HCV-related transformation and new therapeutic strategies: An update

Current Cancer Therapy Reviews

Volumn 2, Issue 1, 2006, Pages 41-56

  Balsano, Clara ^a,b,c,d   Alisi, Anna ^b,c  

^a UNIVERSITY OF L'AQUILA   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

^c IRCCS SAN RAFFAELE PISANA   (Italy)

^d POLICLINICO UMBERTO I   (Italy)

Author keywords

Gene therapy; HCC; HCV; HCV related NHL; IFN; Treatment

Indexed keywords

ALCOHOL; ALPHA INTERFERON; ANGIOSTATIN; ANTIANDROGEN; ANTINEOPLASTIC AGENT; ANTIVIRUS AGENT; CELECOXIB; CISPLATIN; CORTICOSTEROID; CYCLOPHOSPHAMIDE; CYTOTOXIC AGENT; DOXORUBICIN; ENDOSTATIN; FLUDARABINE; FLUOROURACIL; FLUTAMIDE; GEFITINIB; IMMUNOMODULATING AGENT; INTERLEUKIN 12; LEUPRORELIN; PEGINTERFERON; RIBAVIRIN; RITUXIMAB; ROFECOXIB; SORAFENIB; TAMOXIFEN; THALIDOMIDE; THROMBOSPONDIN; UNINDEXED DRUG; VASCULOTROPIN ANTIBODY;

APOPTOSIS; B CELL LYMPHOMA; BONE MARROW SUPPRESSION; CANCER HORMONE THERAPY; CELL PROLIFERATION; CHEMOEMBOLIZATION; CLINICAL TRIAL; CRYOGLOBULINEMIA; CYTOMEGALOVIRUS INFECTION; DISEASE COURSE; DRUG FATALITY; DRUG MEGADOSE; DRUG POTENTIATION; FLAVIVIRUS; GENE TARGETING; GENE THERAPY; GENETIC CODE; HEPATITIS C; HEPATITIS C VIRUS; HERPES ZOSTER; HOMEOSTASIS; HUMAN; IMMUNE RESPONSE; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL CARCINOMA; LIVER TRANSPLANTATION; LYMPHOPROLIFERATIVE DISEASE; META ANALYSIS; NEUROTOXICITY; NONHODGKIN LYMPHOMA; NONHUMAN; OPPORTUNISTIC INFECTION; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN INTERACTION; RADIOFREQUENCY ABLATION; REVIEW; SIGNAL TRANSDUCTION; SYSTEMATIC REVIEW; TRANSGENIC MOUSE; VIROLOGY; VIRUS CELL TRANSFORMATION;

EID: 33746128414     PISSN: 15733947     EISSN: None     Source Type: Journal    
DOI: 10.2174/157339406775471830     Document Type: Review

References (203)

1. Benvegnù L, Gios M, Boccato S, Alberti A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 2004; 53: 744-749.
2. Kyle RA. The monoclonal gammopathies. Clin Chem 1994; 40: 2154-2161.
3. Ferri C, Caracciolo F, Zignego AL, et al. Hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Br J Haematol 1994; 88: 392-394.
4. Zignego AL, Ferri C, Giannelli F, et al. Prevalence of bcl-2 rearrangement in patients with hepatitis C virus-related mixed cryoglobulinemia with or without B-cell lymphomas. Ann Intern Med 2002; 137: 571-580.
5. Fiorilli M, Mecucci C, Farci P, Casato M. HCV-associated lymphomas. Rev Clin Exp Hematol 2003; 7: 406-423.
6. Choo Q-L, Kuo G, Weiner A J, el al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-62.
7. Major ME, Feinstone SM. The molecular virology of hepatitis C. Hepatology 1997; 25: 1527-1538.
8. Penin F, Dubuisson J, Rey FA, et al. Structural biology of hepatitis C virus. Hepatology 2004; 39: 5-19.
9. Barba G, Harper F, Harada T, et al. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci USA 1997; 94: 1200-1205.
10. Suzuki R, Matsuura Y, Suzuki T, et al. Nuclear localization of the truncated hepatitis C virus core protein with its hydrophobic C terminus deleted. J Gen Virol 1995; 76: 53-61.
11. Lai MM, Ware CF. Hepatitis C vinis core protein: possible roles in viral pathogenesis. Curr Top Microbiol Immunol 2000; 242: 117-134.
12. Erhardt A, Hassan M, Heintges T, Haussinges D. 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. Virology 2002; 292: 272-282.
13. Aoki H, Hayashi J, Moriyama M, Arakawa Y, Hino O. Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. J Virol 2000; 74: 1736-1741.
