Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis

Gastroenterology - Tập 132 - Trang 2557-2576 - 2007
Hashem B. El–Serag1, K. Lenhard Rudolph2
1Michael E. DeBakey Veterans Administration Medical Center and Baylor College of Medicine, Houston Center for Quality of Care and Utilization Studies, Houston, Texas
2Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany

Tài liệu tham khảo

Parkin, 2001, Global cancer statistics in the year 2000, Lancet Oncol, 2, 533, 10.1016/S1470-2045(01)00486-7 Parkin, 2002 Okuda, 2002, Cholangiocarcinoma: recent progress, J Gastroenterol Hepatol, 17, 1049, 10.1046/j.1440-1746.2002.02781.x McGlynn, 2001, International trends and patterns of primary liver cancer, Int J Cancer, 94, 290, 10.1002/ijc.1456 Chang, 1997, Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children, N Engl J Med, 336, 1855, 10.1056/NEJM199706263362602 Yu, 1995, Primary prevention of hepatocellular carcinoma, J Gastroenterol Hepatol, 10, 674, 10.1111/j.1440-1746.1995.tb01370.x Rudolph, 2000, Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery, Science, 287, 1253, 10.1126/science.287.5456.1253 Yu, 1993, Elevated serum testosterone levels and risk of hepatocellular carcinoma, Cancer Res, 53, 790 Yu, 2001, Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men, J Natl Cancer Inst, 93, 1644, 10.1093/jnci/93.21.1644 Yoshizawa, 2002, Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: projection to other countries in the foreseeable future, Oncology, 62, 8, 10.1159/000048270 Armstrong, 2000, The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States, Hepatology, 31, 777, 10.1002/hep.510310332 Wong, 2000, Estimating future hepatitis C morbidity, mortality, and costs in the United States, Am J Public Health, 90, 1562, 10.2105/AJPH.90.10.1562 El-Serag, 1999, Rising incidence of hepatocellular carcinoma in the United States, N Engl J Med, 340, 745, 10.1056/NEJM199903113401001 El-Serag, 2004, Hepatocellular carcinoma: recent trends in the United States, Gastroenterology, 127, S27, 10.1053/j.gastro.2004.09.013 El-Serag, 2003, The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update, Ann Intern Med, 139, 817, 10.7326/0003-4819-139-10-200311180-00009 Davila, 2004, Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study, Gastroenterology, 127, 1372, 10.1053/j.gastro.2004.07.020 El-Serag, 2000, Risk factors for the rising rates of primary liver cancer in the United States, Arch Intern Med, 160, 3227, 10.1001/archinte.160.21.3227 Hassan, 2002, Rising prevalence of hepatitis C virus infection among patients recently diagnosed with hepatocellular carcinoma in the United States, J Clin Gastroenterol, 35, 266, 10.1097/00004836-200209000-00013 Kulkarni, 2004, The impact of immigration on the increasing incidence of hepatocellular carcinoma in the United States, Aliment Pharmacol Ther, 20, 445, 10.1111/j.1365-2036.2004.02090.x McMahon, 1990, Hepatitis B-related sequelae, Arch Intern Med, 150, 1051, 10.1001/archinte.150.5.1051 Kao, 2002, Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection, J Clin Microbiol, 40, 1207, 10.1128/JCM.40.4.1207-1209.2002 Camma, 2001, Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach, J Hepatol, 34, 593, 10.1016/S0168-8278(01)00005-8 Torbenson, 2002, Occult hepatitis B, Lancet Infect Dis, 2, 479, 10.1016/S1473-3099(02)00345-6 Yuki, 2003, Long-term histologic and virologic outcomes of acute self-limited hepatitis B, Hepatology, 37, 1172, 10.1053/jhep.2003.50171 Beasley, 1988, Hepatitis B virus, Cancer, 61, 1942, 10.1002/1097-0142(19880515)61:10<1942::AID-CNCR2820611003>3.0.CO;2-J Kane, 2003, Global control of primary hepatocellular carcinoma with hepatitis B vaccine: the contributions of research in Taiwan, Cancer Epidemiol Biomarkers Prev, 12, 2 Goldstein, 2005, A mathematical model to estimate global hepatitis B disease burden and vaccination impact, Int J Epidemiol, 34, 1329, 10.1093/ije/dyi206 Ikeda, 1999, Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis, Hepatology, 29, 1124, 10.1002/hep.510290439 Bruno, 