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Oxidative Stress Mechanisms in Hepatocarcinogenesis

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Studies on Hepatic Disorders

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Abstract

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with multiple molecular and genetic alterations. The major etiological factors for HCC are hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). A large body of observations demonstrates that HBV, HCV, ALD, and NASH induce hepatic oxidative stress, with increased oxidative DNA damage, lipid peroxidation, and decreased activity of cellular antioxidant systems. These evidences are found both in patients and in rodent models. Here we review the mechanisms by which HCV and HBV infection, as well as NASH, promote oxidative stress. We also describe the experimental evidence supporting a mechanistic role for oxidative stress in HCC development, and the rationale for the use of antioxidants in HCC chemoprevention.

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References

  1. Goodgame B, Shaheen NJ, Galanko J, El-Serag HB (2003) The risk of end stage liver disease and hepatocellular carcinoma among persons infected with hepatitis C virus: publication bias? Am J Gastroenterol 98(11):2535–2542

    PubMed  Google Scholar 

  2. Reid AE (2001) Nonalcoholic steatohepatitis. Gastroenterology 121(3):710–723

    CAS  PubMed  Google Scholar 

  3. Befeler AS, di Bisceglie AM (2002) Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 122(6):1609–1619

    PubMed  Google Scholar 

  4. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84

    CAS  PubMed  Google Scholar 

  5. Seitz HK, Stickel F (2006) Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 387(4):349–360

    CAS  PubMed  Google Scholar 

  6. Waris G, Ahsan H (2006) Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 5:14

    PubMed  PubMed Central  Google Scholar 

  7. Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3(4):276–285

    CAS  PubMed  Google Scholar 

  8. Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192(1):1–15

    CAS  PubMed  Google Scholar 

  9. He G, Yu G-Y, Temkin V, Ogata H, Kuntzen C, Sakurai T et al (2010) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 17(3):286–297

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Marra F, Gastaldelli A, Svegliati-Baroni G, Tell G, Tiribelli C (2008) Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med 14(2):72–81

    CAS  PubMed  Google Scholar 

  11. Brenner DA, Seki E, Taura K, Kisseleva T, Deminicis S, Iwaisako K et al (2011) Non-alcoholic steatohepatitis-induced fibrosis: toll-like receptors, reactive oxygen species and Jun N-terminal kinase. Hepatol Res 41(7):683–686

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Tanaka S, Mogushi K, Yasen M, Ban D, Noguchi N, Irie T et al (2011) Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: a prospective, multicenter study. Hepatology 54(4):1273–1281

    CAS  PubMed  Google Scholar 

  13. Hsieh Y-H, Su I-J, Wang H-C, Chang W-W, Lei H-Y, Lai M-D et al (2004) Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 25(10):2023–2032

    CAS  PubMed  Google Scholar 

  14. De Maria N, Colantoni A, Fagiuoli S, Liu GJ, Rogers BK, Farinati F et al (1996) Association between reactive oxygen species and disease activity in chronic hepatitis C. Free Radic Biol Med 21(3):291–295

    PubMed  Google Scholar 

  15. Seronello S, Sheikh MY, Choi J (2007) Redox regulation of hepatitis C in nonalcoholic and alcoholic liver. Free Radic Biol Med 43(6):869–882

    CAS  PubMed  Google Scholar 

  16. Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H et al (2001) Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 61(11):4365–4370

    CAS  PubMed  Google Scholar 

  17. Seki S, Kitada T, Sakaguchi H, Nakatani K, Wakasa K (2003) Pathological significance of oxidative cellular damage in human alcoholic liver disease. Histopathology 42(4):365–371

    CAS  PubMed  Google Scholar 

  18. Ichiba M, Maeta Y, Mukoyama T, Saeki T, Yasui S, Kanbe T et al (2003) Expression of 8-hydroxy-2′-deoxyguanosine in chronic liver disease and hepatocellular carcinoma. Liver Int 23(5):338–345

    CAS  PubMed  Google Scholar 

  19. Jo M, Nishikawa T, Nakajima T, Okada Y, Yamaguchi K, Mitsuyoshi H et al (2011) Oxidative stress is closely associated with tumor angiogenesis of hepatocellular carcinoma. J Gastroenterol 46(6):809–821

    CAS  PubMed  Google Scholar 

  20. Nishikawa T, Nakajima T, Katagishi T, Okada Y, Jo M, Kagawa K et al (2009) Oxidative stress may enhance the malignant potential of human hepatocellular carcinoma by telomerase activation. Liver Int 29(6):846–856