14. Hayashi J, Aoki H, Kajino K, Moriyama M, Arakawa Y, Hino O. 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. Hepatology 2000; 32: 958-961.
15. Giambartolomei S, Covone F, Levrero M, Balsano C. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 2001; 20: 2606-2610.
16. Tsuchihara K, Hijikata M, Fukuda K, Kuroki T, Yamamoto N, Shimotohno K. Hepatitis C virus core protein regulates cell growth and signal transduction pathway transmitting growth stimuli. Virology 1999; 258:100-107.
17. Ray RB, Lagging LM, Meyer K, Ray R. Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J Virol 1996; 70: 4438-4443.
18. Tsutsumi T, Suzuki T, Shimoike T, et al. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology 2002; 35: 937-946.
19. 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: 1065-1070.
20. Marusawa H, Hijikata M, Chiba T, Shimotohno K. Hepatitis C virus core protein inhibits Fas- and tumor necrosis factor alpha-mediated apoptosis via NF-kappaB activation. J Virol 1999; 73: 4713-4720.
21. Zhu N, Khoshnan A, Schneider R, et al. Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 1998; 72: 3691-3697.
22. Hahn CS, Cho YG, Kang BS, Lester IM, Hahn YS. The HCV core protein acts as a positive regulator of fas-mediated apoptosis in a human lymphoblastoid T cell line. Virology 2000; 276: 127-137.
23. Otsuka M, Kato N, Lan KH, et al. Hepatitis C virus core protein enhances p53 function through augmentation of DNA binding affinity and transcriptional ability. J Biol Chem 2000; 275: 34122-34130.
24. Alisi A, Giambartolomei S, Cupelli F, et al. Physical and functional interaction between HCV core protein and the different p73 isoforms. Oncogene 2003; 22: 2573-2580.
25. Di Como CJ, Urist MJ, Babayan I, et al. p63 expression profiles in human normal and tumor tissues. Clin Cancer Res 2002; 8: 494-501.
26. Akahoshi K, Sakazume S, Kosaki K, Ohashi H, Fukushima Y. EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma. Am J Med Genet 2003; 120: 370-373.
27. He Y, Katze MG. To interfere and to anti-interfere: the interplay between hepatitis C virus and interferon. Viral Immunol 2002; 15: 95-119.
28. Clemens MJ. Targets and mechanisms for the regulation of translation in malignant transformation. Oncogene 2004; 23: 3180-3188.
29. Delhem N, Sabile A, Gajardo R, et al. Activation of the interferon-inducible protein kinase PKR by hepatocellular carcinoma derived-hepatitis C vinis core protein. Oncogene 2001; 20: 5836-5845.
30. Alisi A, Mele R, Spaziani A, Tavolaro S, Palescandolo E, Balsano C. Thr 446 phosphorylation of PKR by HCV core protein deregulates G2/M phase in HCC cells. J Cell Physiol 2005; 205(1): 25-31.
31. Lerat H, Honda M, Beard MR, et al. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2002; 122: 352-365.
32. Matsuura Y, Koike K, Miyamura T. Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice. Hepatology 2003; 38: 820-828.
33. Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 2004; 126: 840-848.
34. Moriya K, Yotsuyanagi H, Shintani Y, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic; mice. J Gen Virol 1997; 78:1527-1531.
35. Moriya K, Nakagawa K, Santa T, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001; 61: 4365-4370.
36. Koike K, Moriya K, Ishibashi K, et al. Expression of hepatitis C virus envelope proteins in transgenic mice. J Gen Virol 1995; 76: 3031-3038.
37. Koike K, Moriya K, Ishibashi K, et al. Sialadenitis histologically resembling Sjogren syndrome in mice transgenic for hepatitis C virus envelope genes. Proc Natl Acad Sci USA 1997; 94: 233-236.
38. Machida K, Tsukiyama-Kohara K, Seike E, et al. Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins. J Biol Chem 2001; 276: 12140-12146.
39. Takaku S, Nakagawa Y, Shimizu M, et al. Induction of hepatic injury by hepatitis C virus-specific CD8 murine cytotoxic T lymphocytes in transgenic mice expressing the viral structural genes. Biochem Biophys Res Commun 2003; 301:330-337.
40. Ishikawa T, Shibuya K, Yasui K, Mitamura K, Ueda S. Expression of hepatitis C virus core protein associated with malignant lymphoma in transgenic mice. Comp Immunol Microbiol Infect Dis 2003; 26:115-124.
