Hepatocyte Growth, Proliferation and Experimental Carcinogenesis

  • Giovanna Maria Ledda-Columbano
  • Amedeo Columbano
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Adult liver is normally quiescent and has a very low level of hepatocyte cell division. However, most hepatocytes rapidly proliferate in response to a reduction in liver mass caused by physical, chemical, nutritional, vascular, or virus-induced liver injury. In spite of the several studies aimed to understand the molecular mechanisms responsible for hepatocyte proliferation, the exact mechanisms responsible for the exit from the quiescent state and the re-entry into the cell cycle remain unknown.


Hepatocyte Growth Factor Liver Regeneration Partial Hepatectomy Constitutive Androstane Receptor Hepatocyte Proliferation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43(2 Suppl 1):S45–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Fausto N. Liver regeneration. J Hepatol. 2000;32(1 Suppl):19–31.PubMedCrossRefGoogle Scholar
  3. 3.
    Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007;213(2):286–300.PubMedCrossRefGoogle Scholar
  4. 4.
    Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5(10):836–47.PubMedCrossRefGoogle Scholar
  5. 5.
    Columbano A, Shinozuka H. Liver regeneration versus direct hyperplasia. FASEB J. 1996;10(10):1118–28.PubMedGoogle Scholar
  6. 6.
    Columbano A, Ledda-Columbano GM. Mitogenesis by ligands of nuclear receptors: an attractive model for the study of the molecular mechanisms implicated in liver growth. Cell Death Differ. 2003;10 Suppl 1:S19–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Higgins G, Anderson R. Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol. 1931;12:86–202.Google Scholar
  8. 8.
    Farber JL, Gerson RJ. Mechanisms of cell injury with hepatotoxic chemicals. Pharmacol Rev. 1984;36(2 Suppl):75.Google Scholar
  9. 9.
    Shinozuka H, Lombardi B, Sell S, Iammarino RM. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet. Cancer Res. 1978;38(4):1092–8.PubMedGoogle Scholar
  10. 10.
    Alison MR, Vig P, Russo F, et al. Hepatic stem cells: from inside and outside the liver? Cell Prolif. 2004;37(1):1–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Marie Scearce L, Lee J, Naji L, Greenbaum L, Cressman DE, Taub R. Rapid activation of latent transcription factor complexes reflects initiating signals in liver regeneration. Cell Death Differ. 1996;3(1):47–55.PubMedGoogle Scholar
  12. 12.
    Rao MS, Reddy JK. Peroxisome proliferation and hepatocarcinogenesis. Carcinogenesis. 1987;8(5):631–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Diwan BA, Lubet RA, Ward JM, Hrabie JA, Rice JM. Tumor-promoting and hepatocarcinogenic effects of 1, 4-bis[2-(3, 5-dichloropyridyloxy)]benzene (TCPOBOP) in DBA/2NCr and C57BL/6NCr mice and an apparent promoting effect on nasal cavity tumors but not on hepatocellular tumors in F344/NCr rats initiated with N-nitrosodiethylamine. Carcinogenesis. 1992;13(10):1893–901.PubMedCrossRefGoogle Scholar
  14. 14.
    Ohmura T, Katyal SL, Locker J, Ledda-Columbano GM, Columbano A, Shinozuka H. Induction of cellular DNA synthesis in the pancreas and kidneys of rats by peroxisome proliferators, 9-cis retinoic acid, and 3, 3’, 5-triiodo-L-thyronine. Cancer Res. 1997;57(5):795–8.PubMedGoogle Scholar
  15. 15.
    Short J, Brown RF, Husakova A, Gilbertson JR, Zemel R, Lieberman I. Induction of deoxyribonucleic acid synthesis in the liver of the intact animal. J Biol Chem. 1972;247(6):1757–66.PubMedGoogle Scholar
  16. 16.
    Pibiri M, Ledda-Columbano GM, Cossu C, et al. Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3). FASEB J. 2001;15(6):1006–13.PubMedCrossRefGoogle Scholar
  17. 17.
    Columbano A, Ledda GM, Sirigu P, Perra T, Pani P. Liver cell proliferation induced by a single dose of lead nitrate. Am J Pathol. 1983;110(1):83–8.PubMedGoogle Scholar
  18. 18.
    Nachtomi E. Modulation of the mitotic action of ethylene dibromide. Chem Biol Interact. 1980;32(3):311–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Schulte-Hermann R, Hoffman V, Parzefall W, Kallenbach M, Gerhardt A, Schuppler J. Adaptive responses of rat liver to the gestagen and anti-androgen cyproterone acetate and other inducers. II. Induction of growth. Chem Biol Interact. 1980;31(3):287–300.PubMedCrossRefGoogle Scholar
  20. 20.
    Schulte-Hermann R. Two-stage control of cell proliferation induced in rat liver by alpha-hexachlorocyclohexane. Cancer Res. 1977;37(1):166–71.PubMedGoogle Scholar
  21. 21.
    Kliewer SA, Umesono K, Mangelsdorf DJ, Evans RM. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling. Nature. 1992;355(6359):446–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Lee SS, Pineau T, Drago J, et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995;15(6):3012–22.PubMedGoogle Scholar
  23. 23.
    Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature. 2000;407(6806):920–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Barbason H, Herens C, Robaye B, et al. Importance of cell kinetics rhythmicity for the control of cell proliferation and carcinogenesis in rat liver (review). In Vivo. 1995;9(6):539–48.PubMedGoogle Scholar
  25. 25.
    Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H. Control mechanism of the circadian clock for timing of cell division in vivo. Science. 2003;302(5643):255–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Schibler U. Circadian rhythms. Liver regeneration clocks on. Science. 2003;302(5643):234–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Bucher NL. Regeneration of mammalian liver. New York: Academic Press; 1963.Google Scholar
  28. 28.
