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Hepatology International

, Volume 8, Supplement 2, pp 452–457 | Cite as

Mechanisms of alcohol-induced hepatocellular carcinoma

  • Sreetha Sidharthan
  • Shyam KottililEmail author
Supplement Issue: ALPD

Abstract

Chronic alcohol abuse is a major risk factor for hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide. Alcohol can also function synergistically with other risk factors to cause HCC. Hence, alcohol consumption is a major factor affecting hepatic carcinogenesis in millions and the cause of a substantial public health burden. Chronic alcohol consumption interferes with several host anti-tumor mechanisms, thereby facilitating hepatocyte proliferation and tumorigenesis. This review summarizes the major mechanisms of alcohol-induced HCC. These include pathways of ethanol metabolism, alcohol-induced oxidative stress and hypomethylation of DNA, and interplay of alcohol with iron elevation, retinoid metabolism, the immune system, inflammatory pathways, and neoangiogenesis. The relevance of each pathway in affecting HCC transformation is a topic of intense investigation. Ongoing research will enhance our insight into the alcohol-induced occurrence of HCC and offer hope in developing better therapeutics.

Keywords

Alcohol HCC Carcinogenesis 

Notes

Acknowledgements

This research was supported by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases, and the Clinical Research Center). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Conflict of interest

Sreetha Sidharthan and Shyam Kottilil have no conflicts of interest to report.