41. Okuda M, Li K, Beard MR, et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 2002; 122: 366-375.
42. Flint M, McKeating JA. The role of the hepatitis C virus glycoproteins in infection. Rev Med Virol 2000; 10: 101-117.
43. Deleersnyder V, Pillez A, Wychowski C, et al. Formation of native hepatitis C virus glycoprotein protein complexes. J Virol 1997; 71: 697-704.
44. Rosa D, Campagnoli S, Moretto C, et al. A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells. Proc Natl Acad Sci USA 1996; 93: 1759-1763.
45. Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81. Science 1998; 282: 938-941.
46. Agnello V, Abel G, Elfahal M, Knight GB, Zhang X. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA 1999; 98: 12766-12771.
47. Scarselli E, Ansuini H, Cerino R, et al. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 2002; 21: 5017-5025.
48. Gardner JP, Durso RJ, Arrigale RR, et al. L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C vinis. Proc Natl Acad Sci USA 2003; 100: 4498-4503.
49. Wack A, Soldaini E, Tseng C, Nuti S, Klimpel G, Abrignani S. Binding of the hepatitis C virus envelope protein E2 to CD81 provides a co-stimulatory signal for human T cells. Eur J Immunol 2001; 31:166-175.
50. Zhao LJ, Wang L, Ren H, et al. Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors. Exp Cell Res 2005; 305: 23-32.
51. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 1999; 285: 107-110.
52. Taylor DR, Tian B, Romano PR, Hinnebusch AG, Lai MM, Mathews MB. Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain. J Virol 2001; 75: 1265-1273.
53. Francois C, Duverlie G, Rebouillat D, et al. Expression of hepatitis C virus proteins interferes with the anti-viral action of interferon independently of PKR-mediated control of protein synthesis. J Virol 2000; 74: 5587-5596.
54. Quinn ER, Chan CH, Hadlock KG, Foung SK, Flint M, Levy S. The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis. Blood 2001; 98: 3745-3749.
55. Hijikata M, Mizushima H, Akagi T, et al. Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol 1993; 67: 4665-4675.
56. Tai CL, Chi WK, Chen DS, Hwang LH. The helicase activity associated with hepatitis C virus nonstructural. protein 3 (NS3). J Virol 1996; 70: 8477-8484.
57. Ishido S, Muramatsu. S, Fujita T, el al. Wild-type, but not mutant type, p53 enhances nuclear accumulation of the NS3 protein of hepatitis C virus. Biochem Biophys Res Commun 1997; 230: 431-436.
58. Diepolder HM, Gerlach JT, Zachoval R, et al. Immunodominant CD4+ T cell epitope within nonstructural protein 3 in acute hepatitis C virus infection. J Virol 1997; 71: 6011-6019.
59. Borowski P, Oehlmann K., Heiland M, Laufs R. Nonstructural protein 3 of hepatitis C virus blocks the distribution of the free catalytic subunit of cyclic AMP-dependent protein kinase. J Virol 1997; 71: 2838-2843.
60. Lin W, Choe WH, Hiasa Y, et al. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology 2005; 128:1034-1041.
61. Feng D, Cheng R, Ouyang X, Zheng H, Tsutomu T. Hepatitis C virus nonstructural protein NS (3) and telomerase activity. Chin Med J 2002; 115:597-602.
62. Sakamuro D, Furukawa T, Takegami T. Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J Virol 1995; 69: 3893-3896.
63. He QQ, Cheng RX, Sun Y, Feng DY, Chen ZC, Zheng H. Hepatocyte transformation and tumor development induced by hepatitis C virus NS3 c-terminal deletedprotein. World J Gastroenterol 2003; 9: 474-478.
64. Kwun HJ, Jung EY, Ahn JY, Lee MN, Jang KL. P53-dependent transcriptional repression of p2l(wafl) by hepatitis C virus NS3. J Gen Virol 2001; 82: 2235-2241.
65. Feng DY, Sun Y, Cheng R-X, Ouyang X-M, Zheng H. Effect of hepatitis C virus nonstructural protein NS3 on proliferation and MAPK phosphorylation of normal hepatocyte line. World J Gastroenterol 2005; 11: 2157-2161.
66. Failla C, Tomei L, De Francesco R. Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins. J Virol 1994; 68: 3753-3760.
67. Li K, Foy E, Ferreon JC, Nakamura M, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci USA 2005; 102:2992-2997.
68. Hugle T, Fehrmann F, Bieck E, et al. The hepatitis C virus nonstructural protein 4B is an integral endoplasmic reticulum membrane protein. Virology 2001; 284: 70-81.