    Weglarz TC, Sandgren EP. Timing of hepatocyte entry into DNA synthesis after partial hepatectomy is cell autonomous. Proc Natl Acad Sci U S A. 2000;97(23):12595–600.PubMedCrossRefGoogle Scholar
  29. 29.
    Ledda-Columbano GM, Pibiri M, Loi R, Perra A, Shinozuka H, Columbano A. Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-Bis[2-(3, 5-Dichloropyridyloxy)] benzene. Am J Pathol. 2000;156(1):91–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Menegazzi M. Carcereri-De Prati A, Suzuki H, et al. Liver cell proliferation induced by nafenopin and cyproterone acetate is not associated with increases in activation of transcription factors NF-kappaB and AP-1 or with expression of tumor necrosis factor alpha. Hepatology. 1997;25(3):585–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Leoni V, Simbula M, Pibiri M, et al. Accelerated entry into S phase and increased hepatocyte proliferation in c-jun conditional knockout mice following administration of the CAR agonist TCPOBOP. 44th Annual EASL Meeting. Copenhagen; 2009.Google Scholar
  32. 32.
    Lorup C. An autoradiographic study of the 3H-uridine and 3H-thymidine incorporation in the regenerating mouse liver. Cell Tissue Kinet. 1977;10(5):477–85.PubMedGoogle Scholar
  33. 33.
    Rabes HM. Kinetics of hepatocellular proliferation after partial resection of the liver. Prog Liver Dis. 1976;5:83–99.PubMedGoogle Scholar
  34. 34.
    Gebhardt R. Different proliferative activity in vitro of periportal and perivenous hepatocytes. Scand J Gastroenterol Suppl. 1988;151:8–18.PubMedCrossRefGoogle Scholar
  35. 35.
    Zajicek G, Oren R, Weinreb M. The streaming liver. Liver. 1985;5(6):293–300.PubMedGoogle Scholar
  36. 36.
    Bralet MP, Branchereau S, Brechot C, Ferry N. Cell lineage study in the liver using retroviral mediated gene transfer. Evidence against the streaming of hepatocytes in normal liver. Am J Pathol. 1994;144(5):896–905.PubMedGoogle Scholar
  37. 37.
    Shiojiri N, Sano M, Inujima S, Nitou M, Kanazawa M, Mori M. Quantitative analysis of cell allocation during liver development, using the spf(ash)-heterozygous female mouse. Am J Pathol. 2000;156(1):65–75.PubMedCrossRefGoogle Scholar
  38. 38.
    Bars RG, Bell DR, Elcombe CR, Oinonen T, Jalava T, Lindros KO. Zone-specific inducibility of cytochrome P450 2B1/2 is retained in isolated perivenous hepatocytes. Biochem J. 1992;282(Pt 3):635–8.PubMedGoogle Scholar
  39. 39.
    Oinonen T, Saarikoski S, Husgafvel-Pursiainen K, Hirvonen A, Lindros KO. Pretranslational induction of cytochrome P4501A enzymes by beta-naphthoflavone and 3-methylcholanthrene occurs in different liver zones. Biochem Pharmacol. 1994;48(12):2189–97.PubMedCrossRefGoogle Scholar
  40. 40.
    Barrass NC, Price RJ, Lake BG, Orton TC. Comparison of the acute and chronic mitogenic effects of the peroxisome proliferators methylclofenapate and clofibric acid in rat liver. Carcinogenesis. 1993;14(7):1451–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Malik R, Mellor N, Selden C, Hodgson H. Triiodothyronine enhances the regenerative capacity of the liver following partial hepatectomy. Hepatology. 2003;37(1):79–86.PubMedCrossRefGoogle Scholar
  42. 42.
    Al Kholaifi A, Amer A, Jeffery B, Gray TJ, Roberts RA, Bell DR. Species-specific kinetics and zonation of hepatic DNA synthesis induced by ligands of PPARalpha. Toxicol Sci. 2008;104(1):74–85.PubMedCrossRefGoogle Scholar
  43. 43.
    Brodsky WY, Uryvaeva IV. Cell polyploidy: its relation to tissue growth and function. Int Rev Cytol. 1977;50:275–332.PubMedCrossRefGoogle Scholar
  44. 44.
    Curatola AM, Nadal MS, Schneider RJ. Rapid degradation of AU-rich element (ARE) mRNAs is activated by ribosome transit and blocked by secondary structure at any position 5’ to the ARE. Mol Cell Biol. 1995;15(11):6331–40.PubMedGoogle Scholar
  45. 45.
    Wheatley DN. Binucleation in mammalian liver. Studies on the control of cytokinesis in vivo. Exp Cell Res. 1972;74(2):455–65.PubMedCrossRefGoogle Scholar
  46. 46.
    Celton-Morizur S, Merlen G, Couton D, Margall-Ducos G, Desdouets C. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest. 2009;119(7):1880–7.PubMedGoogle Scholar
  47. 47.
    James J, Schopman M, Delfgaauw P. The nuclear pattern of the parenchymal cells of the liver after partial hepatectomy. Exp Cell Res. 1966;42(2):375–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Melchiorri C, Chieco P, Zedda AI, Coni P, Ledda-Columbano GM, Columbano A. Ploidy and nuclearity of rat hepatocytes after compensatory regeneration or mitogen-induced liver growth. Carcinogenesis. 1993;14(9):1825–30.PubMedCrossRefGoogle Scholar
  49. 49.
    Marsman DS, Cattley RC, Conway JG, Popp JA. Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2, 3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14, 643) in rats. Cancer Res. 1988;48(23):6739–44.PubMedGoogle Scholar
  50. 50.
    Gerlyng P, Grotmol T, Seglen PO. Effect of 4-acetylaminofluorene and other tumour promoters on hepatocellular growth and binucleation. Carcinogenesis. 1994;15(2):371–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Satterwhite LL, Lohka MJ, Wilson KL, et al. Phosphorylation of myosin-II regulatory light chain by cyclin-p34cdc2: a mechanism for the timing of cytokinesis. J Cell Biol. 1992;118(3):595–605.PubMedCrossRefGoogle Scholar
  52. 52.