2001, Long-term beneficial effects in sustained responders to interferon-alfa therapy for chronic hepatitis C, J Hepatol, 34, 748, 10.1016/S0168-8278(01)00062-9 Donato, 2002, Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women, Am J Epidemiol, 155, 323, 10.1093/aje/155.4.323 Freeman, 2001, Estimating progression to cirrhosis in chronic hepatitis C virus infection, Hepatology, 34, 809, 10.1053/jhep.2001.27831 Cramp, 1999, HBV + HCV = HCC?, Gut, 45, 168, 10.1136/gut.45.2.168 Serfaty, 1998, Determinants of outcome of compensated hepatitis C virus-related cirrhosis, Hepatology, 27, 1435, 10.1002/hep.510270535 1998, Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study, Lancet, 351, 1535, 10.1016/S0140-6736(98)07236-5 Imai, 1998, Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C, Ann Intern Med, 129, 94, 10.7326/0003-4819-129-2-199807150-00005 Niederau, 1998, Prognosis of chronic hepatitis C: results of a large, prospective cohort study, Hepatology, 28, 1687, 10.1002/hep.510280632 Valla, 1999, Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment, Hepatology, 29, 1870, 10.1002/hep.510290616 Okanoue, 1999, Interferon therapy lowers the rate of progression to hepatocellular carcinoma in chronic hepatitis C but not significantly in an advanced stage: a retrospective study in 1148 patients, J Hepatol, 30, 653, 10.1016/S0168-8278(99)80196-2 1987, Overall evaluations of carcinogenicity an updating of IARC monographs, IARC Monographs, 83 Garner, 1972, Liver microsomal metabolism of aflatoxin B 1 to a reactive derivative toxic to Salmonella typhimurium TA 1530, Cancer Res, 32, 2058 Bressac, 1991, Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa, Nature, 350, 429, 10.1038/350429a0 Turner, 2002, The role of aflatoxins and hepatitis viruses in the etiopathogenesis of hepatocellular carcinoma: A basis for primary prevention in Guinea-Conakry, West Africa, J Gastroenterol Hepatol, 17, S441, 10.1046/j.1440-1746.17.s4.7.x Qian, 1994, A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China, Cancer Epidemiol Biomarkers Prev, 3, 3 Wolk, 2001, A prospective study of obesity and cancer risk (Sweden), Cancer Causes Control, 12, 13, 10.1023/A:1008995217664 Boffetta, 2003, Meta-analysis of studies of occupational exposure to vinyl chloride in relation to cancer mortality, Scand J Work Environ Health, 29, 220, 10.5271/sjweh.725 Marrero, 2002, NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States, Hepatology, 36, 1349, 10.1053/jhep.2002.36939 Bugianesi, 2002, Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma, Gastroenterology, 123, 134, 10.1053/gast.2002.34168 Regimbeau, 2004, Obesity and diabetes as a risk factor for hepatocellular carcinoma, Liver Transpl, 10, S69, 10.1002/lt.20033 Fiore, 1996, Liver steatosis and chronic hepatitis C: a spurious association?, Eur J Gastroenterol Hepatol, 8, 125, 10.1097/00042737-199602000-00006 Cotrim, 2000, Nonalcoholic steatohepatitis and hepatocellular carcinoma: natural history?, Am J Gastroenterol, 5, 3018, 10.1111/j.1572-0241.2000.03241.x Zen, 2001, Hepatocellular carcinoma arising in non-alcoholic steatohepatitis, Pathol Int, 51, 127, 10.1046/j.1440-1827.2001.01174.x Shimada, 2002, Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis, J Hepatol, 37, 154, 10.1016/S0168-8278(02)00099-5 Adams, 2005, The natural history of nonalcoholic fatty liver disease: a population-based cohort study, Gastroenterology, 129, 113, 10.1053/j.gastro.2005.04.014 Calle, 2003, Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults, N Engl J Med, 348, 1625, 10.1056/NEJMoa021423 Moller, 1994, Obesity and cancer risk: a Danish record-linkage study, Eur J Cancer, 30A, 344, 10.1016/0959-8049(94)90254-2 Ratziu, 2000, Liver fibrosis in overweight patients, Gastroenterology, 118, 1117, 10.1016/S0016-5085(00)70364-7 Ratziu, 2004, Fat, diabetes, and liver injury in chronic hepatitis C, Curr Gastroenterol Rep, 6, 22, 10.1007/s11894-004-0022-5 Adinolfi, 2001, Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity, Hepatology, 33, 1358, 