Hepatocellular carcinoma pathogenesis: from genes to environment (original) (raw)

• Hertl, M. & Cosimi, A. B. Liver transplantation for malignancy. Oncologist 10, 269–281 (2005).
  Article PubMed Google Scholar
• American Cancer Society. Cancer Facts and FIGS 2005. American Cancer Society [online], (2005).
• Anthony, P. in Pathology of the Liver (eds MacSween, R., Burt, A., Portmann, B., Ishak, K., Scheuer P. & Anthony, P.) 711–775 (Churchill Livingstone, London, New York, Sydney, Toronto, 2002).
  Google Scholar
• Sherman, M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin. Liver Dis. 25, 143–154 (2005).
  Article PubMed Google Scholar
• Badvie, S. Hepatocellular carcinoma. Postgrad. Med. J. 76, 4–11 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Lavanchy, D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J. Viral. Hepat. 11, 97–107 (2004).
  Article CAS PubMed Google Scholar
• Chen, C. J. et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295, 65–73 (2006).
  Article CAS PubMed Google Scholar
• Chisari, F. V. Unscrambling hepatitis C virus-host interactions. Nature 436, 930–932 (2005).
  Article CAS PubMed Google Scholar
• Bowen, D. G. & Walker, C. M. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436, 946–952 (2005).
  Article CAS PubMed Google Scholar
• Block, T. M., Mehta, A. S., Fimmel, C. J. & Jordan, R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 22, 5093–5107 (2003).
  Article CAS PubMed Google Scholar
• Tokino, T., Tamura, H., Hori, N. & Matsubara, K. Chromosome deletions associated with hepatitis B virus integration. Virology 185, 879–882 (1991).
  Article CAS PubMed Google Scholar
• Murakami, Y. et al. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 54, 1162–1168 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Tarn, C., Lee, S., Hu, Y., Ashendel, C. & Andrisani, O. M. Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes. J. Biol. Chem. 276, 34671–34680 (2001).
  Article CAS PubMed Google Scholar
• Nijhara, R. et al. Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo. J. Virol. 75, 10348–10358 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Nijhara, R., Jana, S. S., Goswami, S. K., Kumar, V. & Sarkar, D. P. An internal segment (residues 58–119) of the hepatitis B virus X protein is sufficient to activate MAP kinase pathways in mouse liver. FEBS Lett. 504, 59–64 (2001).
  Article CAS PubMed Google Scholar
• Feitelson, M. A. et al. Genetic mechanisms of hepatocarcinogenesis. Oncogene 21, 2593–2604 (2002).
  Article CAS PubMed Google Scholar
• Ueda, H. et al. Functional inactivation but not structural mutation of p53 causes liver cancer. Nature Genet. 9, 41–47 (1995).
  Article CAS PubMed Google Scholar
• Kim, C. M., Koike, K., Saito, I., Miyamura, T. & Jay, G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351, 317–320 (1991). This article shows the carcinogenic potential of hepatitis B viral factors (more specifically, the HBx gene), as HBx transgenic animals develop HCC.
  Article CAS PubMed Google Scholar
• Yu, D. Y. et al. Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. J. Hepatol. 31, 123–132 (1999).
  Article CAS PubMed Google Scholar
• Nowak, M. A. et al. Viral dynamics in hepatitis B virus infection. Proc. Natl Acad. Sci. USA 93, 4398–4402 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Wieland, S., Thimme, R., Purcell, R. H. & Chisari, F. V. Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl Acad. Sci. USA 101, 6669–6674 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol. 5, 215–229 (2005).
  Article CAS Google Scholar
• Lok, A. S., Heathcote, E. J. & Hoofnagle, J. H. Management of hepatitis B: 2000 —summary of a workshop. Gastroenterology 120, 1828–1853 (2001).
  Article CAS PubMed Google Scholar
• Kojima, T. Immune electron microscopic study of hepatitis B virus associated antigens in hepatocytes. Gastroenterol. Jpn 17, 559–575 (1982).
  Article CAS PubMed Google Scholar
• Shimoda, R. et al. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res. 54, 3171–3172 (1994).
  CAS PubMed Google Scholar
• Galli, A. et al. Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology 41, 1074–1084 (2005).
  Article CAS PubMed Google Scholar
• Chen, B. F. et al. High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology 130, 1153–1168 (2006).
  Article CAS PubMed Google Scholar
• Lindenbach, B. D. & Rice, C. M. Unravelling hepatitis C virus replication from genome to function. Nature 436, 933–938 (2005).