    Knecht DA, Loomis WF. Antisense RNA inactivation of myosin heavy chain gene expression in Dictyostelium discoideum. Science. 1987;236(4805):1081–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Lalwani ND, Dethloff LA, Haskins JR, Robertson DG, de la Iglesia FA. Increased nuclear ploidy, not cell proliferation, is sustained in the peroxisome proliferator-treated rat liver. Toxicol Pathol. 1997;25(2):165–76.PubMedCrossRefGoogle Scholar
  54. 54.
    Taub R. Liver regeneration 4: transcriptional control of liver regeneration. FASEB J. 1996;10(4):413–27.PubMedGoogle Scholar
  55. 55.
    Kren BT, Steer CJ. Posttranscriptional regulation of gene expression in liver regeneration: role of mRNA stability. FASEB J. 1996;10(5):559–73.PubMedGoogle Scholar
  56. 56.
    Fausto N, Laird AD, Webber EM. Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration. FASEB J. 1995;9(15):1527–36.PubMedGoogle Scholar
  57. 57.
    Diehl AM, Rai RM. Liver regeneration 3: regulation of signal transduction during liver regeneration. FASEB J. 1996;10(2):215–27.PubMedGoogle Scholar
  58. 58.
    Goyette M, Petropoulos CJ, Shank PR, Fausto N. Expression of a cellular oncogene during liver regeneration. Science. 1983;219(4584):510–2.PubMedCrossRefGoogle Scholar
  59. 59.
    Akerman P, Cote P, Yang SQ, et al. Antibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy. Am J Physiol. 1992;263(4 Pt 1):G579–85.PubMedGoogle Scholar
  60. 60.
    Cornell RP, Liljequist BL, Bartizal KF. Depressed liver regeneration after partial hepatectomy of germ-free, athymic and lipopolysaccharide-resistant mice. Hepatology. 1990;11(6):916–22.PubMedCrossRefGoogle Scholar
  61. 61.
    Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274(5291):1379–83.PubMedCrossRefGoogle Scholar
  62. 62.
    Yamada Y, Kirillova I, Peschon JJ, Fausto N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A. 1997;94(4):1441–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Fujita J, Marino MW, Wada H, et al. Effect of TNF gene depletion on liver regeneration after partial hepatectomy in mice. Surgery. 2001;129(1):48–54.PubMedCrossRefGoogle Scholar
  64. 64.
    Sakamoto T, Liu Z, Murase N, et al. Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy. Hepatology. 1999;29(2):403–11.PubMedCrossRefGoogle Scholar
  65. 65.
    Skrtic S, Ekberg S, Wallenius V, Enerback S, Hedin L, Jansson JO. Changes in expression of CCAAT/enhancer binding protein alpha (C/EBP alpha) and C/EBP beta in rat liver after partial hepatectomy but not after treatment with cyproterone acetate. J Hepatol. 1997;27(5):903–11.PubMedCrossRefGoogle Scholar
  66. 66.
    Columbano A, Ledda-Columbano GM, Pibiri M, et al. Increased expression of c-fos, c-jun and LRF-1 is not required for in vivo priming of hepatocytes by the mitogen TCPOBOP. Oncogene. 1997;14(7):857–63.PubMedCrossRefGoogle Scholar
  67. 67.
    Coni P, Simbula G, de Prati AC, et al. Differences in the steady-state levels of c-fos, c-jun and c-myc messenger RNA during mitogen-induced liver growth and compensatory regeneration. Hepatology. 1993;17(6):1109–16.PubMedCrossRefGoogle Scholar
  68. 68.
    Herbst H, Milani S, Schuppan D, Stein H. Temporal and spatial patterns of proto-oncogene expression at early stages of toxic liver injury in the rat. Lab Invest. 1991;65(3):324–33.PubMedGoogle Scholar
  69. 69.
    Evarts RP, Hu Z, Omori N, Omori M, Marsden ER, Thorgeirsson SS. Effect of vitamin A deficiency on the integrity of hepatocytes after partial hepatectomy. Am J Pathol. 1995;147(3):699–706.PubMedGoogle Scholar
  70. 70.
    Starkel P, Horsmans Y, Sempoux C, et al. After portal branch ligation in rat, nuclear factor kappaB, interleukin-6, signal transducers and activators of transcription 3, c-fos, c-myc, and c-jun are similarly induced in the ligated and nonligated lobes. Hepatology. 1999;29(5):1463–70.PubMedCrossRefGoogle Scholar
  71. 71.
    Behrens A, Sibilia M, David JP, et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J. 2002;21(7):1782–90.PubMedCrossRefGoogle Scholar
  72. 72.
    Makino R, Hayashi K, Sugimura T. C-myc transcript is induced in rat liver at a very early stage of regeneration or by cycloheximide treatment. Nature. 1984;310(5979):697–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Baena E, Gandarillas A, Vallespinos M, et al. c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver. Proc Natl Acad Sci U S A. 2005;102(20):7286–91.PubMedCrossRefGoogle Scholar
  74. 74.
    Li F, Xiang Y, Potter J, Dinavahi R, Dang CV, Lee LA. Conditional deletion of c-myc does not impair liver regeneration. Cancer Res. 2006;66(11):5608–12.PubMedCrossRefGoogle Scholar
  75. 75.
    Ledda-Columbano GM, Curto M, Piga R, et al. In vivo hepatocyte proliferation is inducible through a TNF and IL-6-independent pathway. Oncogene. 1998;17(8):1039–44.PubMedCrossRefGoogle Scholar
  76. 76.
    Columbano A, Ledda-Columbano GM, Pibiri M, et al. Gadd45beta is induced through a CAR-dependent, TNF-independent pathway in murine liver hyperplasia. Hepatology. 2005;42(5):1118–26.PubMedCrossRefGoogle Scholar
  77. 77.