    CAS  PubMed  Google Scholar 

  21. Chuma M, Hige S, Nakanishi M, Ogawa K, Natsuizaka M, Yamamoto Y et al (2008) 8-Hydroxy-2′-deoxy-guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 23(9):1431–1436

    PubMed  Google Scholar 

  22. Shigenaga MK, Gimeno CJ, Ames BN (1989) Urinary 8-hydroxy-2′-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A 86(24):9697–9701

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Goetz ME, Luch A (2008) Reactive species: a cell damaging rout assisting to chemical carcinogens. Cancer Lett 266(1):73–83

    CAS  PubMed  Google Scholar 

  24. Kasai H (1997) Analysis of a form of oxidative DNA damage, 8-hydroxy-2′-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res 387(3):147–163

    CAS  PubMed  Google Scholar 

  25. Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6(9):674–687

    CAS  PubMed  Google Scholar 

  26. Nakae D, Kobayashi Y, Akai H, Andoh N, Satoh H, Ohashi K et al (1997) Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine. Cancer Res 57(7):1281–1287

    CAS  PubMed  Google Scholar 

  27. Kato J, Kobune M, Nakamura T, Kuroiwa G, Takada K, Takimoto R et al (2001) Normalization of elevated hepatic 8-hydroxy-2′-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. Cancer Res 61(24):8697–8702

    CAS  PubMed  Google Scholar 

  28. Fujita N, Sugimoto R, Ma N, Tanaka H, Iwasa M, Kobayashi Y et al (2008) Comparison of hepatic oxidative DNA damage in patients with chronic hepatitis B and C. J Viral Hepat 15(7):498–507

    CAS  PubMed  Google Scholar 

  29. Tanaka S, Miyanishi K, Kobune M, Kawano Y, Hoki T, Kubo T et al (2013) Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. J Gastroenterol 48(11):1249–1258

    CAS  PubMed  Google Scholar 

  30. Bartsch H, Nair J (2006) Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch Surg 391(5):499–510

    PubMed  Google Scholar 

  31. Nair J, Srivatanakul P, Haas C, Jedpiyawongse A, Khuhaprema T, Seitz HK et al (2010) High urinary excretion of lipid peroxidation-derived DNA damage in patients with cancer-prone liver diseases. Mutat Res 683(1–2):23–28

    CAS  PubMed  Google Scholar 

  32. Esterbauer H, Gebicki J, Puhl H, Jürgens G (1992) The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med 13(4):341–390

    CAS  PubMed  Google Scholar 

  33. Chaudhary AK, Nokubo M, Reddy GR, Yeola SN, Morrow JD, Blair IA et al (1994) Detection of endogenous malondialdehyde-deoxyguanosine adducts in human liver. Science 265(5178):1580–1582

    CAS  PubMed  Google Scholar 

  34. Ji C, Rouzer CA, Marnett LJ, Pietenpol JA (1998) Induction of cell cycle arrest by the endogenous product of lipid peroxidation, malondialdehyde. Carcinogenesis 19(7):1275–1283

    CAS  PubMed  Google Scholar 

  35. El Ghissassi F, Barbin A, Nair J, Bartsch H (1995) Formation of 1, N6-ethenoadenine and 3, N4-ethenocytosine by lipid peroxidation products and nucleic acid bases. Chem Res Toxicol 8(2):278–283

    PubMed  Google Scholar 

  36. Horio Y, Chen A, Rice P, Roth JA, Malkinson AM, Schrump DS (1996) Ki-ras and p53 mutations are early and late events, respectively, in urethane-induced pulmonary carcinogenesis in A/J mice. Mol Carcinog 17(4):217–223

    CAS  PubMed  Google Scholar 

  37. Barbin A, Froment O, Boivin S, Marion MJ, Belpoggi F, Maltoni C et al (1997) p53 gene mutation pattern in rat liver tumors induced by vinyl chloride. Cancer Res 57(9):1695–1698

    CAS  PubMed  Google Scholar 

  38. Paradis V, Kollinger M, Fabre M, Holstege A, Poynard T, Bedossa P (1997) In situ detection of lipid peroxidation by-products in chronic liver diseases. Hepatology 26(1):135–142

    CAS  PubMed  Google Scholar 

  39. Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C (1998) Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 27(1):128–133

    CAS  PubMed  Google Scholar 

  40. Zhou L, Yang Y, Tian D, Wang Y (2013) Oxidative stress-induced 1, N6-ethenodeoxyadenosine adduct formation contributes to hepatocarcinogenesis. Oncol Rep 29(3):875–884