  Article CAS PubMed Google Scholar
• Lindenbach, B. D. et al. Complete replication of hepatitis C virus in cell culture. Science 309, 623–626 (2005). This article reports a significant advance for research on HCV, as it shows successful HCV replication and viral particle production in cell culture. These culture systems will now provide a better opportunity to study viral replication and propagation, and provide clues for antiviral therapies.
  Article CAS PubMed Google Scholar
• Wakita, T. et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Med. 11, 791–796 (2005).
  Article CAS PubMed Google Scholar
• Weiner, A. et al. Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant. Proc. Natl Acad. Sci. USA 92, 2755–2759 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Daniel, D. et al. Immune enhancement of skin carcinogenesis by CD4+ T cells. J. Exp. Med. 197, 1017–1028 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Pachiadakis, I., Pollara, G., Chain, B. M. & Naoumov, N. V. Is hepatitis C virus infection of dendritic cells a mechanism facilitating viral persistence? Lancet Infect. Dis. 5, 296–304 (2005).
  Article PubMed Google Scholar
• Park, K. J. et al. 1Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2. J. Biol. Chem. 278, 30711–8 (2003).
  Article CAS PubMed Google Scholar
• Majumder, M. et al. Hepatitis C virus NS5A protein impairs TNF-mediated hepatic apoptosis, but not by an anti-FAS antibody, in transgenic mice. Virology 294, 94–105 (2002).
  Article CAS PubMed Google Scholar
• Melen, K., Fagerlund, R., Nyqvist, M., Keskinen, P. & Julkunen, I. Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J. Med. Virol. 73, 536–547 (2004).
  Article CAS PubMed Google Scholar
• Foy, E. et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc. Natl Acad. Sci. USA 102, 2986–2991 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Li, K. 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 102, 2992–2997 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Gale, M., Jr. & Foy, E. M. Evasion of intracellular host defence by hepatitis C virus. Nature 436, 939–945 (2005).
  Article CAS PubMed Google Scholar
• Hino, O., Kajino, K., Umeda, T. & Arakawa, Y. Understanding the hypercarcinogenic state in chronic hepatitis: a clue to the prevention of human hepatocellular carcinoma. J. Gastroenterol. 37, 883–887 (2002).
  Article CAS PubMed Google Scholar
• Macdonald, A. et al. The hepatitis C virus non-structural NS5A protein inhibits activating protein-1 function by perturbing ras- pathway signaling. J. Biol. Chem. 278, 17775–17784 (2003).
  Article CAS PubMed Google Scholar
• Majumder, M., Ghosh, A. K., Steele, R., Ray, R. & Ray, R. B. Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J. Virol. 75, 1401–1407 (2001). This report shows a potential carcinogenic mechanism of one of the HCV viral proteins (NS5A) through the interaction and consequent functional inactivation of p53.
  Article CAS PubMed PubMed Central Google Scholar
• Moriya, K. et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res. 61, 4365–4370 (2001).
  CAS PubMed Google Scholar
• Kamegaya, Y. et al. Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis. Hepatology 41, 660–667 (2005).
  Article PubMed Google Scholar
• McClain, C. J., Hill, D. B., Song, Z., Deaciuc, I. & Barve, S. Monocyte activation in alcoholic liver disease. Alcohol 27, 53–61 (2002).
  Article CAS PubMed Google Scholar
• Hoek, J. B. & Pastorino, J. G. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 27, 63–68 (2002).
  Article CAS PubMed Google Scholar
• Campbell, J. S. et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc. Natl Acad. Sci. USA 102, 3389–3394 (2005). This article provides evidence for the hepatocarcinogenic potential of the cirrhotic microenvironment, and provides a useful mouse model to investigate the molecular mechanisms underlying cirrhosis-induced HCC.
  Article CAS PubMed PubMed Central Google Scholar
• Comporti, M. et al. F(2)-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis? Lab. Invest. 85, 1381–1391 (2005).
  Article CAS PubMed Google Scholar
• Osna, N. A., Clemens, D. L. & Donohue, T. M., Jr. Ethanol metabolism alters interferon-γ signaling in recombinant HepG2 cells. Hepatology 42, 1109–1117 (2005).
  Article CAS PubMed Google Scholar
• Marrogi, A. J. et al. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma. J. Natl Cancer Inst. 93, 1652–1655 (2001).
  Article CAS PubMed Google Scholar
• Kurz, D. J. et al. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J. Cell Sci. 117, 2417–2426 (2004).