    Lawrence JW, Wollenberg GK, DeLuca JG. Tumor necrosis factor alpha is not required for WY14, 643-induced cell proliferation. Carcinogenesis. 2001;22(3):381–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Anderson SP, Dunn CS, Cattley RC, Corton JC. Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFalpha signaling. Carcinogenesis. 2001;22(11):1843–51.PubMedCrossRefGoogle Scholar
  79. 79.
    Wallenius V, Wallenius K, Jansson JO. Normal pharmacologically-induced, but decreased regenerative liver growth in interleukin-6-deficient (IL-6(-/-)) mice. J Hepatol. 2000;33(6):967–74.PubMedCrossRefGoogle Scholar
  80. 80.
    Matsumoto K, Nakamura T. Hepatocyte growth factor: molecular structure, roles in liver regeneration, and other biological functions. Crit Rev Oncog. 1992;3(1–2):27–54.PubMedGoogle Scholar
  81. 81.
    Masuhara M, Katyal SL, Nakamura T, Shinozuka H. Differential expression of hepatocyte growth factor, transforming growth factor-alpha and transforming growth factor-beta 1 messenger RNAs in two experimental models of liver cell proliferation. Hepatology. 1992;16(5):1241–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Ledda-Columbano GM, Pibiri M, Concas D, Cossu C, Tripodi M, Columbano A. Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli. Hepatology. 2002;36(5):1098–105.PubMedCrossRefGoogle Scholar
  83. 83.
    Locker J, Tian J, Carver R, et al. A common set of immediate-early response genes in liver regeneration and hyperplasia. Hepatology. 2003;38(2):314–25.PubMedCrossRefGoogle Scholar
  84. 84.
    Bungay A, Selden C, Brown D, Malik R, Hubank M, Hodgson H. Microarray analysis of mitogenic effects of T3 on the rat liver. J Gastroenterol Hepatol. 2008;23(12):1926–33.PubMedCrossRefGoogle Scholar
  85. 85.
    De Smaele E, Zazzeroni F, Papa S, et al. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature. 2001;414(6861):308–13.PubMedCrossRefGoogle Scholar
  86. 86.
    Papa S, Zazzeroni F, Fu YX, et al. Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J Clin Invest. 2008;118(5):1911–23.PubMedCrossRefGoogle Scholar
  87. 87.
    Braun L, Mead JE, Panzica M, Mikumo R, Bell GI, Fausto N. Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci U S A. 1988;85(5):1539–43.PubMedCrossRefGoogle Scholar
  88. 88.
    Cattley RC, Marsman DS, Popp JA. Cell proliferation and promotion in the hepatocarcinogenicity of peroxisome proliferating chemicals. Prog Clin Biol Res. 1990;340D:123–32.PubMedGoogle Scholar
  89. 89.
    Ames BN, Gold LS. Too many rodent carcinogens: mitogenesis increases mutagenesis. Science. 1990;249(4972):970–1.PubMedCrossRefGoogle Scholar
  90. 90.
    Dong J, Feldmann G, Huang J, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130(6):1120–33.PubMedCrossRefGoogle Scholar
  91. 91.
    Overholtzer M, Zhang J, Smolen GA, et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 2006;103(33):12405–10.PubMedCrossRefGoogle Scholar
  92. 92.
    Bucher NL, Swaffield MN, Ditroia JF. The Influence of Age Upon the Incorporation of Thymidine-2-C14 into the DNA of Regenerating Rat Liver. Cancer Res. 1964;24:509–12.PubMedGoogle Scholar
  93. 93.
    Stocker E, Heine WD. Regeneration of liver parenchyma under normal and pathological conditions. Beitr Pathol. 1971;144(4):400–8.PubMedGoogle Scholar
  94. 94.
    Fry M, Silber J, Loeb LA, Martin GM. Delayed and reduced cell replication and diminishing levels of DNA polymerase-alpha in regenerating liver of aging mice. J Cell Physiol. 1984;118(3):225–32.PubMedCrossRefGoogle Scholar
  95. 95.
    Vijg J, Campisi J. Puzzles, promises and a cure for ageing. Nature. 2008;454(7208):1065–71.PubMedCrossRefGoogle Scholar
  96. 96.
    Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–40.PubMedCrossRefGoogle Scholar
  97. 97.
    Sedivy JM, Banumathy G, Adams PD. Aging by epigenetics – a consequence of chromatin damage? Exp Cell Res. 2008;314(9):1909–17.PubMedCrossRefGoogle Scholar
  98. 98.
    Timchenko NA. Aging and liver regeneration. Trends Endocrinol Metab. 2009;20(4):171–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Wang H, Iakova P, Wilde M, et al. C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Mol Cell. 2001;8(4):817–28.PubMedCrossRefGoogle Scholar
  100. 100.
    Iakova P, Awad SS, Timchenko NA. Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest. Cell. 2003;113(4):495–506.PubMedCrossRefGoogle Scholar
  101. 101.
    Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433(7027):760–4.PubMedCrossRefGoogle Scholar
  102. 102.
    Wang X, Kiyokawa H, Dennewitz MB, Costa RH. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc Natl Acad Sci U S A. 2002;99(26):16881–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Wang X, Quail E, Hung NJ, Tan Y, Ye H, Costa RH. Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. Proc Natl Acad Sci U S A. 2001;98(20):11468–73.PubMedCrossRefGoogle Scholar
  104. 104.
    Wang GL, Salisbury E, Shi X, Timchenko L, Medrano EE, Timchenko NA. HDAC1 cooperates with C/EBPalpha in the inhibition of liver proliferation in old mice. J Biol Chem. 2008;283(38):26169–78.PubMedCrossRefGoogle Scholar
  105. 105.