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Fujita N, Miyachi H, Tanaka H, Takeo M, Nakagawa N, Kobayashi Y et al (2009) Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev 18(2):424–432

    CAS  PubMed  Google Scholar 

  42. Kadiiska MB, Burkitt MJ, Xiang QH, Mason RP (1995) Iron supplementation generates hydroxyl radical in vivo. An ESR spin-trapping investigation. J Clin Invest 96(3):1653–1657

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cornejo P, Varela P, Videla LA, Fernández V (2005) Chronic iron overload enhances inducible nitric oxide synthase expression in rat liver. Nitric Oxide 13(1):54–61

    CAS  PubMed  Google Scholar 

  44. Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D, Fociani P et al (2001) Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am J Gastroenterol 96(8):2448–2455

    CAS  PubMed  Google Scholar 

  45. Nahon P, Ganne-Carrié N, Trinchet JC, Beaugrand M (2010) Hepatic iron overload and risk of hepatocellular carcinoma in cirrhosis. Gastroenterol Clin Biol 34(1):1–7

    CAS  PubMed  Google Scholar 

  46. Martinelli ALC, Filho ABA, Franco RF, Tavella MH, Ramalho LNZ, Zucoloto S et al (2004) Liver iron deposits in hepatitis B patients: association with severity of liver disease but not with hemochromatosis gene mutations. J Gastroenterol Hepatol 19(9):1036–1041

    CAS  PubMed  Google Scholar 

  47. Blendis L, Oren R, Halpern Z (2000) NASH: can we iron out the pathogenesis? Gastroenterology 118(5):981–983

    CAS  PubMed  Google Scholar 

  48. Videla LA, Fernández V, Tapia G, Varela P (2003) Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells. Biometals 16(1):103–111

    CAS  PubMed  Google Scholar 

  49. Sorrentino P, D’Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R (2009) Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 50(2):351–357

    CAS  PubMed  Google Scholar 

  50. Sebastiani G, Tempesta D, Alberti A (2012) Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus. J Viral Hepat 19(2):e170–e176

    CAS  PubMed  Google Scholar 

  51. Piperno A, Vergani A, Malosio I, Parma L, Fossati L, Ricci A et al (1998) Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations. Hepatology 28(4):1105–1109

    CAS  PubMed  Google Scholar 

  52. Kawamura Y, Akuta N, Sezaki H, Hosaka T, Someya T, Kobayashi M et al (2005) Determinants of serum ALT normalization after phlebotomy in patients with chronic hepatitis C infection. J Gastroenterol 40(9):901–906

    PubMed  Google Scholar 

  53. Falize L, Guillygomarc’h A, Perrin M, Lainé F, Guyader D, Brissot P et al (2006) Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 44(2):472–477

    PubMed  Google Scholar 

  54. Marshall HE, Merchant K, Stamler JS (2000) Nitrosation and oxidation in the regulation of gene expression. FASEB J 14(13):1889–1900

    CAS  PubMed  Google Scholar 

  55. Li C-Q, Wogan GN (2005) Nitric oxide as a modulator of apoptosis. Cancer Lett 226(1):1–15

    CAS  PubMed  Google Scholar 

  56. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17(10):1195–1214

    CAS  PubMed  Google Scholar 

  57. Lala PK, Chakraborty C (2001) Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol 2(3):149–156

    CAS  PubMed  Google Scholar 

  58. Urtasun R, Cubero FJ, Vera M, Nieto N (2009) Reactive nitrogen species switch on early extracellular matrix remodeling via induction of MMP1 and TNFalpha. Gastroenterology 136(4):1410–1422, e1–e4

    Google Scholar 

  59. Muriel P (2009) Role of free radicals in liver diseases. Hepatol Int 3(4):526–536

    PubMed  PubMed Central  Google Scholar 

  60. Horiike S, Kawanishi S, Kaito M, Ma N, Tanaka H, Fujita N et al (2005) Accumulation of 8-nitroguanine in the liver of patients with chronic hepatitis C. J Hepatol 43(3):403–410

    CAS  PubMed  Google Scholar 

  61. Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H et al (2001) Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin Cancer Res 7(5):1325–1332

    CAS  PubMed  Google Scholar 

  62. Roles of nitric oxide in tumor growth (1995). http://www.pnas.org/content/92/10/4392.short

    Google Scholar 

  63. Thomsen LL, Scott JM, Topley P, Knowles RG, Keerie AJ, Frend AJ (1997) Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a novel inhibitor. Cancer Res 57(15):3300–3304