69. Park JS, Yang JM, Min MK. Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene. Biochem Biophys Res Commun 2000; 267: 581-587.
70. Kaneko T, Tanji Y, Satoh S, et al. Production of two phosphoproteins from the NS5A region of the hepatitis C viral genome. Biochem Biophys Res Commun 1994; 205: 320-326
71. Blight KJ, Kolykhalov AA, Rice CM. Efficient initiation of HCV RNA replication in cell culture. Science 2000; 290: 1972-1974.
72. Lohmann V, Korner F, Dobierzewska A, Bartenschlager R. Mutations in hepatitis C virus RNAs conferring cell culture adaptation. J Virol 2001; 75: 1437-1449.
73. Ghosh AK, Majumder M, Steele R, Meyer K, Ray R, Ray RB. Hepatitis C virus NS5A protein protects against. TNF-alpha mediated apoptotic cell death. Virus Res 2000; 67: 173-178.
74. Majumder M, Ghosh AK, Steele R, et al. Hepatitis C virus NS5A protein impairs TNF-mediated hepatic apoptosis, but not by an anti-fas antibody, in transgenic mice. Virology 2002; 294: 94-105.
75. Lan KH, Shen MI, Hwang SJ, et al. HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis. Oncogene 2002; 21: 4801-4811.
76. Reed KE, Gorbalenya AE, Rice CM. The NS5A/NS5 proteins of viruses from three genera of the family flaviviridae are phosphorylated by associated serine/threonine kinases. J Virol 1998; 72: 6199-6206.
77. Tan SL, Nakao H, He Y, et al. NS5A, a nonstructural protein of hepatitis C virus, binds growth factor receptor-bound protein 2 adaptor protein in a Src homology 3 domain/ligand-dependent manner and perturbs mitogenic signaling. Proc Natl Acad Sci USA 1999; 96: 5533-5538.
78. Majumder M, Ghosh AK, Steele R, Ray R. Hepatitis C virus NS5A physically associates with p53 and regulates p2l/wafl gene expression in a p53-dependent manner. J Virol 2001; 75: 1401-1407.
79. Gong GZ, Jiang YF, He Y, Lai LY, Zhu YH, Su XS. HCV NS5A abrogates p53 protein function by interfering with p53-DNA binding. World J Gastroenterol 2004; 10: 2223-2227.
80. Ghosh AK, Majumder M, Steele R, et al. Hepatitis C virus NS5A protein modulates transcription through a novel cellular transcription factor SRCAP. J Biol Chem 2000; 275: 7184-7188.
81. Gong G, Waris G, Tanveer R, Siddiqui A. Human hepatitis C virus NS5A protein alters intracellular calcium level, induces oxidative stress, and activates STAT-3 and NF-kB. Proc Natl Aced Sci U S A 2001; 98: 9599-9604.
82. Ghosh AK, Steele R, Meyer K, Ray R, Ray RB. Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. J Gen Virol 1999; 80:1179-1183.
83. Arima N, Kao CY, Licht T, Padmanabhan R, Sasaguri Y, Padmanabhan R. Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A. J Biol Chem 2001; 276: 12675-12684.
84. Tan SL, Katze MG. How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A. Virology 2001; 284: 1-12.
85. Gale M Jr, Blakely CM, Kwieciszewski B, et al. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 1998; 18: 5208-5218.
86. Taguchi T, Nagano-Fujii M, Akutsu M, et al. Hepatitis C virus NS5A protein interacts with 2',5'-oligoadenylate synthetase and inhibits anti-viral activity of IFN in an IFN sensitivity-determining region-independent manner. J Gen Virol 2004; 85: 959-969.
87. Behrens SE, Tomei L, De Francesco R. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J 1996; 15: 12-22.
88. Yamashita T, Kaneko S, Shirota Y, et al. RNA-dependent RNA polymerase activity of the soluble recombinant hepatitis C virus NS5B protein truncated at the C-terminal region. J Biol Chem 1998; 273: 15479-15486.
89. Dimitrova. M, Imbert I, Kieny MP, Schuster C. Protein-protein interactions between Hepatitis C virus nonstructural proteins. J. Virol 2003; 77: 5401-5414.
90. Piccininni S, Varaklioti A, Nardelli M, Dave B, Raney KD, McCarthy JEG. Modulation of the hepatitis C virus RNA-dependent RNA polymerase activity by the non-structural (NS) 3 helicase and the NS4B membrane protein. J Biol Chem 2002; 277: 45670-45679.
91. You S, Stump DD, Branch A D, Rice CM. A cis-acting replication element in the sequence encoding the NS5B RNA-dependent RNA polymerase is required for hepatitis C virus RNA replication. J Virol 2004; 78: 1352-1366.