    Ledda-Columbano GM, Pibiri M, Cossu C, Molotzu F, Locker J, Columbano A. Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP. Hepatology. 2004;40(4):981–8.PubMedGoogle Scholar
  106. 106.
    Columbano A, Simbula M, Pibiri M, et al. Potential utility of xenobiotic mitogens in the context of liver regeneration in the elderly and living-related transplantation. Lab Invest. 2008;88(4):408–15.PubMedCrossRefGoogle Scholar
  107. 107.
    Columbano A, Simbula M, Pibiri M, et al. Triiodothyronine stimulates hepatocyte proliferation in two models of impaired liver regeneration. Cell Prolif. 2008;41(3):521–31.PubMedCrossRefGoogle Scholar
  108. 108.
    Bockhorn M, Frilling A, Benko T, et al. Tri-iodothyronine as a stimulator of liver regeneration after partial and subtotal hepatectomy. Eur Surg Res. 2007;39(1):58–63.PubMedCrossRefGoogle Scholar
  109. 109.
    Ben-Haim M, Emre S, Fishbein TM, et al. Critical graft size in adult-to-adult living donor liver transplantation: impact of the recipient’s disease. Liver Transpl. 2001;7(11):948–53.PubMedCrossRefGoogle Scholar
  110. 110.
    Pacheco-Moreira LF, Enne M, Balbi E, et al. Selection of donors for living donor liver transplantation in a single center of a developing country: lessons learned from the first 100 cases. Pediatr Transplant. 2006;10(3):311–5.PubMedCrossRefGoogle Scholar
  111. 111.
    Moreno Gonzalez E, Meneu Diaz JC, Garcia Garcia I, et al. Live liver donation: a prospective analysis of exclusion criteria for healthy and potential donors. Transplant Proc. 2003;35(5):1787–90.PubMedCrossRefGoogle Scholar
  112. 112.
    Yokoi H, Isaji S, Yamagiwa K, et al. The role of living-donor liver transplantation in surgical treatment for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2006;13(2):123–30.PubMedCrossRefGoogle Scholar
  113. 113.
    Bockhorn M, Goralski M, Prokofiev D, et al. VEGF is important for early liver regeneration after partial hepatectomy. J Surg Res. 2007;138(2):291–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Florman S, Miller CM. Live donor liver transplantation. Liver Transpl. 2006;12(4):499–510.PubMedCrossRefGoogle Scholar
  115. 115.
    Lechler RI, Sykes M, Thomson AW, Turka LA. Organ transplantation – how much of the promise has been realized? Nat Med. 2005;11(6):605–13.PubMedCrossRefGoogle Scholar
  116. 116.
    Malik R, Habib M, Tootle R, Hodgson H. Exogenous thyroid hormone induces liver enlargement, whilst maintaining regenerative potential – a study relevant to donor preconditioning. Am J Transplant. 2005;5(8):1801–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.PubMedCrossRefGoogle Scholar
  118. 118.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.PubMedCrossRefGoogle Scholar
  119. 119.
    Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674–87.PubMedCrossRefGoogle Scholar
  120. 120.
    Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol. 2009;25(3):186–94.PubMedCrossRefGoogle Scholar
  121. 121.
    Pitot HC. Altered hepatic foci: their role in murine hepatocarcinogenesis. Annu Rev Pharmacol Toxicol. 1990;30:465–500.PubMedCrossRefGoogle Scholar
  122. 122.
    Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31(4):339–46.PubMedCrossRefGoogle Scholar
  123. 123.
    Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int. 2005;25(1):16–27.PubMedCrossRefGoogle Scholar
  124. 124.
    Peraino C, Fry RJ, Staffeldt E. Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res. 1971;31(10):1506–12.PubMedGoogle Scholar
  125. 125.
    Pitot HC, Barsness L, Goldsworthy T, Kitagawa T. Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature. 1978;271(5644):456–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Shinozuka H, Sells MA, Katyal SL, Sell S, Lombardi B. Effects of a choline-devoid diet on the emergence of gamma-glutamyltranspeptidase-positive foci in the liver of carcinogen-treated rats. Cancer Res. 1979;39(7 Pt 1):2515–21.PubMedGoogle Scholar
  127. 127.
    Solt D, Farber E. New principle for the analysis of chemical carcinogenesis. Nature. 1976;263(5579):701–3.CrossRefGoogle Scholar
  128. 128.
    Farber E, Sarma DS. Hepatocarcinogenesis: a dynamic cellular perspective. Lab Invest. 1987;56(1):4–22.PubMedGoogle Scholar
  129. 129.
    Schulte-Hermann R, Bursch W, Grasl-Kraupp B. Active cell death (apoptosis) in liver biology and disease, vol. 13. Philadelphia: Saunders; 1995.Google Scholar
  130. 130.
    Yokoyama S, Sells MA, Reddy TV, Lombardi B. Hepatocarcinogenic and promoting action of a choline-devoid diet in the rat. Cancer Res. 1985;45(6):2834–42.PubMedGoogle Scholar
  131. 131.
    Farber E. Cellular biochemistry of the stepwise development of cancer with chemicals: G. H. A. Clowes memorial lecture. Cancer Res. 1984;44(12 Pt 1):5463–74.PubMedGoogle Scholar
  132. 132.
    Enomoto K, Farber E. Kinetics of phenotypic maturation of remodeling of hyperplastic nodules during liver carcinogenesis. Cancer Res. 1982;42(6):2330–5.PubMedGoogle Scholar
  133. 133.
    Glauert HP, Schwarz M, Pitot HC. The phenotypic stability of altered hepatic foci: effect of the short-term withdrawal of phenobarbital and of the long-term feeding of purified diets after the withdrawal of phenobarbital. Carcinogenesis. 1986;7(1):117–21.PubMedCrossRefGoogle Scholar
  134. 134.
    Chandar N, Lombardi B. Liver cell proliferation and incidence of hepatocellular carcinomas in rats fed consecutively a choline-devoid and a choline-supplemented diet. Carcinogenesis. 1988;9(2):259–63.PubMedCrossRefGoogle Scholar
  135. 135.