10.1053/jhep.2001.24432 Hwang, 2001, Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation, J Gastroenterol Hepatol, 16, 190, 10.1046/j.1440-1746.2001.02407.x Poynard, 2003, Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C, Hepatology, 38, 75, 10.1053/jhep.2003.50267 Westin, 2002, Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients, J Hepatol, 37, 837, 10.1016/S0168-8278(02)00299-4 Wong, 1996, Fibrosis and other histological features in chronic hepatitis C virus infection: a statistical model, J Clin Pathol, 49, 465, 10.1136/jcp.49.6.465 Ong, 2001, Chronic hepatitis C and superimposed nonalcoholic fatty liver disease, Liver, 21, 266, 10.1034/j.1600-0676.2001.021004266.x Ohata, 2003, Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection, Cancer, 97, 3036, 10.1002/cncr.11427 Rubbia-Brandt, 2000, Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3, J Hepatol, 33, 106, 10.1016/S0168-8278(00)80166-X Bugianesi, 2004, Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver, Hepatology, 39, 179, 10.1002/hep.20023 El Serag, 2004, Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma, Gastroenterology, 126, 460, 10.1053/j.gastro.2003.10.065 Adami, 1996, Excess risk of primary liver cancer in patients with diabetes mellitus, J Natl Cancer Inst, 88, 1472, 10.1093/jnci/88.20.1472 Wideroff, 1997, Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark, J Natl Cancer Inst, 89, 1360, 10.1093/jnci/89.18.1360 El-Serag, 2006, The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence, Clin Gastroenterol Hepatol, 4, 369, 10.1016/j.cgh.2005.12.007 Evans, 2002, Eight-year follow-up of the 90,000-person Haimen City cohort: I, Cancer Epidemiol Biomarkers Prev, 11, 369 Tanaka, 1995, Risk factors for hepatocellular carcinoma among Japanese women, Cancer Causes Control, 6, 91, 10.1007/BF00052768 Yu, 2004, Environmental factors and risk for hepatocellular carcinoma, Gastroenterology, 127, S72, 10.1016/j.gastro.2004.09.018 De, 1996, p53 mutations in hepatocellular carcinoma related to oral contraceptive use, Carcinogenesis, 17, 145, 10.1093/carcin/17.1.145 Korula, 1991, Hepatocellular carcinoma coexisting with hepatic adenoma, West J Med, 155, 416 Rosenberg, 1991, The risk of liver neoplasia in relation to combined oral contraceptive use, Contraception, 43, 643, 10.1016/0010-7824(91)90007-3 Maheshwari S, Kramer J, El-Serag HB. The association between oral contracepatives and hepatocellular carcinoma: a meta-analysis. J Hepatol (In press). Cauza, 2003, Mutations of the HFE gene in patients with hepatocellular carcinoma, Am J Gastroenterol, 98, 442, 10.1111/j.1572-0241.2003.07222.x Willis, 2005, Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional study, BMC Gastroenterol, 5, 17, 10.1186/1471-230X-5-17 Blanc, 2000, Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular carcinoma developed in non-cirrhotic liver, J Hepatol, 32, 805, 10.1016/S0168-8278(00)80250-0 Fracanzani, 2005, Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma, Blood Cells Mol Dis, 35, 27, 10.1016/j.bcmd.2005.03.007 Boige, 2003, Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis, Gut, 52, 1178, 10.1136/gut.52.8.1178 Hellerbrand, 2003, HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence, Clin Gastroenterol Hepatol, 1, 279, 10.1016/S1542-3565(03)00132-0 Yu, 1995, Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma, Cancer Res, 55, 1301 Yu, 1999, Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection, Am J Epidemiol, 150, 367, 10.1093/oxfordjournals.aje.a010016 Talamini, 2006, Food groups and risk of hepatocellular carcinoma: A multicenter case-control study in Italy, Int J Cancer, 119, 2916, 10.1002/ijc.22267 Sauvaget, 2003, Vegetables and fruit intake and cancer mortality in the Hiroshima/Nagasaki Life Span Study, Br J Cancer, 88, 689, 10.1038/sj.bjc.6600775 Gallus, 2002, Does coffee protect against hepatocellular carcinoma?, Br J Cancer, 87, 956, 10.1038/sj.bjc.6600582 Gelatti, 2005, Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study, J Hepatol, 42, 528, 