  Article CAS PubMed Google Scholar
• Aguilar, F., Harris, C. C., Sun, T., Hollstein, M. & Cerutti, P. Geographic variation of p53 mutational profile in nonmalignant human liver. Science 264, 1317–1319 (1994).
  Article CAS PubMed Google Scholar
• Bressac, B., Kew, M., Wands, J. & Ozturk, M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431 (1991). This article shows the occurrence of p53 mutations in human HCCs induced after aflatoxin B1 exposure. It points to the mutagenic properties of aflatoxin, as well as the key role that p53 inactivation might have in hepatocarcinogenesis.
  Article CAS PubMed Google Scholar
• Hsu, I. C. et al. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350, 427–428 (1991).
  Article CAS PubMed Google Scholar
• Ozturk, M. p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet 338, 1356–1359 (1991).
  Article CAS PubMed Google Scholar
• Riley, J., Mandel, H. G., Sinha, S., Judah, D. J. & Neal, G. E. In vitro activation of the human Harvey-ras proto-oncogene by aflatoxin B1. Carcinogenesis 18, 905–910 (1997).
  Article CAS PubMed Google Scholar
• Kew, M. C. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int. 23, 405–409 (2003).
  Article CAS PubMed Google Scholar
• Okuda, K. Hepatocellular carcinoma. J. Hepatol. 32, 225–237 (2000).
  Article CAS PubMed Google Scholar
• Minouchi, K., Kaneko, S. & Kobayashi, K. Mutation of p53 gene in regenerative nodules in cirrhotic liver. J. Hepatol. 37, 231–239 (2002).
  Article CAS PubMed Google Scholar
• Nose, H., Imazeki, F., Ohto, M. & Omata, M. p53 gene mutations and 17p allelic deletions in hepatocellular carcinoma from Japan. Cancer 72, 355–360 (1993).
  Article CAS PubMed Google Scholar
• Nishida, N. et al. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 53, 368–372 (1993).
  CAS PubMed Google Scholar
• Hosono, S., Chou, M. J., Lee, C. S. & Shih, C. Infrequent mutation of p53 gene in hepatitis B virus positive primary hepatocellular carcinomas. Oncogene 8, 491–496 (1993).
  CAS PubMed Google Scholar
• Farazi, P. A., Glickman, J., Horner, J. & Depinho, R. A. Cooperative Interactions of p53 Mutation, Telomere Dysfunction, and Chronic Liver Damage in Hepatocellular Carcinoma Progression. Cancer Res. 66, 4766–4773 (2006).
  Article CAS PubMed Google Scholar
• Huang, S. N. & Chisari, F. V. Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice. Hepatology 21, 620–626 (1995).
  CAS PubMed Google Scholar
• Ghebranious, N. & Sell, S. Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice. Hepatology 27, 383–391 (1998).
  Article CAS PubMed Google Scholar
• Ghebranious, N. & Sell, S. The mouse equivalent of the human p53ser249 mutation p53ser246 enhances aflatoxin hepatocarcinogenesis in hepatitis B surface antigen transgenic and p53 heterozygous null mice. Hepatology 27, 967–973 (1998).
  Article CAS PubMed Google Scholar
• Gregorieff, A. & Clevers, H. Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev. 19, 877–890 (2005).
  Article CAS PubMed Google Scholar
• Ishizaki, Y. et al. Immunohistochemical analysis and mutational analyses of β-catenin, Axin family and APC genes in hepatocellular carcinomas. Int. J. Oncol. 24, 1077–1083 (2004). This article shows alterations of the Wnt signalling pathway in human HCC. It shows increased nuclear expression of β-catenin, as well as mutations in β-catenin, axin1 and axin2.
  CAS PubMed Google Scholar
• Edamoto, Y. et al. Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. Int. J. Cancer 106, 334–341 (2003).
  Article CAS PubMed Google Scholar
• Thorgeirsson, S. S. & Grisham, J. W. Molecular pathogenesis of human hepatocellular carcinoma. Nature Genet. 31, 339–346 (2002).
  Article CAS PubMed Google Scholar
• Peng, S. Y. et al. High α-fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: significance of hepatitis virus infection, age, p53 and β-catenin mutations. Int. J. Cancer 112, 44–50 (2004).
  Article CAS PubMed Google Scholar
• An, F. Q. et al. Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 AND β-catenin. Int. J. Cancer 93, 468–474 (2001).