    Bursch W, Lauer B, Timmermann-Trosiener I, Barthel G, Schuppler J, Schulte-Hermann R. Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis. 1984;5(4):453–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Garcea R, Daino L, Pascale R, et al. Inhibition of promotion and persistent nodule growth by S-adenosyl-L-methionine in rat liver carcinogenesis: role of remodeling and apoptosis. Cancer Res. 1989;49(7):1850–6.PubMedGoogle Scholar
  137. 137.
    Ledda-Columbano GM, Perra A, Loi R, Shinozuka H, Columbano A. Cell proliferation induced by triiodothyronine in rat liver is associated with nodule regression and reduction of hepatocellular carcinomas. Cancer Res. 2000;60(3):603–9.PubMedGoogle Scholar
  138. 138.
    Perra A, Kowalik MA, Pibiri M, Ledda-Columbano GM, Columbano A. Thyroid hormone receptor ligands induce regression of rat preneoplastic liver lesions causing their reversion to a differentiated phenotype. Hepatology. 2009;49(4):1287–96.PubMedCrossRefGoogle Scholar
  139. 139.
    Ledda-Columbano GM, Perra A, Concas D, et al. Different effects of the liver mitogens triiodo-thyronine and ciprofibrate on the development of rat hepatocellular carcinoma. Toxicol Pathol. 2003;31(1):113–20.PubMedGoogle Scholar
  140. 140.
    Hayashi M, Tamura T, Kuroda J, et al. Different inhibitory effects in the early and late phase of treatment with KAT-681, a liver-selective thyromimetic, on rat hepatocarcinogenesis induced by 2-acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation. Toxicol Sci. 2005;84(1):22–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Lin KH, Wu YH, Chen SL. Impaired interaction of mutant thyroid hormone receptors associated with human hepatocellular carcinoma with transcriptional coregulators. Endocrinology. 2001;142(2):653–62.PubMedCrossRefGoogle Scholar
  142. 142.
    Lin KH, Zhu XG, Hsu HC, et al. Dominant negative activity of mutant thyroid hormone alpha1 receptors from patients with hepatocellular carcinoma. Endocrinology. 1997;138(12):5308–15.PubMedCrossRefGoogle Scholar
  143. 143.
    Laszlo V, Dezso K, Baghy K, et al. Triiodothyronine accelerates differentiation of rat liver progenitor cells into hepatocytes. Histochem Cell Biol. 2008;130(5):1005–14.PubMedCrossRefGoogle Scholar
  144. 144.
    Pound AW, McGuire LJ. Repeated partial hepatectomy as a promoting stimulus for carcinogenic response of liver to nitrosamines in rats. Br J Cancer. 1978;37(4):585–94.PubMedCrossRefGoogle Scholar
  145. 145.
    Ledda-Columbano GM, Columbano A, Pani P. Lead and liver cell proliferation. Effect of repeated administrations. Am J Pathol. 1983;113(3):315–20.PubMedGoogle Scholar
  146. 146.
    Ledda-Columbano GM, Perra A, Piga R, et al. Cell proliferation induced by 3, 3’, 5-triiodo-L-thyronine is associated with a reduction in the number of preneoplastic hepatic lesions. Carcinogenesis. 1999;20(12):2299–304.PubMedCrossRefGoogle Scholar
  147. 147.
    Santoni-Rugiu E, Nagy P, Jensen MR, Factor VM, Thorgeirsson SS. Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. Am J Pathol. 1996;149(2):407–28.PubMedGoogle Scholar
  148. 148.
    Eacho PI, Lanier TL, Brodhecker CA. Hepatocellular DNA synthesis in rats given peroxisome proliferating agents: comparison of WY-14, 643 to clofibric acid, nafenopin and LY171883. Carcinogenesis. 1991;12(9):1557–61.PubMedCrossRefGoogle Scholar
  149. 149.
    Lake BG, Evans JG, Cunninghame ME, Price RJ. Comparison of the hepatic effects of nafenopin and WY-14, 643 on peroxisome proliferation and cell replication in the rat and Syrian hamster. Environ Health Perspect. 1993;101 Suppl 5:241–7.PubMedCrossRefGoogle Scholar
  150. 150.
    Heindryckx F, Colle I, Van Vlierberghe H. Experimental mouse models for hepatocellular carcinoma research. Int J Exp Pathol. 2009;90(4):367–86.PubMedCrossRefGoogle Scholar
  151. 151.
    Trichopoulos D, Lipworth L, Petridou E, Adami H. Epidemiology of cancer. Philadelphia: Lippincott-Raven; 1997.Google Scholar
  152. 152.
    Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E. Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinoma. Hepatology. 1997;25(4):862–6.PubMedCrossRefGoogle Scholar
  153. 153.
    Prat M, Narsimhan RP, Crepaldi T, Nicotra MR, Natali PG, Comoglio PM. The receptor encoded by the human c-MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors. Int J Cancer. 1991;49(3):323–8.PubMedCrossRefGoogle Scholar
  154. 154.
    Boix L, Rosa JL, Ventura F, et al. c-met mRNA overexpression in human hepatocellular carcinoma. Hepatology. 1994;19(1):88–91.PubMedCrossRefGoogle Scholar
  155. 155.
    Suzuki K, Hayashi N, Yamada Y, et al. Expression of the c-met protooncogene in human hepatocellular carcinoma. Hepatology. 1994;20(5):1231–6.PubMedCrossRefGoogle Scholar
  156. 156.
    Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol. 2001;153(5):1023–34.PubMedCrossRefGoogle Scholar
  157. 157.
    Tward AD, Jones KD, Yant S, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A. 2007;104(37):14771–6.PubMedCrossRefGoogle Scholar
  158. 158.