    CAS  PubMed  Google Scholar 

  64. Tsan MF, Clark RN, Goyert SM, White JE (2001) Induction of TNF-α and MnSOD by endotoxin: role of membrane CD14 and toll-like receptor-4. Am J Physiol Cell Physiol 280(6):C1422–C1430

    CAS  PubMed  Google Scholar 

  65. Casaril M, Corso F, Bassi A, Capra F, Gabrielli GB, Stanzial AM et al (1994) Decreased activity of scavenger enzymes in human hepatocellular carcinoma, but not in liver metastases. Int J Clin Lab Res 24(2):94–97

    CAS  PubMed  Google Scholar 

  66. Lin MT, Wang MY, Liaw KY, Lee PH, Chien SF, Tsai JS et al (2001) Superoxide dismutase in hepatocellular carcinoma affects patient prognosis. Hepatogastroenterology 48(40):1102–1105

    CAS  PubMed  Google Scholar 

  67. Clemente C, Elba S, Buongiorno G, Guerra V, D’Attoma B, Orlando A et al (2007) Manganese superoxide dismutase activity and incidence of hepatocellular carcinoma in patients with Child-Pugh class A liver cirrhosis: a 7-year follow-up study. Liver Int 27(6):791–797

    CAS  PubMed  Google Scholar 

  68. Takami Y, Uto H, Tamai T, Sato Y, Ishida Y-I, Morinaga H et al (2010) Identification of a novel biomarker for oxidative stress induced by hydrogen peroxide in primary human hepatocytes using the 2-nitrobenzenesulfenyl chloride isotope labeling method. Hepatol Res 40(4):438–445

    CAS  PubMed  Google Scholar 

  69. Tamai T, Uto H, Takami Y, Oda K, Saishoji A, Hashiguchi M et al (2011) Serum manganese superoxide dismutase and thioredoxin are potential prognostic markers for hepatitis C virus-related hepatocellular carcinoma. World J Gastroenterol 17(44):4890–4898

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H et al (2005) CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24(3):367–380

    CAS  PubMed  Google Scholar 

  71. Fridovich I (1995) Superoxide radical and superoxide dismutases. Annu Rev Biochem 64:97–112

    CAS  PubMed  Google Scholar 

  72. Kruidenier L, van Meeteren ME, Kuiper I, Jaarsma D, Lamers CB, Zijlstra FJ et al (2003) Attenuated mild colonic inflammation and improved survival from severe DSS-colitis of transgenic Cu/Zn-SOD mice. Free Radic Biol Med 34(6):753–765

    CAS  PubMed  Google Scholar 

  73. Skrzycki M, Ścibior D, Podsiad M, Czeczot H (2008) Activity and protein level of CuZnSOD and MnSOD in benign and malignant liver tumors. Clin Biochem 41(1–2):91–96

    CAS  PubMed  Google Scholar 

  74. Chai YC, Ashraf SS, Rokutan K, Johnston RB, Thomas JA (1994) S-thiolation of individual human neutrophil proteins including actin by stimulation of the respiratory burst: evidence against a role for glutathione disulfide. Arch Biochem Biophys 310(1):273–281

    CAS  PubMed  Google Scholar 

  75. Ścibior D, Skrzycki M, Podsiad M, Czeczot H (2008) Glutathione level and glutathione-dependent enzyme activities in blood serum of patients with gastrointestinal tract tumors. Clin Biochem 41(10–11):852–858

    PubMed  Google Scholar 

  76. Ivanov AV, Bartosch B, Smirnova OA, Isaguliants MG, Kochetkov SN (2013) HCV and oxidative stress in the liver. Viruses 5(2):439–469

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Sumida Y, Niki E, Naito Y, Yoshikawa T (2013) Special issue on “Oxidative stress and redox signaling in the gastrointestinal tract and related organs” for Free Radical Research Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radic Res 47(11):869–880

    CAS  PubMed  Google Scholar 

  78. Lu SC, Mato JM (2012) S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 92(4):1515–1542

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Fernandez-Checa JC, Kaplowitz N (2005) Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicol Appl Pharmacol 204(3):263–273

    CAS  PubMed  Google Scholar 

  80. Lee K-T, Tsai S-M, Wang S-N, Lin S-K, Wu S-H, Chuang S-C et al (2007) Glutathione status in the blood and tissues of patients with virus-originated hepatocellular carcinoma. Clin Biochem 40(15):1157–1162

    CAS  PubMed  Google Scholar 

  81. Motohashi H, Yamamoto M (2004) Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 10(11):549–557

    CAS  PubMed  Google Scholar 

  82. Ivanov AV, Smirnova OA, Ivanova ON, Masalova OV, Kochetkov SN, Isaguliants MG (2011) Hepatitis C virus proteins activate NRF2/ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells. PLoS One 6(9):e24957