  Article CAS PubMed Google Scholar
• Hsu, H. C. et al. β-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am. J. Pathol. 157, 763–770 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, H. et al. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am. J. Pathol. 155, 1795–1801 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Cha, M. Y., Kim, C. M., Park, Y. M. & Ryu, W. S. Hepatitis B virus X protein is essential for the activation of Wnt/β-catenin signaling in hepatoma cells. Hepatology 39, 1683–1693 (2004).
  Article CAS PubMed Google Scholar
• Torbenson, M. et al. Concurrent evaluation of p53, β-catenin, and α-fetoprotein expression in human hepatocellular carcinoma. Am. J. Clin. Pathol. 122, 377–382 (2004).
  Article CAS PubMed Google Scholar
• Prange, W. et al. β-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes. J. Pathol. 201, 250–259 (2003).
  Article CAS PubMed Google Scholar
• Gross-Goupil, M. et al. Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation. Int. J. Cancer 104, 745–751 (2003).
  Article CAS PubMed Google Scholar
• Calvisi, D. F., Factor, V. M., Ladu, S., Conner, E. A. & Thorgeirsson, S. S. Disruption of β-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice. Gastroenterology 126, 1374–1386 (2004).
  Article CAS PubMed Google Scholar
• Ito, Y. et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br. J. Cancer 84, 1377–1383 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Hopfner, M. et al. Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J. Hepatol. 41, 1008–1016 (2004).
  Article CAS PubMed Google Scholar
• Schiffer, E. et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 41, 307–314 (2005).
  Article CAS PubMed Google Scholar
• Philip, P. A. et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J. Clin. Oncol. 23, 6657–6663 (2005).
  Article CAS PubMed Google Scholar
• Jhappan, C. et al. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61, 1137–1146 (1990). This work points to the hepatocarcinogenic potential of TGFα signalling, and complements findings of ErbB receptor overexpression in human HCCs.
  Article CAS PubMed Google Scholar
• Sandgren, E. P., Luetteke, N. C., Palmiter, R. D., Brinster, R. L. & Lee, D. C. Overexpression of TGF α in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61, 1121–1135 (1990).
  Article CAS PubMed Google Scholar
• Webber, E. M., Wu, J. C., Wang, L., Merlino, G. & Fausto, N. Overexpression of transforming growth factor-α causes liver enlargement and increased hepatocyte proliferation in transgenic mice. Am. J. Pathol. 145, 398–408 (1994).
  CAS PubMed PubMed Central Google Scholar
• Russell, W. E., Kaufmann, W. K., Sitaric, S., Luetteke, N. C. & Lee, D. C. Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice. Mol. Carcinog. 15, 183–189 (1996).
  Article CAS PubMed Google Scholar
• Sandgren, E. P. et al. Transforming growth factor-α dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol. Cell Biol. 13, 320–330 (1993).
  Article CAS PubMed PubMed Central Google Scholar
• Sargent, L. M. et al. Nonrandom cytogenetic alterations in hepatocellular carcinoma from transgenic mice overexpressing c-Myc and transforming growth factor-α in the liver. Am. J. Pathol. 154, 1047–1055 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Murakami, H. et al. Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res. 53, 1719–1723 (1993).
  CAS PubMed Google Scholar
• Santoni-Rugiu, E., Nagy, P., Jensen, M. R., Factor, V. M. & Thorgeirsson, S. S. Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-α. Am. J. Pathol. 149, 407–428 (1996).
  CAS PubMed PubMed Central Google Scholar
• Jakubczak, J. L., Chisari, F. V. & Merlino, G. Synergy between transforming growth factor α and hepatitis B virus surface antigen in hepatocellular proliferation and carcinogenesis. Cancer Res. 57, 3606–3611 (1997).
  CAS PubMed Google Scholar
• Daveau, M. et al. Hepatocyte growth factor, transforming growth factor-α, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol. Carcinog. 36, 130–141 (2003).
  Article CAS PubMed Google Scholar
• Sakata, H. et al. Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal development, and tumor formation in transgenic mouse livers. Cell Growth Differ. 7, 1513–1523 (1996).
  CAS PubMed Google Scholar
• Wang, R., Ferrell, L. D., Faouzi, S., Maher, J. J. & Bishop, J. M. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J. Cell Biol. 153, 1023–1034 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Kanai, Y., Ushijima, S., Tsuda, H., Sakamoto, M. & Hirohashi, S. Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis. Cancer Lett. 148, 73–80 (2000).
  Article CAS PubMed Google Scholar
• Kanai, Y. et al. DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology 29, 703–709 (1999).