92. Hirano M, Kaneko S, Yamashita T, et al. Direct interaction between nucleolin and hepatitis C virus NS5B. J Biol Chem 2003; 278: 5109-5115.
93. Kyono K, Miyashiro M, Taguchi I. Human eukaryotic initiation factor 4AII associates with hepatitis C virus NS5B protein in vitro. Biochem. Biophys Res Commun 2002; 292: 659-666.
94. Llovet JM, Burroughs A, Bruix J. Hepatocellular Carcinoma. Lancet 2003; 362: 1907-1917.
95. Yoo HY, Patt CH, Geschwind JF, et al. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 2003; 21: 4329-4335.
96. Colombo M. Treatment of hepatocellular carcinoma. Anti-viral Res 2001; 52: 209-215.
97. Finkelstein SD, Marsh W, Demetris AJ, et al. Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma. Hepatology 2003; 37: 871-879.
98. Iwatsuki S, Dvorchik I, Marsh JW, et al. Liver transplantation for hepatocellular carcinoma: a proposal of a prognostic scoring system. J Am Coll Surg 2000; 191: 389-394.
99. Jeng KS, Sheen IS, Wang YC, et al. Prognostic significance of preoperative circulating vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma: a prospective study. World J Gastroenterol 2004; 10: 643-648.
100. Poon RT, Chung KK, Cheung ST, et al. Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma. Clin Cancer Res 2004; 10: 4150-4157.
101. Kim JW, Ye Q, Forgues M, et al. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology 2004; 39: 518-527.
102. Prieto M, Berenguer M, Rayon JM, et al. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology 1999; 29: 250-256.
103. Poon RT, Fan ST, Lo CM, et al. Improving survival results after resection of hepatocellular carcinoma: A prospective study of 377 patients over 10 years. Ann Surg 2001; 234: 63-70.
104. Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003; 138:299-306.
105. Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine-131-labelled Lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999; 353: 797-801.
106. Wu CC, Ho YZ, Ho WL, Wu TC, Liu TJ, P'eng FK. Preoperative transcatheter arterial chemoembolization for resectable large hepatocellular carcinoma: a reappraisal. Br J Surg 1995; 82: 122-126.
107. Vilana R, Bruix J, Bru C, et al: Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatoceltular carcinoma. Hepatology 1992; 16: 353-357.
108. Llovet JM, Bruix J. Systemic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429-442.
109. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002; 224: 47-54.
110. Yeo W, Zee B, Leung WT, et al. A phase II study of doxorubicin (A) versus cisplatin (P)/interferon-2b (I)/doxorubicin (A)/fluorouracil (F) combination chemotherapy (PIAF) for inoperable hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 2004; 23: 4026-4032.
111. Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002; 359: 1734-1739.
112. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial Lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164-1171.
113. Nowak AK, Stockler MR, Chow PK, Findlay M. Use of tamoxifen in advanced-stage hepatocellular carcinoma. A systematic review. Cancer 2005; 103: 1408-1414.
114. CLIP Group (Cancer of the Liver Italian Programme): Tamoxifen in treatment of hepatocellular carcinoma: A randomized controlled trial. Lancet 1998; 352: 17-20.
115. Tan CK, Chow PK, Findlay M, et al. Use of tamoxifen in hepatocellular carcinoma: A review and paradigm shift. J Gastroenterol Hepatol 2000; 15: 725-729.
116. Perrone F, Gallo C, Daniele B, et al: Tamoxifen in the treatment of hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre randomised controlled trial. Curr Pharm 2002; 8: 1013-1019.
117. Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: A randomised controlled study. Gut 1998; 42: 442-447.
118. Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire. Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology 2004; 40: 1361-1369.
119. Mele A, Pulsioni A, Bianco E, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood 2003; 102: 996-999.
120. Zignego AL, Brechot C. Extrahepatic manifestations of HCV infection: facts and controversies. J Hepatol 1999; 31: 369-376.
121. Pozzato G, Mazzaro C, Santini G, Burrone O. Hepatitis C virus and non-Hodgkin's lymphoma. Leuk Lymph 1996; 22: 53-60.
122. Musto P. Hepatitis C virus infection and B-cell non-Hodgkin's lymphoma: more than a simple association. Clin Lymphoma 2002; 3: 150-160.
123. Amiel A, Kitay-Cohen Y, Fejgin MD, Lishner M. Replication status as a marker for predisposition for lymphoma in patients with chronic hepatitis C with and without cryoglobulinemia. Exp Hematol 2000; 28: 156-160.