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Carvajal-Yepes M, Himmelsbach K, Schaedler S, Ploen D, Krause J, Ludwig L et al (2011) Hepatitis C virus impairs the induction of cytoprotective Nrf2 target genes by delocalization of small Maf proteins. J Biol Chem 286(11):8941–8951

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kitamura Y, Umemura T, Kanki K, Kodama Y, Kitamoto S, Saito K et al (2007) Increased susceptibility to hepatocarcinogenicity of Nrf2-deficient mice exposed to 2-amino-3-methylimidazo[4,5-f]quinoline. Cancer Sci 98(1):19–24

    CAS  PubMed  Google Scholar 

  85. Anisimov VN (2007) Biology of aging and cancer. Cancer Control 14(1):23–31

    PubMed  Google Scholar 

  86. Siomek A (2012) NF-κB signaling pathway and free radical impact. Acta Biochim Pol 59(3):323–331

    CAS  PubMed  Google Scholar 

  87. Kabe Y, Ando K, Hirao S, Yoshida M, Handa H (2005) Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxid Redox Signal 7(3–4):395–403

    CAS  PubMed  Google Scholar 

  88. Beraza N, Lüdde T, Assmus U, Roskams T, Vander Borght S, Trautwein C (2007) Hepatocyte-specific IKK gamma/NEMO expression determines the degree of liver injury. Gastroenterology 132(7):2504–2517

    CAS  PubMed  Google Scholar 

  89. Kamata H, Honda S-I, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120(5):649–661

    CAS  PubMed  Google Scholar 

  90. DiDonato JA, Mercurio F, Karin M (2012) NF-κB and the link between inflammation and cancer. Immunol Rev 246(1):379–400

    PubMed  Google Scholar 

  91. Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R et al (2007) Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11(2):119–132

    CAS  PubMed  Google Scholar 

  92. Maeda S, Kamata H, Luo J-L, Leffert H, Karin M (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121(7):977–990

    CAS  PubMed  Google Scholar 

  93. Sakurai T, He G, Matsuzawa A, Yu G-Y, Maeda S, Hardiman G et al (2008) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14(2):156–165

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Glauert HP, Calfee-Mason K, Li Y, Nilakantan V, Twaroski ML, Tharappel J et al (2009) The role of NF-κB in PPAR α-mediated hepatocarcinogenesis. PPAR Res 2008:286249

    PubMed Central  Google Scholar 

  95. Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM et al (2002) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122(2):366–375

    CAS  PubMed  Google Scholar 

  96. Gong G, Waris G, Tanveer R, Siddiqui A (2001) Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B. Proc Natl Acad Sci U S A 98(17):9599–9604

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Tang W, Lázaro CA, Campbell JS, Parks WT, Katze MG, Fausto N (2007) Responses of nontransformed human hepatocytes to conditional expression of full-length hepatitis C virus open reading frame. Am J Pathol 171(6):1831–1846

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Nakagawa H, Maeda S (2012) Molecular mechanisms of liver injury and hepatocarcinogenesis: focusing on the role of stress-activated MAPK. Patholog Res Int 2012:172894

    PubMed  PubMed Central  Google Scholar 

  99. Sakurai T, Kudo M, Umemura A, He G, Elsharkawy AM, Seki E et al (2013) p38α inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res 73(1):215–224

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Feng H, Hu B, Liu K-W, Li Y, Lu X, Cheng T et al (2011) Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans. J Clin Invest 121(12):4670–4684

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Koch KS, Maeda S, He G, Karin M, Leffert HL (2009) Targeted deletion of hepatocyte Ikkbeta confers growth advantages. Biochem Biophys Res Commun 380(2):349–354

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S et al (1989) Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59(6):1145–1156

    CAS  PubMed  Google Scholar 

  103. Hagen TM, Huang S, Curnutte J, Fowler P, Martinez V, Wehr CM et al (1994) Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc Natl Acad Sci U S A 91(26):12808–12812

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Lee YI, Hwang JM, Im JH, Lee YI, Kim NS, Kim DG et al (2004) Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells. J Biol Chem 279(15):15460–15471

    CAS  PubMed  Google Scholar 

  105. Shirakata Y, Koike K (2003) Hepatitis B virus X protein induces cell death by causing loss of mitochondrial membrane potential. J Biol Chem 278(24):22071–22078

