma. Hepatology 53:1776; author reply 1777
155. Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, et al. 2014. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-Analysis. Am. J. Gastroenterol. 109:325-34
156. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, et al. 2011. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat. Genet. 43:455-58
157. Miki D, Ochi H, Hayes CN, Aikata H, Chayama K. 2012. Hepatocellular carcinoma: towards personalized medicine. Cancer Sci. 103:846-50
158. Lange CM, Bibert S, Dufour JF, Cellerai C, Cerny A, et al. 2013. Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-Associated hepatocellular carcinoma. J. Hepatol. 59:504-9
159. Llovet JM, Chen Y, Wurmbach E, Roayaie S, Fiel MI, et al. 2006. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 131:1758-67
160. Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, et al. 2007. Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45:938-47
161. Hoshida Y, Villanueva A, Sangiovanni A, Sole M, HurC, et al. 2013. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 144:1024-30
162. Ambros V. 2004. The functions of animal microRNAs. Nature 431:350-55
163. Ji J, Shi J, Budhu A, Yu Z, Forgues M, et al. 2009. MicroRNA expression, survival, and response to interferon in liver cancer. N. Engl. J. Med. 361:1437-47
164. Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, et al. 2008. MicroRNA gene expression profile of hepatitis C virus-Associated hepatocellular carcinoma. Hepatology 47:1223-32
165. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. 2005. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309:1577-81
166. Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, et al. 2007. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 67:6092-99
167. Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, et al. 2006. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J. Cell. Biochem. 99:671-78
168. Banaudha K, Kaliszewski M, Korolnek T, Florea L, Yeung ML, et al. 2011. MicroRNA silencing of tumor suppressorDLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes. Hepatology 53:53-61
169. Harder J, Opitz OG, Brabender J, Olschewski M, Blum HE, et al. 2008. Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver. Int. J. Cancer 122:2800-4
170. Lim SO, Gu JM, Kim MS, Kim HS, Park YN, et al. 2008. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology 135:2128-40.e8
171. Matsuda Y, Ichida T, Matsuzawa J, Sugimura K, Asakura H. 1999. p16INK4 is inactivated by extensive CpG methylation in human hepatocellular carcinoma. Gastroenterology 116:394-400
172. Revill K, Wang T, Lachenmayer A, Kojima K, Harrington A, et al. 2013. Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma. Gastroenterology 145:1424-35.e25
173. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. 2008. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 134:1752-63
174. Davila JA, Duan Z, McGlynn KA, El-Serag HB. 2012. Utilization and outcomes of palliative therapy for hepatocellular carcinoma: a population-based study in the United States. J. Clin. Gastroenterol. 46:71-77
175. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. 2008. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther. 7:3129-40
176. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. 2013. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: ameta-Analysis of observational studies. Ann. Intern. Med. 158:329-37
177. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, et al. 2012. Association between sustained virological response and all-cause mortality among patients with chronic hepatitisCand advanced hepatic fibrosis. JAMA 308:2584-93
178. Manns MP, McCone J Jr., Davis MN, Rossaro L, Schiff E, et al. 2014. Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials. Liver Int. 34:707-19
179. Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, et al. 2010. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376:705-16
180. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, et al. 2011. Telaprevir for previously untreated chronic hepatitis C virus infection. N. Engl. J. Med. 364:2405-16
181. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, et al. 2011. Response-guided telaprevir combination treatment for hepatitis C virus infection. N. Engl. J. Med. 365:1014-24
182. McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, et al. 2010. Telaprevir for previously treated chronic HCV infection. N. Engl. J. Med. 362:1292-303
183. Lawitz E, Gane EJ. 2013. Sofosbuvir for previously untreated chronic hepatitis C infection. N. Engl. J. Med. 369:678-79
184. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, et al. 2013. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N. Engl. J. Med. 368:1867-77
185. Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, et al. 2014. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N. Engl. J. Med. 370:1993-2001
186. Jacobson IM, Dore GJ, Foster GR, Fried MW, RaduM, et al. 2014. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 384:403-13
187. Manns M, Marcellin P, Poordad F, deAraujo ES, Buti M, et al. 2014. Simeprevirwith pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 384:414-26
188. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, et al. 2014. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in nonresponders to pegylated interferon and ribavirin and treatment-naive patients: theCOSMOSrandomised study. Lancet. In press. doi: 10.1016/S0140-6736(14)61036-9
189. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, et al. 2014. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N. Engl. J. Med. 370:1879-88
190. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, et al. 2014. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N. Engl. J. Med. 370:1483-93
191. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, et al. 2014. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N. Engl. J. Med. 370:1889-98
192. Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, et al. 2014. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N. Engl. J. Med. 370:1973-82
193. Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, et al. 2014. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N. Engl. J. Med. 370:1604-14
194. Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, et al. 2014. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N. Engl. J. Med. 370:1983-92
195. Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, et al. 2014. Treatment of HCV with ABT-450/rombitasvir and dasabuvir with ribavirin. N. Engl. J. Med. 370:1594-603