Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer.
The development of hepatocellular carcinoma (HCC) in persons who are persistently infected with hepatitis C virus (HCV) is a growing problem worldwide. Current antiviral therapies are not effective in many patients with chronic hepatitis C, and a greater understanding of the factors leading to progression of HCC will be necessary to design novel approaches to prevention of HCV-associated HCC. The lack of a small animal model of chronic HCV infection has hampered understanding of these factors. As HCV is an RNA virus with little potential for integration of its genetic material into the host genome, the mechanisms underlying HCV promotion of cancer are likely to differ from other models of viral carcinogenesis. In patients persistently infected with HCV, chronic inflammation resulting from immune responses against infected hepatocytes is associated with progressive fibrosis and cirrhosis. Cirrhosis is an important risk factor for HCC independent of HCV infection, and a majority of HCV-associated HCC arises in the setting of cirrhosis. However, a significant minority arises in the absence of cirrhosis, indicating that cirrhosis is not a prerequisite for cancer. Other lines of evidence suggest that direct, virus-specific mechanisms may be involved. Transgenic mice expressing HCV proteins develop cancer in the absence of inflammation or immune recognition of the transgene. In vitro studies have revealed multiple interactions of HCV-encoded proteins with cell cycle regulators and tumor suppressor proteins, raising the possibility that HCV can disrupt control of cellular proliferation, or impair the cell's response to DNA damage. A combination of virus-specific, host genetic, environmental and immune-related factors are likely to determine the progression to HCC in patients who are chronically infected with HCV. Here, we summarize current knowledge of the virus-specific mechanisms that may contribute to HCV-associated HCC.
Lineberger Comprehensive Cancer Center, Center for Translational Research, Inflammatory Diseases Institute, and the Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292, USA.
D R
DR
McGivern
S M
SM
Lemon
D000818:Animals; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D006526:Hepatitis C / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology*
Cancer Sci. 2003 Aug;94(8):679-85
12901792
Virology. 2004 Nov 10;329(1):53-67
15476874
Oncogene. 2006 Aug 28;25(38):5210-9
16936739
J Gastroenterol. 2009;44 Suppl 19:102-7
19148802
Cell. 1988 Jul 15;54(2):275-83
2839300
J Virol. 2008 Nov;82(21):10375-85
18768989
Hepatology. 2000 Aug;32(2):200-4
10915724
Mol Cell Biol. 2008 Nov;28(21):6557-67
18779317
Biochem Pharmacol. 2002 Nov 15;64(10):1425-30
12417255
Liver. 1999 Jun;19(3):212-9
10395041
Oncogene. 2010 Sep 9;29(36):4989-5005
20639898
Virology. 1997 Apr 14;230(2):217-27
9143277
Cancer Res. 2009 Jul 15;69(14):5761-7
19584283
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5533-8
10318918
Gastroenterology. 2009 Jan;136(1):138-48
18848939
J Virol. 2001 Feb;75(3):1401-7
11152513
Curr Opin Pharmacol. 2009 Oct;9(5):537-44
19762279
J Exp Med. 1998 Jul 20;188(2):341-50
9670046
J Viral Hepat. 2005 Nov;12(6):635-41
16255765
J Virol. 2005 Apr;79(8):5006-16
15795286
Gastroenterology. 2009 Oct;137(4):1448-58
19632233
J Virol. 2005 Feb;79(3):1569-80
15650183
Mod Pathol. 2010 Feb;23(2):276-83
19935643
EMBO J. 2005 Feb 9;24(3):543-53
15660129
Trans Am Clin Climatol Assoc. 2009;120:361-8
19768189