References

  1. 1.
    Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–543PubMedCrossRefGoogle Scholar
  2. 2.
    Marrero JA. Hepatocellular carcinoma. Curr Opin Gastroenterol 2005;21:308–312PubMedCrossRefGoogle Scholar
  3. 3.
    El-Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 2000;160:3227–3230PubMedCrossRefGoogle Scholar
  4. 4.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557–2576PubMedCrossRefGoogle Scholar
  5. 5.
    Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35–S50PubMedCrossRefGoogle Scholar
  6. 6.
    El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–50PubMedCrossRefGoogle Scholar
  7. 7.
    Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC. Increase in primary liver cancer in the UK, 1979–94. Lancet 1997;350:1142–1143PubMedCrossRefGoogle Scholar
  8. 8.
    Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004;127:S87–S96PubMedCrossRefGoogle Scholar
  9. 9.
    Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002;155:323–331PubMedCrossRefGoogle Scholar
  10. 10.
    Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Croce LS, Mazzoran L, et al. Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut 1999;44:874–880PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Kew MC. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int 2003;23:405–409PubMedCrossRefGoogle Scholar
  12. 12.
    Dellarco VL. A mutagenicity assessment of acetaldehyde. Mutat Res 1988;195:1–20PubMedCrossRefGoogle Scholar
  13. 13.
    Helander A, Lindahl-Kiessling K. Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutat Res 1991;264:103–107PubMedCrossRefGoogle Scholar
  14. 14.
    Simanowski UA, Suter P, Russell RM, Heller M, Waldherr R, Ward R, et al. Enhancement of ethanol induced rectal mucosal hyper regeneration with age in F344 rats. Gut 1994;35:1102–1106PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Lieber CS, DeCarli LM. The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo. J Pharmacol Exp Ther 1972;181:279–287PubMedGoogle Scholar
  16. 16.
    Matsuda T, Terashima I, Matsumoto Y, Yabushita H, Matsui S, Shibutani S. Effective utilization of N 2-ethyl-2′-deoxyguanosine triphosphate during DNA synthesis catalyzed by mammalian replicative DNA polymerases. Biochemistry 1999;38:929–935PubMedCrossRefGoogle Scholar
  17. 17.
    Brooks PJ, Theruvathu JA. DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. Alcohol 2005;35:187–193PubMedCrossRefGoogle Scholar
  18. 18.
    Espina N, Lima V, Lieber CS, Garro AJ. In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase. Carcinogenesis 1988;9:761–766PubMedCrossRefGoogle Scholar
  19. 19.
    Lieber CS. Alcohol and the liver: 1994 update. Gastroenterology 1994;106:1085–1105PubMedGoogle Scholar
  20. 20.
    Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993;328:1828–1835PubMedCrossRefGoogle Scholar
  21. 21.
    Albano E, Goria-Gatti L, Clot P, Jannone A, Tomasi A. Possible role of free radical intermediates in hepatotoxicity of hydrazine derivatives. Toxicol Ind Health 1993;9:529–538PubMedCrossRefGoogle Scholar
  22. 22.
    Dupont I, Lucas D, Clot P, Menez C, Albano E. Cytochrome P4502E1 inducibility and hydroxyethyl radical formation among alcoholics. J Hepatol 1998;28:564–671PubMedCrossRefGoogle Scholar
  23. 23.
    Bradford BU, Kono H, Isayama F, Kosyk O, Wheeler MD, Akiyama TE, et al. Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanol-induced oxidative DNA damage in rodent liver. Hepatology 2005;41:336–344PubMedCrossRefGoogle Scholar
  24. 24.
    Morgan K, French SW, Morgan TR. Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology 2002;36:122–134PubMedCrossRefGoogle Scholar
  25. 25.
    Aleynik SI, Leo MA, Aleynik MK, Lieber CS. Increased circulating products of lipid peroxidation in patients with alcoholic liver disease. Alcohol Clin Exp Res 1998;22:192–196PubMedCrossRefGoogle Scholar
  26. 26.
    Hu W, Feng Z, Eveleigh J, Iyer G, Pan J, Amin S, et al. The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis 2002;23:1781–1789PubMedCrossRefGoogle Scholar
  27. 27.
    Fernandez-Checa JC, Kaplowitz N. Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicol Appl Pharmacol 2005;204:263–273PubMedCrossRefGoogle Scholar
  28. 28.
    Kawase T, Kato S, Lieber CS. Lipid peroxidation and antioxidant defense systems in rat liver after chronic ethanol feeding. Hepatology 1989;10:815–821PubMedCrossRefGoogle Scholar
  29. 29.
    Rouach H, Fataccioli V, Gentil M, French SW, Morimoto M, Nordmann R. Effect of chronic ethanol feeding on lipid peroxidation and protein oxidation in relation to liver pathology. Hepatology 1997;25:351–355PubMedCrossRefGoogle Scholar
  30. 30.
    Polavarapu R, Spitz DR, Sim JE, Follansbee MH, Oberley LW, Rahemtulla A, Nanji AA. Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and fish oil. Hepatology 1998;27:1317–1323PubMedCrossRefGoogle Scholar