  Article CAS PubMed Google Scholar
• Kanai, Y. et al. Aberrant DNA methylation on chromosome 16 is an early event in hepatocarcinogenesis. Jpn J. Cancer Res. 87, 1210–1217 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, J. et al. Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis. Cell Res. 13, 319–333 (2003).
  Article CAS PubMed Google Scholar
• Lee, S. et al. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am. J. Pathol. 163, 1371–1378 (2003). This article shows the presence of epigenetic alterations (hypermethylation) in human HCCs. This work shows hypermethylation in the earliest stages of hepatocarcinogenesis, and to a greater extent in tumour progression.
  Article CAS PubMed PubMed Central Google Scholar
• Wong, I. H. et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 59, 71–73 (1999).
  CAS PubMed Google Scholar
• Matsuda, Y., Ichida, T., Matsuzawa, J., Sugimura, K. & Asakura, H. p16(INK4) is inactivated by extensive CpG methylation in human hepatocellular carcinoma. Gastroenterology 116, 394–400 (1999).
  Article CAS PubMed Google Scholar
• Liew, C. T. et al. High frequency of p16INK4A gene alterations in hepatocellular carcinoma. Oncogene 18, 789–795 (1999).
  Article CAS PubMed Google Scholar
• Murata, H. et al. Promoter hypermethylation silences cyclooxygenase-2 (Cox-2) and regulates growth of human hepatocellular carcinoma cells. Lab. Invest. 84, 1050–1059 (2004).
  Article CAS PubMed Google Scholar
• Kubo, T. et al. Apoptotic speck protein-like, a highly homologous protein to apoptotic speck protein in the pyrin domain, is silenced by DNA methylation and induces apoptosis in human hepatocellular carcinoma. Cancer Res. 64, 5172–5177 (2004).
  Article CAS PubMed Google Scholar
• Wong, C. M., Lee, J. M., Ching, Y. P., Jin, D. Y. & Ng, I. O. Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res. 63, 7646–7651 (2003).
  CAS PubMed Google Scholar
• Maeta, Y., Shiota, G., Okano, J. & Murawaki, Y. Effect of promoter methylation of the p16 gene on phosphorylation of retinoblastoma gene product and growth of hepatocellular carcinoma cells. Tumour Biol. 26, 300–305 (2005).
  Article CAS PubMed Google Scholar
• Urabe, Y. et al. Telomere length in human liver diseases. Liver 16, 293–297 (1996). This article shows telomere shortening during human chronic liver disease and the induction of liver cirrhosis. It also suggests that telomerase might be re-activated during the late stages of hepatocarcinogenesis as the telomere length of advanced HCCs is slightly longer than that of early-stage HCCs, suggestive of telomerase activation.
  Article CAS PubMed Google Scholar
• Miura, N. et al. Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis. Cancer Genet. Cytogenet. 93, 56–62 (1997).
  Article CAS PubMed Google Scholar
• Rudolph, K. L., DrPinho, R. A. in The Liver Biology and Pathobiology (eds Arias, I., Fausto, N., Boyer, J., Chisari, F. & Shafritz, D.) 1001–1011 (Lippincott Williams and Wilkins, Philadelphia, 2001).
  Google Scholar
• Kitada, T., Seki, S., Kawakita, N., Kuroki, T. & Monna, T. Telomere shortening in chronic liver diseases. Biochem. Biophys. Res. Commun. 211, 33–39 (1995).
  Article CAS PubMed Google Scholar
• Wiemann, S. U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. Faseb J. 16, 935–942 (2002).
  Article CAS PubMed Google Scholar
• Plentz, R. R. et al. Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma. Hepatology 40, 80–86 (2004).
  Article CAS PubMed Google Scholar
• Plentz, R. R. et al. Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma. Hepatology 42, 522–526 (2005).
  Article CAS PubMed Google Scholar
• Farazi, P. A. et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 63, 5021–5027 (2003). The role of telomere dysfunction in HCC initiation and progression is addressed in this work. Whereas telomere dysfunction promotes liver cancer initiation in mice, it suppresses progression, therefore pointing to the importance of telomerase re-activation in HCC progression.
  CAS PubMed Google Scholar
• Nagao, K., Tomimatsu, M., Endo, H., Hisatomi, H. & Hikiji, K. Telomerase reverse transcriptase mRNA expression and telomerase activity in hepatocellular carcinoma. J. Gastroenterol. 34, 83–87. (1999).