World J Gastroenterol. 2009 Feb 7;15(5):578-82
19195059
J Virol. 1999 Apr;73(4):2841-53
10074132
Nature. 2009 Jul 23;460(7254):529-33
19626115
J Biol Chem. 2004 Mar 26;279(13):12232-41
14709551
Hepatology. 2008 Sep;48(3):863-70
18752332
Oncogene. 2005 Sep 8;24(40):6119-32
16007207
Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9599-604
11481452
Gastroenterology. 2002 Feb;122(2):352-65
11832450
PLoS One. 2009;4(2):e4355
19190755
Eur J Immunol. 2010 Apr;40(4):940-8
20127681
Nature. 2005 Aug 18;436(7053):946-52
16107834
Int J Cancer. 2003 Sep 1;106(3):334-41
12845670
FEBS Lett. 2003 Dec 18;555(3):528-32
14675768
MMWR Morb Mortal Wkly Rep. 2010 May 7;59(17):517-20
20448528
Oncogene. 2008 Oct 20;27(48):6228-44
18931690
J Hepatol. 2006 Mar;44(3):441-3
16426700
Nature. 1988 Jul 14;334(6178):124-9
2968522
Virology. 2006 Apr 10;347(2):466-75
16427673
Oncology. 2001;60(4):346-54
11408803
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):264-9
20018759
J Pathol. 2009 Oct;219(2):253-62
19621337
Science. 1999 Jul 2;285(5424):110-3
10390360
J Virol. 2005 Nov;79(21):13594-605
16227280
Nature. 2005 Dec 1;438(7068):685-9
16258535
Oncogene. 2008 Jun 26;27(28):3912-22
18264132
J Gen Virol. 1998 Jun;79 ( Pt 6):1383-6
9634078
Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):232-6
7678339
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2992-7
15710891
J Virol. 1999 Aug;73(8):6506-16
10400746
Hepatology. 1997 Mar;25(3):719-27
9049225
Clin Liver Dis. 2003 Feb;7(1):149-61
12691464
Gut. 2006 Dec;55(12):1801-8
16581947
Science. 2005 Sep 2;309(5740):1577-81
16141076
J Immunol. 2005 Dec 15;175(12):8226-35
16339562
Virology. 2003 Dec 5;317(1):24-35
14675622
J Gen Virol. 2010 Jan;91(Pt 1):122-32
19793905
EMBO J. 2008 Aug 6;27(15):2147-57
18636090
Nature. 2004 Aug 12;430(7001):797-802
15306814
Cell Host Microbe. 2008 Jul 17;4(1):77-85
18621012
Hepatology. 2007 Sep;46(3):649-57
17654742
Nat Rev Cancer. 2002 Dec;2(12):910-7
12459729
Gastroenterology. 2004 Nov;127(5):1513-24
15521019
Nature. 2008 Jul 24;454(7203):523-7
18548002
Cell. 1991 Jun 14;65(6):1053-61
1828392
J Virol. 2004 Dec;78(24):13779-92
15564486
Cancer Res. 2006 Jul 1;66(13):6579-88
16818630
J Virol. 1998 May;72(5):3691-7
9557650
Cancer Res. 2001 Jun 1;61(11):4365-70
11389061
Gastroenterology. 2010 Feb;138(2):513-21, 521.e1-6
19861128
Oncology. 2002;62 Suppl 1:8-17
11868791
Biochim Biophys Acta. 2002 Oct 21;1592(2):193-204
12379483
Hepatology. 2008 Dec;48(6):1843-50
19003912
J Biol Chem. 2003 Apr 25;278(17):15272-8
12582166
Cancer Detect Prev. 2004;28(6):385-91
15582261
J Biol Chem. 2003 May 16;278(20):18256-64
12595532
J Gen Virol. 1995 Dec;76 ( Pt 12):3031-8
8847508
Virology. 2010 Mar 1;398(1):57-67
20006370
J Biol Chem. 2000 Nov 3;275(44):34122-30
10924497
Gene. 1998 Feb 27;208(2):331-6
9524287
J Biol Chem. 2005 Mar 25;280(12):11329-39
15611113
Oncogene. 2002 Jul 18;21(31):4801-11
12101418
RNA Biol. 2004 Jul;1(2):106-13
17179747
Nat Med. 2001 Aug;7(8):927-33
11479625
Carcinogenesis. 2009 Dec;30(12):2064-9
19917630
PLoS Pathog. 2009 Jan;5(1):e1000269
19148281
Nat Med. 1998 Sep;4(9):1065-7
9734402
Science. 1989 Feb 17;243(4893):934-7
2537532
Nat Genet. 2002 Aug;31(4):339-46
12149612
Nat Rev Microbiol. 2007 Jun;5(6):453-63
17487147
Gastroenterology. 2006 Jun;130(7):2087-98
16762631
J Virol. 2007 Dec;81(24):13922-6
17855521
Virology. 1999 May 10;257(2):330-40
10329544
Gastroenterology. 2004 Feb;126(2):529-40
14762790
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15584-9
12438687
J Biol Chem. 2003 Oct 17;278(42):40778-87
12909638