124. Zignego AL, Ferri C, Giannini C, et al. Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia. Ann Intern Med 1996; 124: 31-34.
125. Ferri C, La Civita L, Zignego AL, Pasero G. Viruses and cancers: possible role of hepatitis C virus. Eur J Clin Invest 1997; 27: 711-718.
126. Dammacco F, Sansonno D, Piccoli C, Racanelli V, D'Amore FP, Lauletta G. The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and overt B-cell malignancy. Semin Liver Dis 2000; 20: 143-157.
127. Ferri C, Marzo E, Longombardo G, et al. Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover controlled trial. Blood 1993; 81: 1132-1136.
128. Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994; 330: 751-756.
129. Calleja JL, Albillos A, Moreno-Otero R, et al. Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinemia. Aliment Pharmacol Ther 1999; 13: 1179-1186.
130. Kryczka W, Kisiel E. Hematologic syndromes in hepatitis C virus infection. Przegl Lek 2000; 57: 672-675.
131. Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy. Cancer 1996; 77: 2604-2613.
132. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. New Engl. J Med 1992; 327: 1490-1495.
133. Dammacco F, Sansonno D, Han JH, et al. Natural interferon alpha versus its combination with 6-methyl-prednisolone in the therapy of type II mixed cryoglobulinemia: a longterm, randomized, controlled study. Blood 1994; 84: 3336-3343.
134. Giannelli F, Moscarella S, Giannini C, et al. Effect of anti-viral treatment in patients with chronic HCV infection and t(14;18) translocation. Blood 2003; 102: 1196-1201.
135. Zignego AL, Giannelli F, Marrocchi ME, et al. T(14;18) translocation in chronic hepatitis C virus infection. Hepatology 2000; 31: 474-479.
136. Kitay-Cohen Y, Amiel A, Hilzenrat N, et al. Bc1-2 rearrangement in patients with chronic hepatitis C associated with essential mixed cryoglobulinemia type II. Blood 2000; 96: 2910-2912.
137. Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a now entity? Blood 2005; 105: 74-76.
138. Arcaini L, Paulli M, Boveri E, et al. Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles. Cancer 2004; 100: 107-115.
139. Patriarca, F, Silvestri F, Fanin R, Zaja F, Sperotto A, Baccarani M. Long-lasting complete remission of hepatitis C virus (HCV) infection and HCV-associated immunocytoma with alpha interferon treatment. Br J Haematol 2001; 112: 370-372.
140. Caramaschi P, Biasi D, Carletto A, et al. MALT lymphomas of the salivary glands. Review of the literature apropos of a case in a patient with hepatitis C virus infection. Recenti Prog Med 1999; 90: 585-591.
141. Moccia F, Tognoni E, Boccaccio P. The relationship between splenic marginal zone B-cell lymphoma and chronic liver disease associated with hepatitis C virus infection. Ann Ital Med Int 1999; 14: 288-293.
142. Zuckerman E, Zuckerman T, Sahar D, et al. The effect of anti-viral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood 2001; 97:1555-1559.
143. Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003; 101: 3827-3834.
144. Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood 2003; 101: 3818-3826.
145. Peter HH, Weiner SM. Kinetics of hepatitis C (HCV) viremia and quasispecies during treatment of HCV associated cryoglobulinemia with pulse cyclophosphamide. Ann Rheum Dis 2002; 61: 838-841.
146. Rosenstock JL, Stern L, Sherman WH, Appel GB, Radhakrishman J. Fludarabine treatment of cryoglobulinemic glomerulonephritis. Am J Kidney Dis 2002; 40: 644-648.
147. Van der Kolk LE, Baars JW, Prins MH, van Oers MH. Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood 2002; 100: 2257-2259.
148. Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med 2001; 345:1000.
149. Bermudez A, Marco F, Conde E, Mazo E, Recio M, Zubizarreta A. Fatal visceral varicella- zoster infection following rituximab and chemotherapy treatment in a patient with follicular lymphoma. Haematologica 2000; 85: 894-895.
150. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randormised trial. Lancet 2001; 358: 958-965.
151. Okuda K. Hepatocellular carcinoma. J Hepatol 2000; 32: 225-237.
152. Sorokin P. New agents and future directions in biotherapy. Clin J Oncol Nurs 2002; 6: 19-24.
153. Tsai S-L. Interleukin-12 gene therapy for hepatocellular carcinoma: A dream comes true? J Gastroenterol Hepatol 2004; 19: 1097-1100.
154. Zogakis TG, Libutti SK. General aspects of anti-angiogenesis and cancer therapy. Expert Opin Biol Ther 2001; 1: 253-275.