10.1016/j.jhep.2004.11.039 Tanaka, 2007, Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan, Cancer Sci, 98, 214, 10.1111/j.1349-7006.2006.00368.x Ohfuji, 2006, Coffee consumption and reduced risk of hepatocellular carcinoma among patients with chronic type C liver disease: A case-control study, Hepatol Res, 36, 201, 10.1016/j.hepres.2006.07.010 Montella, 2007, Coffee and tea consumption and risk of hepatocellular carcinoma in Italy, Int J Cancer, 120, 1555, 10.1002/ijc.22509 Shimazu, 2005, Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan, Int J Cancer, 116, 150, 10.1002/ijc.20989 Inoue, 2005, Influence of coffee drinking on subsequent risk of hepatocellular carcinoma: a prospective study in Japan, J Natl Cancer Inst, 97, 293, 10.1093/jnci/dji040 Kurozawa, 2005, Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan, Br J Cancer, 93, 607, 10.1038/sj.bjc.6602737 Pagliaro, 2002, Familial clustering of (mostly) HCV-related cirrhosis, J Hepatol, 37, 762, 10.1016/S0168-8278(02)00304-5 Abdelmalek, 2006, Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease 10, Clin Gastroenterol Hepatol, 4, 1162, 10.1016/j.cgh.2006.06.001 Yu, 2000, Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives, J Natl Cancer Inst, 92, 1159, 10.1093/jnci/92.14.1159 Yu, 2002, Increased risk for hepatitis B-related liver cirrhosis in relatives of patients with hepatocellular carcinoma in northern Taiwan, Int J Epidemiol, 31, 1008, 10.1093/ije/31.5.1008 Burton, 2005, Key concepts in genetic epidemiology, Lancet, 366, 941, 10.1016/S0140-6736(05)67322-9 Dawn, 2005, Genetic linkage studies, Lancet, 366, 1036, 10.1016/S0140-6736(05)67382-5 Cordell, 2005, Genetic association studies, Lancet, 366, 1121, 10.1016/S0140-6736(05)67424-7 Davey, 2005, Genetic epidemiology and public health: hope, hype, and future prospects, Lancet, 366, 1484, 10.1016/S0140-6736(05)67601-5 Hattersley, 2005, What makes a good genetic association study?, Lancet, 366, 1315, 10.1016/S0140-6736(05)67531-9 Hopper, 2005, Population-based family studies in genetic epidemiology, Lancet, 366, 1397, 10.1016/S0140-6736(05)67570-8 Khoury, 2000, Human genome epidemiologic reviews: the beginning of something HuGE, Am J Epidemiol, 151, 2, 10.1093/oxfordjournals.aje.a010117 Little, 2003, The human genome project is complete, Am J Epidemiol, 157, 667, 10.1093/aje/kwg048 White, 2007, The glutathione S-transferase variants as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis, Gastroenterology, 132, A179 Barbason, 1983, Promotion mechanism of phenobarbital and partial hepatectomy in DENA hepatocarcinogenesis cell kinetics effect, Br J Cancer, 47, 517, 10.1038/bjc.1983.82 Kawai, 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, 10.1053/jhep.2000.7298 Delhaye, 1996, Relationship between hepatocyte proliferative activity and liver functional reserve in human cirrhosis, Hepatology, 23, 1003, 10.1002/hep.510230510 Wege, 2003, In vitro expansion of human hepatocytes is restricted by telomere-dependent replicative aging, Cell Transplant, 12, 897, 10.3727/000000003771000138 Levy, 1992, Telomere end-replication problem and cell aging, J Mol Biol, 225, 951, 10.1016/0022-2836(92)90096-3 Wiemann, 2002, Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis, FASEB J, 16, 935, 10.1096/fj.01-0977com Wright, 1992, The two-stage mechanism controlling cellular senescence and immortalization, Exp Gerontol, 27, 383, 10.1016/0531-5565(92)90069-C d’Adda di Fagagna, 2003, A DNA damage checkpoint response in telomere-initiated senescence, Nature, 426, 194, 10.1038/nature02118 Smogorzewska, 2002, DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2, Curr Biol, 12, 1635, 10.1016/S0960-9822(02)01179-X Maser, 2007, DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse, Mol Cell Biol, 27, 2253, 10.1128/MCB.01354-06 Artandi, 2000, Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice, Nature, 406, 641, 10.1038/35020592 Farazi, 2003, Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma, Cancer Res, 63, 5021 Satyanarayana, 2004, Telomeres and