FEBS Lett. 1998 Nov 6;438(3):258-62
9827557
Biochem Biophys Res Commun. 2006 Feb 17;340(3):792-9
16380082
Best Pract Res Clin Gastroenterol. 2008;22(6):1137-51
19187872
J Gen Virol. 2006 Jun;87(Pt 6):1703-1713
16690937
J Hepatol. 2009 Nov;51(5):853-64
19726098
Hepatology. 2008 Apr;47(4):1223-32
18307259
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2310-5
16461899
Gut. 2010 Jan;59(1):88-97
19850960
Hepatology. 2009 Apr;49(4):1098-112
19173277
J Virol. 2009 Aug;83(15):7422-33
19458004
Cancer Res. 2007 Jul 1;67(13):6092-9
17616664
J Gen Virol. 2005 Aug;86(Pt 8):2185-2196
16033966
J Virol. 2009 Oct;83(19):9824-34
19625408
J Clin Oncol. 2009 Mar 20;27(9):1485-91
19224838
Science. 2010 Jan 8;327(5962):198-201
19965718
Hum Pathol. 1998 Nov;29(11):1279-84
9824107
Hepatology. 1997 Apr;25(4):1014-21
9096613
J Med Virol. 1999 Nov;59(3):281-9
10502257
Hepatology. 2010 Apr;51(4):1373-82
20131405
Hepatol Res. 2010 Mar;40(3):237-47
20394672
Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17717-22
16301520
J Virol. 2010 Jul;84(13):6615-25
20427538
Nat Med. 2005 Jul;11(7):791-6
15951748
Ann Intern Med. 2006 May 16;144(10):705-14
16702586
Genes Dev. 2000 Apr 1;14(7):804-16
10766737
J Gen Virol. 2010 Feb;91(Pt 2):373-81
19846673
Hepatology. 2000 Jun;31(6):1351-9
10827163
J Virol. 2009 Dec;83(23):12590-600
19793824
Liver Int. 2009 Jan;29 Suppl 1:74-81
19207969
Virology. 1999 Nov 10;264(1):134-41
10544138
PLoS One. 2009;4(4):e5025
19340302
Oncogene. 2009 Oct 8;28(40):3526-36
19617899
Virology. 2008 Jul 5;376(2):397-407
18455749
J Biol Chem. 2010 Jul 23;285(30):22741-7
20457596
J Cell Biochem. 2006 Oct 15;99(3):671-8
16924677
J Gen Virol. 1997 Jul;78 ( Pt 7):1527-31
9225025
J Virol. 2010 Jan;84(1):666-70
19846523
J Virol. 2004 May;78(10):5288-98
15113910
J Immunol. 2005 Feb 15;174(4):2160-6
15699147
J Gen Virol. 2004 Mar;85(Pt 3):721-729
14993658
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18159-64
16332962
PLoS Pathog. 2007 Sep 7;3(9):1335-47
17907805
J Biol Chem. 2005 Nov 11;280(45):37481-8
16150732
J Virol. 2008 Oct;82(19):9639-46
18667510
J Gen Virol. 1999 May;80 ( Pt 5):1179-1183
10355764
Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7431-6
20231459
Hepatology. 2002 May;35(5):1237-46
11981774
J Biol Chem. 2009 Nov 13;284(46):32015-27
19726678
Oncogene. 2004 Apr 1;23(14):2472-83
14968111
Nature. 2008 Apr 17;452(7189):896-9
18368051
Gastroenterology. 2002 Feb;122(2):366-75
11832451
EMBO J. 2008 Dec 17;27(24):3300-10
19020517
Virology. 2008 Jan 20;370(2):295-309
17931678
Am J Pathol. 2002 Feb;160(2):641-54
11839585
J Biol Chem. 1999 May 28;274(22):15751-6
10336476
Hepatology. 1996 Jun;23(6):1468-75
8675166
Science. 1998 Oct 2;282(5386):103-7
9756471
Neoplasia. 2002 Sep-Oct;4(5):380-7
12192596
Hepatology. 2005 Mar;41(3):660-7
15723444
Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1548-53
19171902
Proc Natl Acad Sci U S A. 1990 Mar;87(5):1973-7
2155427
Pharmacol Ther. 1998 Apr;78(1):29-46
9593328
Oncogene. 2008 Jan 24;27(5):700-14
17667941
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12884-9
17616579
J Virol. 2010 Jul;84(13):6810-24
20392846
J Gen Virol. 2001 Sep;82(Pt 9):2235-2241
11514734
Oncogene. 2006 Mar 30;25(14):1991-2003
16301996
Nature. 2005 Oct 20;437(7062):1167-72
16177806
PLoS Pathog. 2009 Feb;5(2):e1000291
19242562
Gut. 2000 Jul;47(1):131-6
10861275
J Gen Virol. 2006 Jul;87(Pt 7):1935-1945
16760395
Oncogene. 2004 Oct 14;23(47):7821-38
15334054
Hepatology. 2008 Apr;47(4):1136-49
18220274
Nature. 2005 Aug 18;436(7053):933-8
16107832