  Article CAS PubMed Google Scholar
• Shimojima, M. et al. Detection of telomerase activity, telomerase RNA component, and telomerase reverse transcriptase in human hepatocellular carcinoma. Hepatol. Res. 29, 31–38 (2004).
  Article CAS PubMed Google Scholar
• Lee, C. M. et al. Telomerase activity and telomerase catalytic subunit in hepatocellular carcinoma. Hepatogastroenterology 51, 796–800 (2004).
  CAS PubMed Google Scholar
• Ferber, M. J. et al. Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene 22, 3813–3820 (2003).
  Article CAS PubMed Google Scholar
• Takeo, S. et al. Examination of oncogene amplification by genomic DNA microarray in hepatocellular carcinomas: comparison with comparative genomic hybridization analysis. Cancer Genet. Cytogenet. 130, 127–132 (2001).
  Article CAS PubMed Google Scholar
• Nishimoto, A. et al. Functional evidence for a telomerase repressor gene on human chromosome 10p15. 1. Oncogene 20, 828–835 (2001).
  Article CAS PubMed Google Scholar
• Piao, Y. F., He, M., Shi, Y. & Tang, T. Y. Relationship between microvessel density and telomerase activity in hepatocellular carcinoma. World J. Gastroenterol. 10, 2147–2149 (2004).
  Article PubMed PubMed Central Google Scholar
• Kobayashi, T., Kubota, K., Takayama, T. & Makuuchi, M. Telomerase activity as a predictive marker for recurrence of hepatocellular carcinoma after hepatectomy. Am. J. Surg. 181, 284–288 (2001).
  Article CAS PubMed Google Scholar
• Hytiroglou, P. et al. Telomerase activity in precancerous hepatic nodules. Cancer 82, 1831–1838 (1998).
  Article CAS PubMed Google Scholar
• Tahara, H. et al. Telomerase activity in human liver tissues: comparison between chronic liver disease and hepatocellular carcinomas. Cancer Res. 55, 2734–2736 (1995).
  CAS PubMed Google Scholar
• Youssef, N., Paradis, V., Ferlicot, S. & Bedossa, P. In situ detection of telomerase enzymatic activity in human hepatocellular carcinogenesis. J. Pathol. 194, 459–465 (2001).
  Article CAS PubMed Google Scholar
• Oh, B. K. et al. Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis. J. Hepatol. 39, 786–792 (2003).
  Article CAS PubMed Google Scholar
• Ogami, M. et al. Quantitative analysis and in situ localization of human telomerase RNA in chronic liver disease and hepatocellular carcinoma. Lab. Invest. 79, 15–26 (1999).
  CAS PubMed Google Scholar
• Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Gollin, S. M. Mechanisms leading to chromosomal instability. Semin. Cancer Biol. 15, 33–42 (2005).
  Article CAS PubMed Google Scholar
• Smith, M. W. et al. Identification of novel tumor markers in hepatitis C virus-associated hepatocellular carcinoma. Cancer Res. 63, 859–864 (2003).
  CAS PubMed Google Scholar
• Yu, C. T. et al. Phosphorylation and stabilization of HURP by Aurora-A: implication of HURP as a transforming target of Aurora-A. Mol. Cell Biol. 25, 5789–5800 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Andrews, P. D. Aurora kinases: shining lights on the therapeutic horizon? Oncogene 24, 5005–5015 (2005).
  Article CAS PubMed Google Scholar
• Saeki, A. et al. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer 94, 2047–2054 (2002).
  Article CAS PubMed Google Scholar
• Olive, K. P. et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119, 847–860 (2004).
  Article CAS PubMed Google Scholar
• Lang, G. A. et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119, 861–872 (2004).
  Article CAS PubMed Google Scholar
• Kuroki, T. et al. Evidence for the presence of two tumour-suppressor genes for hepatocellular carcinoma on chromosome 13q. Br. J. Cancer 72, 383–385 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Martins, C., Kedda, M. A. & Kew, M. C. Characterization of six tumor suppressor genes and microsatellite instability in hepatocellular carcinoma in southern African blacks. World J. Gastroenterol. 5, 470–476 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Wong, N. et al. A comprehensive karyotypic study on human hepatocellular carcinoma by spectral karyotyping. Hepatology 32, 1060–1068 (2000).
  Article CAS PubMed Google Scholar
• Hwang, H. J. et al. A comprehensive karyotypic analysis on Korean hepatocellular carcinoma cell lines by cross-species color banding and comparative genomic hybridization. Cancer Genet. Cytogenet. 141, 128–137 (2003).