155. Patt YZ, Hassan MM, Lozano RD, et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 2005; 103: 749-755.
156. Li L, Huang JL, Liu OC, et al. Endostatin gene therapy for liver cancer by a recombinant adenovirus delivery. World J Gastroenterol 2004; 10: 1867-1871.
157. Li PY, Lin JS, Feng ZH, et al. Combined gene therapy of endostatin and interleukin 12 with polyvinylpyrrolidone induces a potent antitumor effect on hepatoma. World J Gastroenterol 2004; 10: 2195-2200.
158. Kern MA, Schoneweiss MM, Sahi D, et al. Cyclooxygenase-2 inhibitors suppress the growth of human hepatocellular carcinoma implants in nude mice. Carcinogenesis 2004; 25: 1193-1199.
159. Huang DS, Shen KZ, Wei JF, Liang TB, Zheng SS, Xie HY. Specific COX-2 inhibitor NS398 induces apoptosis in human liver cancer cell line HepG2 through BCL-2. World J Gastroenterol 2005; 11: 204-207.
160. Malka D, Pacault V, De Baere T, Ducreux M, Boige V. Antitumoral Effect of Celecoxib in Hepatocellular Carcinoma. J Clin Oncol 2005; 23: 4805-4806.
161. Carr BI. Hepatic arterial 90Yttrium glass microspheres (Therasphere) for unresectable hepatocellular carcinoma: interim safety and survival data on 65 patients. Liver Transpl 2004; 10: S107-S110.
162. Lee JT, McCubrey JA. BAY-43-9006 Bayer/Onyx. Curr Opin Investig Drugs 2003; 4: 757-763
163. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005; 23: 965-972.
164. Schiffer E, Housset C, Cacheux W, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 2005; 41: 307-314.
165. Zhu BD, Yuan SJ, Zhao QC, Li X, Li Y, Lu QY. Antitumor effect of Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with cytotoxic agent on murine hepatocellular carcinoma. World J Gastroenterol 2005; 11: 1382-1386.
166. Carloni V, Vizzutti F, Pantaleo P. Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent. Clin Cancer Res 2005; 11: 4266-4274.
167. Slijkhuis WA, Stadheim L, Hassoun ZM, et al. Octreotide therapy for advanced hepatocellular carcinoma. J Clin Gastroenterol 2005; 39: 333-338.
168. Xu HY, Yang YL, Liu SM, Bi L, Chen SX. Effect of arsenic trioxide on human hepatocarcinoma in nude mice. World J Gastroenterol 2004; 10: 3677-3679.
169. Hitomi M, Yokoyama F, Kita, Y, et al. Antitumor effects of vitamins K1, K2 and K3 on hepatocellular carcinoma in vito and in vivo. Int J Oncol 2005; 26: 713-720.
170. Clerici C, Castellani D, Russo G, et al. Treatment with all-transretinoic acid plus tamoxifen and vitamin E in advanced hepatocellular carcinoma. Anticancer Res 2004; 24: 1255-1260.
171. Sakakima Y, Inoue S, Takeda S, Kaneko T, Nakao A. Factors in successful radiofrequency ablation therapy for malignant liver tumors. Hepatogastroenterology 2004; 51: 1761-1765.
172. Habu D, Shiomi S, Tamori A, et al. Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver. JAMA 2004; 292: 358-361.
173. Tuschl T, Borkhardt A. Small interfering RNAs: A revolutionary tool for the analysis of gene function and gene therapy. Mol Interv 2002; 2:158-167.
174. Stevenson M. Therapeutic Potential of RNA Interference. N Engl J Med 2004; 351: 1772-1777.
175. Wilson JA, Jayasena S, Khvorova A, et al. RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells. Proc Natl Acad Sci USA 2003; 100: 2783-2788
176. Wilson JA, Richardson CD. Hepatitis C virus replicons escape RNA interference induced by a short interfering RNA directed against the NS5b coding region. J Virol 2005; 79, 7050-8.
177. Li K, Lin SY, Brunicardi FC, Seu. P. Use of RNA interference to target cyclin E-overexpressing hepatocellular carcinoma. Cancer Res 2003; 63: 3593-3597.
178. Cheng S-Q, Wang W-L, Yan W, Li Q-L, Wang L, Wang W-Y. Knockdown of survivin gene expression by RNAi induces apoptosis in human hepatocellular carcinoma cell line SMMC-7721. World J Gastroenterol 2005; 11: 756-759.