    CAS  PubMed  Google Scholar 

  106. Wu Y-F, Fu S-L, Kao C-H, Yang C-W, Lin C-H, Hsu M-T et al (2008) Chemopreventive effect of silymarin on liver pathology in HBV X protein transgenic mice. Cancer Res 68(6):2033–2042

    CAS  PubMed  Google Scholar 

  107. Wang H-C, Huang W, Lai M-D, Su I-J (2006) Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis. Cancer Sci 97(8):683–688

    CAS  PubMed  Google Scholar 

  108. Su I-J, Wang H-C, Wu H-C, Huang W-Y (2008) Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection. J Gastroenterol Hepatol 23(8 Pt 1):1169–1174

    CAS  PubMed  Google Scholar 

  109. Huang SN, Chisari FV (1995) Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice. Hepatology 21(3):620–626

    CAS  PubMed  Google Scholar 

  110. Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, Matsuura Y et al (1997) Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 78(Pt 7):1527–1531

    CAS  PubMed  Google Scholar 

  111. Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K et al (1998) The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4(9):1065–1067

    CAS  PubMed  Google Scholar 

  112. Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y et al (2002) Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 122(2):352–365

    CAS  PubMed  Google Scholar 

  113. Koike K, Moriya K, Ishibashi K, Matsuura Y, Suzuki T, Saito I et al (1995) Expression of hepatitis C virus envelope proteins in transgenic mice. J Gen Virol 76(Pt 12):3031–3038

    CAS  PubMed  Google Scholar 

  114. Heindryckx F, Colle I, Van Vlierberghe H (2009) Experimental mouse models for hepatocellular carcinoma research. Int J Exp Pathol 90(4):367–386

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chrétien Y et al (2002) Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J 16(2):185–194

    CAS  PubMed  Google Scholar 

  116. Koike K (2005) Steatosis in chronic hepatitis C: fuel for overproduction of oxidative stress? J Gastroenterol 40(6):664–665

    PubMed  Google Scholar 

  117. Baric I, Cuk M, Fumić K, Vugrek O, Allen RH, Glenn B et al (2005) S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy. J Inherit Metab Dis 28(6):885–902

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Avila MA, Mingorance J, Martínez-Chantar M-L, Casado M, Martín-Sanz P, Boscá L et al (1997) Regulation of rat liver S-adenosylmethionine synthetase during septic shock: role of nitric oxide. Hepatology 25(2):391–396

    CAS  PubMed  Google Scholar 

  119. Avila MA, García-Trevijano ER, Lu SC, Corrales FJ, Mato JM (2004) Methylthioadenosine. Int J Biochem Cell Biol 36(11):2125–2130

    CAS  PubMed  Google Scholar 

  120. Latasa MU, Boukaba A, García-Trevijano ER, Torres L, Rodríguez JL, Caballeria J et al (2001) Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration. FASEB J 15(7):1248–1250

    CAS  PubMed  Google Scholar 

  121. Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H et al (2000) Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 33(6):907–914

    CAS  PubMed  Google Scholar 

  122. Martínez-Chantar ML, Corrales FJ, Martínez-Cruz LA, García-Trevijano ER, Huang Z-Z, Chen L et al (2002) Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J 16(10):1292–1294

    PubMed  Google Scholar 

  123. Lu SC, Alvarez L, Huang Z-Z, Chen L, An W, Corrales FJ et al (2001) Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci U S A 98(10):5560–5565

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Cook WS, Jain S, Jia Y, Cao WQ, Yeldandi AV, Reddy JK et al (2001) Peroxisome proliferator-activated receptor alpha-responsive genes induced in the newborn but not prenatal liver of peroxisomal fatty acyl-CoA oxidase null mice. Exp Cell Res 268(1):70–76

    CAS  PubMed  Google Scholar 

  125. Fan C-Y, Pan J, Usuda N, Yeldandi AV, Rao MS, Reddy JK (1998) Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase: implications for peroxisome proliferator-activated receptor α natural ligand metabolism. J Biol Chem 273(25):15639–15645

    CAS  PubMed  Google Scholar 

  126. Mauad TH, van Nieuwkerk CM, Dingemans KP, Smit JJ, Schinkel AH, Notenboom RG et al (1994) Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 145(5):1237–1245

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S, et al (2012) Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 142(1):140–151.e12

    Google Scholar 

  128. Katzenellenbogen M, Mizrahi L, Pappo O, Klopstock N, Olam D, Barash H et al (2007) Molecular mechanisms of the chemopreventive effect on hepatocellular carcinoma development in Mdr2 knockout mice. Mol Cancer Ther 6(4):1283–1291