  Article CAS PubMed Google Scholar
• Okabe, H. et al. Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and-negative tumors. Hepatology 31, 1073–1079 (2000).
  Article CAS PubMed Google Scholar
• Wong, N. et al. Genomic aberrations in human hepatocellular carcinomas of differing etiologies. Clin. Cancer Res. 6, 4000–4009 (2000).
  CAS PubMed Google Scholar
• Kusano, N. et al. Chromosomal imbalances detected by comparative genomic hybridization are associated with outcome of patients with hepatocellular carcinoma. Cancer 94, 746–751 (2002).
  Article PubMed Google Scholar
• Kitay-Cohen, Y. et al. Analysis of chromosomal aberrations in large hepatocellular carcinomas by comparative genomic hybridization. Cancer Genet. Cytogenet. 131, 60–64 (2001).
  Article CAS PubMed Google Scholar
• Koo, S. H. et al. Genetic alterations in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Genet. Cytogenet. 130, 22–28 (2001).
  Article CAS PubMed Google Scholar
• Marchio, A. et al. Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 18, 59–65 (1997).
  Article CAS PubMed Google Scholar
• Hashimoto, K. et al. Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH. Mod. Pathol. 17, 617–622 (2004).
  Article CAS PubMed Google Scholar
• Sakakura, C. et al. Chromosomal aberrations in human hepatocellular carcinomas associated with hepatitis C virus infection detected by comparative genomic hybridization. Br. J. Cancer 80, 2034–2039 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, L. H. et al. Allelic imbalance regions on chromosomes 8p, 17p and 19p related to metastasis of hepatocellular carcinoma: comparison between matched primary and metastatic lesions in 22 patients by genome-wide microsatellite analysis. J. Cancer Res. Clin. Oncol. 129, 279–286 (2003).
  CAS PubMed Google Scholar
• Kusano, N. et al. Genetic aberrations detected by comparative genomic hybridization in hepatocellular carcinomas: their relationship to clinicopathological features. Hepatology 29, 1858–1862 (1999).
  Article CAS PubMed Google Scholar
• Zondervan, P. E. et al. Molecular cytogenetic evaluation of virus-associated and non-viral hepatocellular carcinoma: analysis of 26 carcinomas and 12 concurrent dysplasias. J. Pathol. 192, 207–215 (2000).
  Article CAS PubMed Google Scholar
• Marchio, A. et al. Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients. Oncogene 19, 3733–3738 (2000).
  Article CAS PubMed Google Scholar
• Balsara, B. R. et al. Human hepatocellular carcinoma is characterized by a highly consistent pattern of genomic imbalances, including frequent loss of 16q23. 1–24. 1. Genes Chromosomes Cancer 30, 245–253 (2001).
  Article CAS PubMed Google Scholar
• Kawai, H. et al. Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology 31, 1246–1250 (2000).
  Article CAS PubMed Google Scholar
• Guan, X. Y. et al. Recurrent chromosome alterations in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer 29, 110–116 (2000).
  Article CAS PubMed Google Scholar
• Wilkens, L. et al. Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma. Proc. Natl Acad. Sci. USA 101, 1309–1314 (2004). This study shows a correlation between increasing levels of chromosomal instability and progression of HCC, suggesting that marked genome instability characterizes the more advanced stages of the disease.
  Article CAS PubMed PubMed Central Google Scholar
• Wong, N. et al. Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis: relationship to disease stage, tumor size, and cirrhosis. Am. J. Pathol. 154, 37–43 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Okabe, H. et al. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res. 61, 2129–2137 (2001).
  CAS PubMed Google Scholar
• Iizuka, N. et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 361, 923–929 (2003).
  Article CAS PubMed Google Scholar
• Lee, J. S. et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 40, 667–676 (2004). This work shows the successful use of gene-expression profiling to classify human HCCs. Gene-expression patterns could distinguish between HCCs with different prognoses.
  Article CAS PubMed Google Scholar
• Lee, J. S. et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nature Genet. 36, 1306–1311 (2004). This paper compared gene-expression profiles of human HCCs with HCCs from various mouse models. It shows commonalities in gene-expression patterns in tumours from both species, and points to the promising use of comparative functional genomics to understand the molecular basis of human cancer.
  Article CAS PubMed Google Scholar
• Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006). This paper shows the successful use of comparative genomics in the identification and validation of new oncogenes important in hepatocarcinogenesis.
  Article CAS PubMed PubMed Central Google Scholar
• Lee, J. S. & Thorgeirsson, S. S. Genetic profiling of human hepatocellular carcinoma. Semin. Liver Dis. 25, 125–132 (2005).