179. Lin E, Nemunaitis J. Oncolytic viral therapies. Cancer Gene Ther 2004; 11: 643-664.
180. Pei Z, Chu L, Zou W, et al. An oncolytic adenoviral vector of Smac increases antitumor activity of TRAIL against HCC in human cells; and in mice. Hepatology 2004; 39: 1371-1381.
181. Wen J, Matsumoto K, Taniura N, Tomioka D, Nakamura T. Hepatic gene expression of NK4, an HGF-antagonistlangiogenesis inhibitor, suppresses liver metastasis and invasive growth of colon cancer in mice. Cancer Gene Ther 2004; 11: 419-430.
182. Irving J, Wang Z, Powell S, et al. Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrurn antitumor activity without liver toxicity. Cancer Gene Ther 2004; 11: 174-185.
183. Jakubczak JL, Ryan P, Gorziglia M, et al. An oncolytic adenovirus selective for retinoblastoma tumor suppressor protein pathway-defective tumors: dependence on EIA, the E2F-1 promoter, and viral replication for selectivity and efficacy. Cancer Res 2003; 63: 1490-1499.
184. Herraiz M, Beraza N, Solano A, et al. Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion. Hum Gene Ther 2003; 14: 463-472.
185. Bilbao R, Gerolami R, Bralet MP, et al. Transduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir therapy of hepatocellular carcinoma: the woodchuck animal model. Cancer Gene Ther 2000; 7: 657-662.
186. Qian C, Bilbao R, Bruna O, Prieto J. Induction of sensitivity to ganciclovir in human hepatocellular carcinoma cells by adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase. Hepatology 1995; 22: 118-123.
187. Qian C, Idoate M, Bilbao R, et al. Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. Hum Gene Ther 1997; 8: 349-358.
188. Sangro B, Qian C, Schmitz V, Prieto J. Gene therapy of hepatocellular carcinoma and gastrointestinal tumors. Ann NY Acad Sci 2002; 963: 6-12.
189. Qiao J, Doubrovin M, Sauter BV, et al. Tumor specific transcriptional targeting of suicide gene therapy. Gene Ther 2002; 9:168-175.
190. Lamarre D, Anderson PC, Bailey M, et al. An NS3 protease inhibitor with anti-viral effects in humans infected with hepatitis C virus. Nature 2003; 426: 186-189.
191. Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 2004; 127: 1347-1355.
192. Reiser M, Hinrichsen H, Benhamou Y, et al. Anti-viral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology 2005; 41: 832-835.
193. Lu L, Pilot-Matias TJ, Stewart KD, et al. Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vito. Antimicrob Agents Chemother 2004; 48: 2260-2266.
194. Lin C, Gates CA, Rao BG, et al. ℏ vito resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J Biol Chem 2004; 279: 17508-17514.
195. Tomei L, Altamura S, Bartholomew L, et al. Mechanism of action and anti-viral activity of benzimidazole-based allosteric inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. J Virol 2003; 77: 13225-13231.
196. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003; 21: 335-376.
197. O'Neill LA. TLRs: Professor Mechnikov, sit on your hat. Trends Immunol 2004; 25: 687-693.
198. Nevens F, Roskams T, Van Vlierberghe H, et al. A pilot study of therapeutic vaccination with envelope protein El in 35 patients with chronic hepatitis C. Hepatology 2003; 38: 1289-1296.
199. Grakoui A, Shoukry NH, Woollard DJ, et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 2003; 302: 659-662.
200. Murata K, Lechman M, Qiao M, Gunji T, Alter HJ, Liang TJ. Immunization with hepatitis C virus-like particles protects mice from recombinant hepatitis C virus-vaccinia infection. Proc Natl Acad Sci USA 2003; 100: 6753-6758.
201. Duenas-Carrera S, Vina A, Martinez R, et al. Immunization with a DNA vaccine encoding the hepatitis C virus structural antigens elicits specific immune response against the capsid and envelope proteins in rabbits and macaques irus. Biotechnol Appl Biochem 2004; 39: 249-255.
202. Pancholi P, Perkus M, Tricoche N, Liu Q, Prince AM. DNA immunization with hepatitis C virus (HCV) polycistronic genes or immunization by HCV DNA priming-recombinant canarypox virus boosting induces immune responses and protection from recombinant HCV-vaccinia virus infection in HLA-A2.1-transgenic mice. J Virol 2003; 77: 382-390.
203. Isaguliants MG, Petrakova NV, Mokhonov VV, et al. DNA immunization efficiently targets conserved functional domain of protease and ATPase/ helicase of nonstructural 3 protein (NS3) of human hepatitis C virus. Immunol Lett 2003; 88: 1-13.