    Kaposi-Novak P, Lee J-S, Gomez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest. 2006;116(6):1582–95.PubMedCrossRefGoogle Scholar
  159. 159.
    Takami T, Kaposi-Novak P, Uchida K, et al. Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine induced hepatocarcinogenesis. Cancer Res. 2007;67(20):9844–51.PubMedCrossRefGoogle Scholar
  160. 160.
    Marx-Stoelting P, Borowiak M, Knorpp T, Birchmeier C, Buchmann A, Schwarz M. Hepatocarcinogenesis in mice with a conditional knockout of the hepatocyte growth factor receptor c-Met. Int J Cancer. 2009;124(8):1767–72.PubMedCrossRefGoogle Scholar
  161. 161.
    Thorgeirsson SS, Santoni-Rugiu E. Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis. Br J Clin Pharmacol. 1996;42(1):43–52.PubMedCrossRefGoogle Scholar
  162. 162.
    Sakata H, Takayama H, Sharp R, Rubin JS, Merlino G, LaRochelle WJ. Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal development, and tumor formation in transgenic mouse livers. Cell Growth Differ. 1996;7(11):1513–23.PubMedGoogle Scholar
  163. 163.
    Suga T, Motoki Y, Tamura H, Watanabe T. Involvement of hepatocyte growth factor on hepatocarcinogenesis induced by peroxisome proliferators. Cell Biochem Biophys. 2000;32:221–8.PubMedCrossRefGoogle Scholar
  164. 164.
    Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis – a look outside the nucleus. Science. 2000;287(5458):1606–9.PubMedCrossRefGoogle Scholar
  165. 165.
    Laurent-Puig P, Legoix P, Bluteau O, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120(7):1763–73.PubMedCrossRefGoogle Scholar
  166. 166.
    Zucman-Rossi J, Benhamouche S, Godard C, et al. Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas. Oncogene. 2007;26(5):774–80.PubMedCrossRefGoogle Scholar
  167. 167.
    Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275(5307):1787–90.PubMedCrossRefGoogle Scholar
  168. 168.
    Strovel ET, Wu D, Sussman DJ. Protein phosphatase 2Calpha dephosphorylates axin and activates LEF-1-dependent transcription. J Biol Chem. 2000;275(4):2399–403.PubMedCrossRefGoogle Scholar
  169. 169.
    Sun TQ, Lu B, Feng JJ, et al. PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nat Cell Biol. 2001;3(7):628–36.PubMedCrossRefGoogle Scholar
  170. 170.
    de La Coste A, Romagnolo B, Billuart P, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998;95(15):8847–51.CrossRefGoogle Scholar
  171. 171.
    Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999;155(3):703–10.PubMedCrossRefGoogle Scholar
  172. 172.
    Huang H, Fujii H, Sankila A, et al. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol. 1999;155(6):1795–801.PubMedCrossRefGoogle Scholar
  173. 173.
    Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol. 2000;157(3):763–70.PubMedCrossRefGoogle Scholar
  174. 174.
    Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis. J Pathol. 2001;193(1):95–9101.PubMedCrossRefGoogle Scholar
  175. 175.
    Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer. 2001;92(1):136–45.PubMedCrossRefGoogle Scholar
  176. 176.
    Schmitt-Graff A, Ertelt V, Allgaier H-P, et al. Cellular retinol-binding protein-1 in hepatocellular carcinoma correlates with beta-catenin, Ki-67 index, and patient survival. Hepatology. 2003;38(2):470–80.PubMedCrossRefGoogle Scholar
  177. 177.
    Cadoret A, Ovejero C, Saadi-Kheddouci S, et al. Hepatomegaly in transgenic mice expressing an oncogenic form of beta-catenin. Cancer Res. 2001;61(8):3245–9.PubMedGoogle Scholar
  178. 178.
    Tan X, Apte U, Micsenyi A, et al. Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver. Gastroenterology. 2005;129(1):285–302.PubMedCrossRefGoogle Scholar
  179. 179.
    Harada N, Miyoshi H, Murai N, et al. Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. Cancer Res. 2002;62(7):1971–7.PubMedGoogle Scholar
  180. 180.
    Colnot S, Decaens T, Niwa-Kawakita M, et al. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci U S A. 2004;101(49):17216–21.PubMedCrossRefGoogle Scholar
  181. 181.
    Aydinlik H, Nguyen TD, Moennikes O, Buchmann A, Schwarz M. Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta-catenin-mutated mouse liver tumors. Oncogene. 2001;20(53):7812–6.PubMedCrossRefGoogle Scholar
  182. 182.
    Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999;19(1):1–11.PubMedGoogle Scholar
  183. 183.
    Grandori C, Cowley SM, James LP, Eisenman RN. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol. 2000;16:653–99.PubMedCrossRefGoogle Scholar
  184. 184.
    Hoffman B, Liebermann DA. The proto-oncogene c-myc and apoptosis. Oncogene. 1998;17(25):3351–7.PubMedCrossRefGoogle Scholar
  185. 185.
    Obaya AJ, Mateyak MK, Sedivy JM. Mysterious liaisons: the relationship between c-Myc and the cell cycle. Oncogene. 1999;18(19):2934–41.PubMedCrossRefGoogle Scholar
  186. 186.
    Evan G, Littlewood T. A matter of life and cell death. Science. 1998;281(5381):1317–22.PubMedCrossRefGoogle Scholar
  187. 187.
    Ikeguchi M, Hirooka Y. Expression of c-myc mRNA in hepatocellular carcinomas, noncancerous livers, and normal livers. Pathobiology. 2004;71(5):281–6.PubMedCrossRefGoogle Scholar
  188. 188.
    Sandgren EP, Quaife CJ, Pinkert CA, Palmiter RD, Brinster RL. Oncogene-induced liver neoplasia in transgenic mice. Oncogene. 1989;4(6):715–24.PubMedGoogle Scholar
  189. 189.