    CAS  PubMed  Google Scholar 

  129. Kakehashi A, Wei M, Fukushima S, Wanibuchi H (2013) Oxidative stress in the carcinogenicity of chemical carcinogens. Cancers (Basel) 5(4):1332–1354

    PubMed Central  Google Scholar 

  130. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM et al (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317(5834):121–124

    CAS  PubMed  Google Scholar 

  131. Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31(4):339–346

    CAS  PubMed  Google Scholar 

  132. Vesselinovitch SD, Mihailovich N (1983) Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse. Cancer Res 43(9):4253–4259

    CAS  PubMed  Google Scholar 

  133. Park S, Choi Y, Um S-J, Yoon SK, Park T (2011) Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice. J Hepatol 54(5):984–993

    CAS  PubMed  Google Scholar 

  134. Lee G-H (2000) Review article: paradoxical effects of phenobarbital on mouse hepatocarcinogenesis. Toxicol Pathol 28(2):215–225

    CAS  PubMed  Google Scholar 

  135. Ingawale DK, Mandlik SK, Naik SR (2014) Models of hepatotoxicity and the underlying cellular, biochemical and immunological mechanism(s): a critical discussion. Environ Toxicol Pharmacol 37(1):118–133

    CAS  PubMed  Google Scholar 

  136. Chieli E, Malvaldi G (1984) Role of the microsomal FAD-containing monooxygenase in the liver toxicity of thioacetamide S-oxide. Toxicology 31(1):41–52

    CAS  PubMed  Google Scholar 

  137. Petermann H, Heymann S, Vogl S, Dargel R (1996) Phagocytic function and metabolite production in thioacetamide-induced liver cirrhosis: a comparative study in perfused livers and cultured Kupffer cells. J Hepatol 24(4):468–477

    CAS  PubMed  Google Scholar 

  138. Gervasi PG, Longo V, Marzano M, Saviozzi M, Malvaldi G (1989) Chronic liver injury by thioacetamide and promotion of hepatic carcinogenesis. J Cancer Res Clin Oncol 115(1):29–35

    CAS  PubMed  Google Scholar 

  139. Ahangar-Darabi M, Setorki M, Rafieian-kopaei M (2013) The effect of silymarin on liver injury induced by thioacetamide in rats. J HerbMed Pharmacol 2(2):29–33

    Google Scholar 

  140. Weisburger EK (1977) Carcinogenicity studies on halogenated hydrocarbons. Environ Health Perspect 21:7–16

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Avasarala S, Yang L, Sun Y, Leung AW-C, Chan W-Y, Cheung W-T et al (2006) A temporal study on the histopathological, biochemical and molecular responses of CCl(4)-induced hepatotoxicity in Cyp2e1-null mice. Toxicology 228(2–3):310–322

    CAS  PubMed  Google Scholar 

  142. Sheweita SA, El-Gabar MA, Bastawy M (2001) Carbon tetrachloride changes the activity of cytochrome P450 system in the liver of male rats: role of antioxidants. Toxicology 169(2):83–92

    CAS  PubMed  Google Scholar 

  143. Luckey SW, Petersen DR (2001) Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 71(3):226–240

    CAS  PubMed  Google Scholar 

  144. Dapito DH, Mencin A, Gwak G-Y, Pradere J-P, Jang M-K, Mederacke I et al (2012) Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21(4):504–516

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Pogribny IP, James SJ, Beland FA (2012) Molecular alterations in hepatocarcinogenesis induced by dietary methyl deficiency. Mol Nutr Food Res 56(1):116–125

    CAS  PubMed  Google Scholar 

  146. de Lima VMR, Oliveira CPMS, Alves VAF, Chammas MC, Oliveira EP, Stefano JT et al (2008) A rodent model of NASH with cirrhosis, oval cell proliferation and hepatocellular carcinoma. J Hepatol 49(6):1055–1061

    PubMed  Google Scholar 

  147. Lin H, Liu X-B, Yu J-J, Hua F, Hu Z-W (2013) Antioxidant N-acetylcysteine attenuates hepatocarcinogenesis by inhibiting ROS/ER stress in TLR2 deficient mouse. PLoS One 8(10):e74130

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Ueno Y, Sollano JD, Farrell GC (2009) Prevention of hepatocellular carcinoma complicating chronic hepatitis C. J Gastroenterol Hepatol 24(4):531–536

    CAS  PubMed  Google Scholar 

  149. Hayes JD, McMahon M (2001) Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett 174(2):103–113

    CAS  PubMed  Google Scholar 

  150. Bishayee A, Politis T, Darvesh AS (2010) Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma. Cancer Treat Rev 36(1):43–53