  31. 31.
    Seitz HK, Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 2006;387:349–360PubMedCrossRefGoogle Scholar
  32. 32.
    Pogribny IP, Basnakian AG, Miller BJ, Lopatina NG, Poirier LA, James SJ. Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res 1995;55:1894–1901PubMedGoogle Scholar
  33. 33.
    Lauret E, Rodriguez M, Gonzalez S, Linares A, Lopez-Vazquez A, Martinez-Borra J, et al. HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma. Am J Gastroenterol 2002;97:1016–1021PubMedCrossRefGoogle Scholar
  34. 34.
    Petersen DR. Alcohol, iron-associated oxidative stress, and cancer. Alcohol 2005;35:243–249PubMedCrossRefGoogle Scholar
  35. 35.
    Marrogi AJ, Khan MA, van Gijssel HE, Welsh JA, Rahim H, Demetris AJ, et al. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma. J Natl Cancer Inst 2001;93:1652–1655PubMedCrossRefGoogle Scholar
  36. 36.
    Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996;10:940–954PubMedGoogle Scholar
  37. 37.
    Leo MA, Lieber CS. Hepatic vitamin A depletion in alcoholic liver injury. N Engl J Med 1982;307:597–601PubMedCrossRefGoogle Scholar
  38. 38.
    Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 1999;69:1071–1085PubMedGoogle Scholar
  39. 39.
    Wang XD, Liu C, Chung J, Stickel F, Seitz HK, Russell RM. Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver. Hepatology 1998;28:744–750PubMedCrossRefGoogle Scholar
  40. 40.
    Chung J, Liu C, Smith DE, Seitz HK, Russell RM, Wang XD. Restoration of retinoic acid concentration suppresses ethanol-enhanced c-Jun expression and hepatocyte proliferation in rat liver. Carcinogenesis 2001;22:1213–1219PubMedCrossRefGoogle Scholar
  41. 41.
    Trinchieri G. Biology of natural killer cells. Adv Immunol 1989;47:187–376PubMedCrossRefGoogle Scholar
  42. 42.
    Laso FJ, Madruga JI, Giron JA, Lopez A, Ciudad J, San Miguel JF, et al. Decreased natural killer cytotoxic activity in chronic alcoholism is associated with alcohol liver disease but not active ethanol consumption. Hepatology 1997;25:1096–1100PubMedCrossRefGoogle Scholar
  43. 43.
    Cook RT, Garvey MJ, Booth BM, Goeken JA, Stewart B, Noel M. Activated CD-8 cells and HLA DR expression in alcoholics without overt liver disease. J Clin Immunol 1991;11:246–253PubMedCrossRefGoogle Scholar
  44. 44.
    Koike K, Tsutsumi T, Miyoshi H, Shinzawa S, Shintani Y, Fujie H, et al. Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis. J Gastroenterol Hepatol 2008;23(Suppl 1):S87–S91PubMedCrossRefGoogle Scholar
  45. 45.
    Machida K, Tsukamoto H, Mkrtchyan H, Duan L, Dynnyk A, Liu HM, et al. Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci USA 2009;106:1548–1553PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Ribatti D, Vacca A, Nico B, Sansonno D, Dammacco F. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma. Cancer Treat Rev 2006;32:437–444PubMedCrossRefGoogle Scholar
  47. 47.
    Bauer I, Bauer M, Pannen BH, Leinwand MJ, Zhang JX, Clemens MG. Chronic ethanol consumption exacerbates liver injury following hemorrhagic shock: role of sinusoidal perfusion failure. Shock 1995;4:324–331PubMedCrossRefGoogle Scholar
  48. 48.
    Karaa A, Kamoun WS, Clemens MG. Chronic ethanol sensitizes the liver to endotoxin via effects on endothelial nitric oxide synthase regulation. Shock 2005;24:447–454PubMedCrossRefGoogle Scholar
  49. 49.
    Bjarnason I, Peters TJ, Wise RJ. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet 1984;1:179–182PubMedCrossRefGoogle Scholar
  50. 50.
    Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 2008;48:322–335PubMedCrossRefGoogle Scholar
  51. 51.
    Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 1995;108:218–224PubMedCrossRefGoogle Scholar
  52. 52.
    Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG. Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol 2001;166:4737–4742PubMedCrossRefGoogle Scholar
  53. 53.
    Urbaschek R, McCuskey RS, Rudi V, Becker KP, Stickel F, Urbaschek B, et al. Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease. Alcohol Clin Exp Res 2001;25:261–268PubMedCrossRefGoogle Scholar
  54. 54.
    Bartsch H, Nair J. Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis. Cancer Detect Prev 2004;28:385–3891PubMedCrossRefGoogle Scholar
  55. 55.
    Lin MT, Juan CY, Chang KJ, Chen WJ, Kuo ML. IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1. Carcinogenesis 2001;22:1947–1953PubMedCrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2013

Authors and Affiliations

  1. 1.Critical Care Medicine Department, Department of Health and Human Services, Clinical CenterNational Institutes of HealthBethesdaUSA
  2. 2.Laboratory of Immunoregulation, Department of Health and Human ServicesNational Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA

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