    Murakami H, Sanderson ND, Nagy P, Marino PA, Merlino G, Thorgeirsson SS. 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. 1993;53(8):1719–23.PubMedGoogle Scholar
  190. 190.
    Wu Y, Renard CA, Apiou F, et al. Recurrent allelic deletions at mouse chromosomes 4 and 14 in Myc-induced liver tumors. Oncogene. 2002;21(10):1518–26.PubMedCrossRefGoogle Scholar
  191. 191.
    Simile MM, De Miglio MR, Muroni MR, et al. Down-regulation of c-myc and Cyclin D1 genes by antisense oligodeoxy nucleotides inhibits the expression of E2F1 and in vitro growth of HepG2 and Morris 5123 liver cancer cells. Carcinogenesis. 2004;25(3):333–41.PubMedCrossRefGoogle Scholar
  192. 192.
    Calvisi DF, Thorgeirsson SS. Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer. Toxicol Pathol. 2005;33(1):181–4.PubMedCrossRefGoogle Scholar
  193. 193.
    Cheung RSY, Brooling JT, Johnson MM, Riehle KJ, Campbell JS, Fausto N. Interactions between MYC and transforming growth factor alpha alter the growth and tumorigenicity of liver progenitor cells. Carcinogenesis. 2007;28(12):2624–31.PubMedCrossRefGoogle Scholar
  194. 194.
    Cavin LG, Wang F, Factor VM, et al. Transforming growth factor-alpha inhibits the intrinsic pathway of c-Myc-induced apoptosis through activation of nuclear factor-kappaB in murine hepatocellular carcinomas. Mol Cancer Res. 2005;3(7):403–12.PubMedCrossRefGoogle Scholar
  195. 195.
    Santoni-Rugiu E, Jensen MR, Thorgeirsson SS. Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor alpha. Cancer Res. 1998;58(1):123–34.PubMedGoogle Scholar
  196. 196.
    Shachaf CM, Kopelman AM, Arvanitis C, et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004;431(7012):1112–7.PubMedCrossRefGoogle Scholar
  197. 197.
    Jochum W, Passegue E, Wagner EF. AP-1 in mouse development and tumorigenesis. Oncogene. 2001;20(19):2401–12.PubMedCrossRefGoogle Scholar
  198. 198.
    Vogt PK. Jun, the oncoprotein. Oncogene. 2001;20(19):2365–77.PubMedCrossRefGoogle Scholar
  199. 199.
    Yuen MF, Wu PC, Lai VC, Lau JY, Lai CL. Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma. Cancer. 2001;91(1):106–12.PubMedCrossRefGoogle Scholar
  200. 200.
    Johnson R, Spiegelman B, Hanahan D, Wisdom R. Cellular transformation and malignancy induced by ras require c-jun. Mol Cell Biol. 1996;16(8):4504–11.PubMedGoogle Scholar
  201. 201.
    Schreiber M, Kolbus A, Piu F, et al. Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev. 1999;13(5):607–19.PubMedCrossRefGoogle Scholar
  202. 202.
    Knight B, Yeoh GC, Husk KL, et al. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J Exp Med. 2000;192(12):1809–18.PubMedCrossRefGoogle Scholar
  203. 203.
    Kanzler S, Meyer E, Lohse AW, et al. Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene. 2001;20(36):5015–24.PubMedCrossRefGoogle Scholar
  204. 204.
    Eferl R, Ricci R, Kenner L, et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell. 2003;112(2):181–92.PubMedCrossRefGoogle Scholar
  205. 205.
    Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002;2(2):103–12.PubMedCrossRefGoogle Scholar
  206. 206.
    Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007;27(1):55–76.PubMedCrossRefGoogle Scholar
  207. 207.
    Harvey M, McArthur MJ, Montgomery CA, Butel JS, Bradley A, Donehower LA. Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet. 1993;5(3):225–9.PubMedCrossRefGoogle Scholar
  208. 208.
    Kemp CJ. Hepatocarcinogenesis in p53-deficient mice. Mol Carcinog. 1995;12(3):132–6.PubMedCrossRefGoogle Scholar
  209. 209.
    Dass SB, Bucci TJ, Heflich RH, Casciano DA. Evaluation of the transgenic p53+/- mouse for detecting genotoxic liver carcinogens in a short-term bioassay. Cancer Lett. 1999;143(1):81–5.PubMedCrossRefGoogle Scholar
  210. 210.
    Sukata T, Ozaki K, Uwagawa S, et al. Organ-specific, carcinogen-induced increases in cell proliferation in p53-deficient mice. Cancer Res. 2000;60(1):74–9.PubMedGoogle Scholar
  211. 211.
    French JE, Lacks GD, Trempus C, et al. Loss of heterozygosity frequency at the Trp53 locus in p53-deficient (+/-) mouse tumors is carcinogen-and tissue-dependent. Carcinogenesis. 2001;22(1):99–9106.PubMedCrossRefGoogle Scholar
  212. 212.
    Uehara T, Kashida Y, Watanabe T, et al. Susceptibility of liver proliferative lesions in heterozygous p53 deficient CBA mice to various carcinogens. J Vet Med Sci. 2002;64(7):551–6.PubMedCrossRefGoogle Scholar
  213. 213.
    Jaworski M, Hailfinger S, Buchmann A, et al. Human p53 knock-in (hupki) mice do not differ in liver tumor response from their counterparts with murine p53. Carcinogenesis. 2005;26(10):1829–34.PubMedCrossRefGoogle Scholar
  214. 214.
    Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445(7128):656–60.PubMedCrossRefGoogle Scholar
  215. 215.
    Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501–9.PubMedCrossRefGoogle Scholar
  216. 216.
    Hassan MM, Kaseb A, Li D, et al. Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States. Hepatology. 2009;49(5):1563–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Giovanna Maria Ledda-Columbano
  • Amedeo Columbano
    • 1
  1. 1.Department of Toxicology, School of MedicineUniversity of CagliariCagliariItaly

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