    CAS  PubMed  Google Scholar 

  151. Calvisi DF, Ladu S, Hironaka K, Factor VM, Thorgeirsson SS (2004) Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer. J Hepatol 41(5):815–822

    CAS  PubMed  Google Scholar 

  152. Nepka C, Sivridis E, Antonoglou O, Kortsaris A, Georgellis A, Taitzoglou I et al (1999) Chemopreventive activity of very low dose dietary tannic acid administration in hepatoma bearing C3H male mice. Cancer Lett 141(1–2):57–62

    CAS  PubMed  Google Scholar 

  153. Sun B, Karin M (2008) NF-kappaB signaling, liver disease and hepatoprotective agents. Oncogene 27(48):6228–6244

    CAS  PubMed  Google Scholar 

  154. Popova NV (2002) Perinatal selenium exposure decreases spontaneous liver tumorogenesis in CBA mice. Cancer Lett 179(1):39–42

    CAS  PubMed  Google Scholar 

  155. Pirola L, Fröjdö S (2008) Resveratrol: one molecule, many targets. IUBMB Life 60(5):323–332

    CAS  PubMed  Google Scholar 

  156. Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL (2009) Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys 486(2):95–102

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C (2004) Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 364(9441):1219–1228

    CAS  PubMed  Google Scholar 

  158. Murakoshi M, Nishino H, Satomi Y, Takayasu J, Hasegawa T, Tokuda H et al (1992) Potent preventive action of alpha-carotene against carcinogenesis: spontaneous liver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by beta-carotene. Cancer Res 52(23):6583–6587

    CAS  PubMed  Google Scholar 

  159. Krinsky NI (1989) Carotenoids as chemopreventive agents. Prev Med 18(5):592–602

    CAS  PubMed  Google Scholar 

  160. Lynch SR (1997) Interaction of iron with other nutrients. Nutr Rev 55(4):102–110

    CAS  PubMed  Google Scholar 

  161. Kowdley KV (2004) Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127(5):S79–S86

    CAS  PubMed  Google Scholar 

  162. Glauert HP, Calfee-Mason K, Stemm DN, Tharappel JC, Spear BT (2010) Dietary antioxidants in the prevention of hepatocarcinogenesis: a review. Mol Nutr Food Res 54(7):875–896

    CAS  PubMed  Google Scholar 

  163. Pascale RM, Simile MM, De Miglio MR, Feo F (2002) Chemoprevention of hepatocarcinogenesis: S-adenosyl-L-methionine. Alcohol 27(3):193–198

    CAS  PubMed  Google Scholar 

  164. Lu SC, Ramani K, Ou X, Lin M, Yu V, Ko K et al (2009) S-adenosylmethionine in the chemoprevention and treatment of hepatocellular carcinoma in a rat model. Hepatology 50(2):462–471

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Stagos D, Amoutzias GD, Matakos A, Spyrou A, Tsatsakis AM, Kouretas D (2012) Chemoprevention of liver cancer by plant polyphenols. Food Chem Toxicol 50(6):2155–2170

    CAS  PubMed  Google Scholar 

  166. Kwon KH, Barve A, Yu S, Huang M-T, Kong A-NT (2007) Cancer chemoprevention by phytochemicals: potential molecular targets, biomarkers and animal models. Acta Pharmacol Sin 28(9):1409–1421

    CAS  PubMed  Google Scholar 

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Acknowledgments

Work in the authors’ laboratory is funded by: The agreement between FIMA and the “UTE project CIMA”; RTICC-RD06 00200061; CIBEREhd; FIS PI10/02642, PI13/00359, PI10/00038 and PI13/00385 from Instituto de Salud Carlos III. R. Urtasun is supported by a “Torres Quevedo” contract from Ministerio de Educación, Spain.

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Authors and Affiliations

  1. Division of Hepatology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain

    Raquel Urtasun

  2. Division of Hepatology, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain

    Carmen Berasain & Matías A. Avila

  3. Networked Biomedical Research Center for Hepatic and Digestive Diseases, Clinical University of Navarra, Instituto de Salud Carlos III, Pamplona, Spain

    Carmen Berasain & Matías A. Avila

Authors
  1. Raquel Urtasun
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  2. Carmen Berasain
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  3. Matías A. Avila
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Correspondence to Carmen Berasain or Matías A. Avila .

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Editors and Affiliations

  1. Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy

    Emanuele Albano

  2. Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Torino, Italy

    Maurizio Parola

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Urtasun, R., Berasain, C., Avila, M.A. (2015). Oxidative Stress Mechanisms in Hepatocarcinogenesis. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_20

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