telomerase: a dual role in hepatocarcinogenesis, Hepatology, 40, 276, 10.1002/hep.20308 Plentz, 2004, Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma, Hepatology, 40, 80, 10.1002/hep.20271 Plentz, 2007, Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis, Hepatology, 45, 968, 10.1002/hep.21552 Plentz, 2005, Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma, Hepatology, 42, 522, 10.1002/hep.20847 van Gijssel, 1997, p53 protein expression by hepatocarcinogens in the rat liver and its potential role in mitoinhibition of normal hepatocytes as a mechanism of hepatic tumour promotion, Carcinogenesis, 18, 1027, 10.1093/carcin/18.5.1027 Laconi, 2001, A growth-constrained environment drives tumor progression invivo, Proc Natl Acad Sci U S A, 98, 7806, 10.1073/pnas.131210498 Bilousova, 2005, Impaired DNA replication within progenitor cell pools promotes leukemogenesis, PLoS Biol, 3, e401, 10.1371/journal.pbio.0030401 Satyanarayana, 2003, Telomere shortening impairs organ regeneration by inhibiting cell cycle re-entry of a subpopulation of cells, EMBO J, 22, 4003, 10.1093/emboj/cdg367 Choudhury, 2007, Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation, Nat Genet, 39, 99, 10.1038/ng1937 Wagayama, 2001, p21WAF1/CTP1 expression and hepatitis virus type, Dig Dis Sci, 46, 2074, 10.1023/A:1011977923941 Iakova, 2003, Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest, Cell, 113, 495, 10.1016/S0092-8674(03)00318-0 Poynard, 2003, A comparison of fibrosis progression in chronic liver diseases, J Hepatol, 38, 257, 10.1016/S0168-8278(02)00413-0 Pasciu, 2006, Aging is associated with increased clonogenic potential in rat liver in vivo, Aging Cell, 5, 373, 10.1111/j.1474-9726.2006.00230.x Wang, 2004, Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity, Genes Dev, 18, 912, 10.1101/gad.1183304 Stanger, 2007, Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver, Nature, 445, 886, 10.1038/nature05537 Bataller, 2005, Liver fibrosis, J Clin Invest, 115, 209, 10.1172/JCI24282 Giannelli, 2005, Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma, Gastroenterology, 129, 1375, 10.1053/j.gastro.2005.09.055 Ogata, 2006, Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis, Gastroenterology, 131, 179, 10.1053/j.gastro.2006.04.025 Budhu, 2006, Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment, Cancer Cell, 10, 99, 10.1016/j.ccr.2006.06.016 Sakurai, 2006, Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation, Proc Natl Acad Sci U S A, 103, 10544, 10.1073/pnas.0603499103 Luedde, 2007, Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma, Cancer Cell, 11, 119, 10.1016/j.ccr.2006.12.016 Pikarsky, 2004, NF-kappaB functions as a tumour promoter in inflammation-associated cancer, Nature, 431, 461, 10.1038/nature02924 Parrinello, 2005, Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation, J Cell Sci, 118, 485, 10.1242/jcs.01635 Schnabl, 2003, Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype, Hepatology, 37, 653, 10.1053/jhep.2003.50097 Di, 2006, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication, Nature, 444, 638, 10.1038/nature05327 Tannapfel, 2001, INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas, Oncogene, 20, 7104, 10.1038/sj.onc.1204902 Jablkowski, 2005, A comparative study of P53/MDM2 genes alterations and P53/MDM2 proteins immunoreactivity in liver cirrhosis and hepatocellular carcinoma, J Exp Clin Cancer Res, 24, 117 Llovet, 2006, A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis, Gastroenterology, 131, 1758, 10.1053/j.gastro.2006.09.014 Higashitsuji, 2000, Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas, Nat Med, 6, 96, 10.1038/71600 Higashitsuji, 2005, The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53, Cancer Cell, 8, 75, 10.1016/j.ccr.2005.06.006 Lechel, 2005, The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo, EMBO Rep, 6, 275, 10.1038/sj.embor.7400352 Kalinichenko, 2004, Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor, Genes Dev, 18, 830, 10.1101/gad.1200704 Ito, 