  Article CAS PubMed Google Scholar
• Lee, J. S., Grisham, J. W. & Thorgeirsson, S. S. Comparative functional genomics for identifying models of human cancer. Carcinogenesis 26, 1013–1020 (2005).
  Article CAS PubMed Google Scholar
• O'Hagan, R. C. et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2, 149–155 (2002).
  Article CAS PubMed Google Scholar
• Roskams, T., Libbrecht, L. in Malignant Liver Tumours: Basic Concepts and Clinical Management (eds Berr, F., B. J., Hauss, J., Wands, J. & Wittekind, C.) 44–56 (Kluwer Academic Publishers, Dordrecht, 2003).
  Google Scholar
• Fausto, N. & Campbell, J. S. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech. Dev. 120, 117–130 (2003).
  Article CAS PubMed Google Scholar
• Shachaf, C. M. et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431, 1112–1117 (2004). This study shows the ability of tumour cells to differentiate into hepatocytes on oncogene inactivation, and their ability to restore their cancerous phenotype on oncogene re-activation. Therefore, this work suggests a possible stem cell origin of HCC.
  Article PubMed Google Scholar
• Dumble, M. L., Croager, E. J., Yeoh, G. C. & Quail, E. A. Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis 23, 435–445 (2002).
  Article CAS PubMed Google Scholar
• Lee, J. S. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nature Med. 12, 410–416 (2006).
  Article CAS PubMed Google Scholar
• Sell, S. Cellular origin of hepatocellular carcinomas. Semin. Cell Dev. Biol. 13, 419–424 (2002).
  Article PubMed Google Scholar
• Braun, L., Mikumo, R. & Fausto, N. Production of hepatocellular carcinoma by oval cells: cell cycle expression of c-myc and p53 at different stages of oval cell transformation. Cancer Res. 49, 1554–1561 (1989).
  CAS PubMed Google Scholar
• Fotiadu, A. et al. Progenitor cell activation in chronic viralhepatitis. Liver Int. 24, 268–274 (2004).
  Article PubMed Google Scholar
• Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Beachy, P. A., Karhadkar, S. S. & Berman, D. M. Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324–331 (2004).
  Article CAS PubMed Google Scholar
• Wu, P. C. et al. Hepatocellular carcinoma expressing both hepatocellular and biliary markers also expresses cytokeratin 14, a marker of bipotential progenitor cells. J. Hepatol. 31, 965–966 (1999).
  Article CAS PubMed Google Scholar
• Huang, T., Chesnokov, V., Yokoyama, K. K., Carr, B. I. & Itakura, K. Expression of the Hoxa-13 gene correlates to hepatitis B and C virus associated HCC. Biochem. Biophys. Res. Commun. 281, 1041–1044 (2001).
  Article CAS PubMed Google Scholar
• Zhu, A. X. et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 24, 1898–1903 (2006).
  Article CAS PubMed Google Scholar
• Sy, T. & Jamal, M. M. Epidemiology of hepatitis C virus (HCV) infection. Int. J. Med. Sci. 3, 41–46 (2006).
  Article PubMed PubMed Central Google Scholar
• Limdi, J. K. & Crampton, J. R. Hereditary haemochromatosis. Qjm 97, 315–324 (2004).
  Article CAS PubMed Google Scholar
• Sarkany, R. P. The management of porphyria cutanea tarda. Clin. Exp. Dermatol. 26, 225–232 (2001).
  Article CAS PubMed Google Scholar
• Parfrey, H., Mahadeva, R. & Lomas, D. A. α(1)-antitrypsin deficiency, liver disease and emphysema. Int. J. Biochem. Cell Biol. 35, 1009–1014 (2003).
  Article CAS PubMed Google Scholar
• Tanguay, R. M., Jorquera, R., Poudrier, J. & St-Louis, M. Tyrosine and its catabolites: from disease to cancer. Acta Biochim. Pol. 43, 209–216 (1996).
  CAS PubMed Google Scholar
• El-Serag, H. B., Tran, T. & Everhart, J. E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126, 460–468 (2004).
  Article PubMed Google Scholar
• Farrell, G. C. & Larter, C. Z. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43, S99–S112 (2006).
  Article CAS PubMed Google Scholar
• Adams, L. A. & Angulo, P. Recent concepts in non-alcoholic fatty liver disease. Diabet. Med. 22, 1129–1133 (2005).
  Article CAS PubMed Google Scholar