1999, Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence, Hepatology, 30, 90, 10.1002/hep.510300114 Azechi, 2001, Disruption of the p16/cyclin D1/retinoblastoma protein pathway in the majority of human hepatocellular carcinomas, Oncology, 60, 346, 10.1159/000058531 Matsuda, 2005, Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16, Cancer, 104, 1037, 10.1002/cncr.21259 Yamada, 1997, Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis, Proc Natl Acad Sci U S A, 94, 10351, 10.1073/pnas.94.19.10351 Dennis, 1991, Cellular activation of latent transforming growth factor beta requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor, Proc Natl Acad Sci U S A, 88, 580, 10.1073/pnas.88.2.580 Breuhahn, 2004, Molecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression, Cancer Res, 64, 6058, 10.1158/0008-5472.CAN-04-0292 Acquati, 1994, A 2-Mb YAC contig linking the plasminogen-apoprotein(a) gene family to the insulin-like growth factor 2 receptor (IGF2R) gene on the telomeric region of chromosome 6 (6q26-q27), Genomics, 22, 664, 10.1006/geno.1994.1450 Higashitsuji, 2002, A novel protein overexpressed in hepatoma accelerates export of NF-kappa B from the nucleus and inhibits p53-dependent apoptosis, Cancer Cell, 2, 335, 10.1016/S1535-6108(02)00152-6 Lechel, 2007, Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease, Gastroenterology, 132, 1465, 10.1053/j.gastro.2007.01.045 Martin, 2006, Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma, Gastroenterology, 130, 2179, 10.1053/j.gastro.2006.03.024 Yang, 2006, Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2, Cancer Cell, 9, 445, 10.1016/j.ccr.2006.04.025 Chen, 1998, Suppression of transforming growth factor-beta-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway, Oncogene, 17, 1959, 10.1038/sj.onc.1202111 Micsenyi, 2004, Beta-catenin is temporally regulated during normal liver development, Gastroenterology, 126, 1134, 10.1053/j.gastro.2003.12.047 de La, 1998, Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas, Proc Natl Acad Sci U S A, 95, 8847, 10.1073/pnas.95.15.8847 Chan, 2006, Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer, Gastroenterology, 131, 1218, 10.1053/j.gastro.2006.07.020 Colnot, 2004, Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas, Proc Natl Acad Sci U S A, 101, 17216, 10.1073/pnas.0404761101 Sicklick, 2006, Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis, Carcinogenesis, 27, 748, 10.1093/carcin/bgi292 Kaposi-Novak, 2006, Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype, J Clin Invest, 116, 1582, 10.1172/JCI27236 Yin, 2007, CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity, Int J Cancer, 120, 1444, 10.1002/ijc.22476 Chiba, 2006, Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties, Hepatology, 44, 240, 10.1002/hep.21227 Lee, 2006, A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells, Nat Med, 12, 410, 10.1038/nm1377 Hu, 2003, Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma, Cancer, 97, 1929, 10.1002/cncr.11266 He, 2007, PTEN-deficient intestinal stem cells initiate intestinal polyposis, Nat Genet, 39, 189, 10.1038/ng1928 Shachaf, 2004, MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer, Nature, 431, 1112, 10.1038/nature03043 Wang, 2002, Prognostic significance of c-myc and AIB1 amplification in hepatocellular carcinoma, Cancer, 95, 2346, 10.1002/cncr.10963 Wilkens, 2004, Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma, Proc Natl Acad Sci U S A, 101, 1309, 10.1073/pnas.0305817101 Zender, 2006, Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach, Cell, 125, 1253, 10.1016/j.cell.2006.05.030 Hahn, 1999, Creation of human tumour cells with defined genetic elements, Nature, 400, 464, 10.1038/22780 Djojosubroto, 2005, Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma, Hepatology, 42, 1127, 10.1002/hep.20822 Fattovich, 1995, Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B, Hepatology, 21, 77 Hu, 1999, The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States, Hepatology, 29, 1311, 10.1002/hep.510290424