Skip to main content
SpringerLink
Log in

Chronic Ingestion of Ethanol Induces Hepatocellular Carcinoma in Mice Without Additional Hepatic Insult

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Chronic intake of alcohol increases the risk of gastrointestinal and hepatic carcinogenesis. The present study was focused to investigate the incidence and mechanism of pathogenesis of hepatocellular carcinoma (HCC) during chronic ingestion of alcohol without any additional hepatic injury.

Methods

Ethanol was administered to Institute for Cancer Research male mice through drinking water for 70 weeks at concentrations of 5 % (first week), 10 % (next 8 weeks), and 15 % thereafter. The animals were killed at 60 and 70 weeks, the livers were examined for hepatic tumors, and evaluated for foci of cellular alteration (FCA). Immunohistochemical staining was performed in the liver sections for cytochrome P4502E1 (CYP2E1), 4-hydroxy-nonenal (4-HNE), and proto-oncogene, c-Myc.

Results

At the 60th week, 40 % of the mice in the ethanol group had visible white nodules (5–10 mm) in the liver, but not in the control mice. At the 70th week, several larger nodules (5–22 mm) were present in the livers of 50 % mice in the ethanol group. In the control group, one mouse developed a single nodule. All nodules were histologically trabecular HCC composed of eosinophilic and vacuolated cells. In the livers of both control and ethanol group, several foci with cellular alteration were present, which were significantly higher in ethanol group. Staining for CYP2E1, 4-HNE and c-Myc depicted marked upregulation of all these molecules in the FCA.

Conclusions

Our data demonstrated that upregulation of CYP2E1 and subsequent production of reactive oxygen species along with the persistent expression of c-Myc play a significant role in the pathogenesis of HCC during chronic ingestion of ethanol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Chun JM, Kwon HJ, Sohn J, et al. Prognostic factors after early recurrence in patients who underwent curative resection for hepatocellular carcinoma. J Surg Oncol. 2011;103:148–151.

    Article  Google Scholar 

  2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  Google Scholar 

  3. Cornellà H, Alsinet C, Villanueva A. Molecular pathogenesis of hepatocellular carcinoma. Alcohol Clin Exp Res. 2011;35:821–825.

    Article  Google Scholar 

  4. French SW, Oliva J, French BA, Li J, Bardag-Gorce F. Alcohol, nutrition and liver cancer: role of Toll-like receptor signaling. World J Gastroenterol. 2010;16:1344–1348.

    Article  CAS  Google Scholar 

  5. Chemin I, Zoulim F. Hepatitis B virus-induced hepatocellular carcinoma. Cancer Lett. 2009;286:52–59.

    Article  CAS  Google Scholar 

  6. Vezali E, Aghemo A, Colombo M. A review of the treatment of chronic hepatitis C virus infection in cirrhosis. Clin Ther. 2010;32:2117–2138.

    Article  CAS  Google Scholar 

  7. Rehm J, Taylor B, Mohapatra S, et al. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev. 2010;29:437–445.

    Article  Google Scholar 

  8. Lefton HB, Rosa A, Cohen M. Diagnosis and epidemiology of cirrhosis. Med Clin N Am. 2009;93:787–799.

    Article  CAS  Google Scholar 

  9. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–346.

    Article  CAS  Google Scholar 

  10. Wong N, Lai P, Pang E, et al. Genomic aberrations in human hepatocellular carcinomas of differing etiologies. Clin Cancer Res. 2000;6:4000–4009.

    CAS  Google Scholar 

  11. Wogan GN. Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res. 1992;52:2114s–2118s.

    CAS  Google Scholar 

  12. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci. 2002;963:13–20.

    Article  Google Scholar 

  13. Pan H, Fu X, Huang W. Molecular mechanism of liver cancer. Anticancer Agents Med Chem. 2011;11:493–499.

    Article  CAS  Google Scholar 

  14. Moradpour D, Blum HE. Pathogenesis of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2005;17:477–4783.

    Article  Google Scholar 

  15. Pöschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol. 2004;39:155–165.

    Article  Google Scholar 

  16. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7:599–612.

    Article  CAS  Google Scholar 

  17. Wang Y, Millonig G, Nair J, et al. Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease. Hepatology. 2009;50:453–461.

    Article  CAS  Google Scholar 

  18. Quertemont E. Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism. Mol Psychiatry. 2004;9:570–581.

    Article  CAS  Google Scholar 

  19. Tsutsumi M, George J, Ishizawa K, Fukumura A, Takase S. Effect of chronic dietary ethanol in the promotion of N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. J Gastroenterol Hepatol. 2006;21:805–813.

    Article  Google Scholar 

  20. Lieber CS, Garro A, Leo MA, Mak KM, Worner T. Alcohol and cancer. Hepatology. 1986;6:1005–1019.

    Article  CAS  Google Scholar 

  21. Anttila S, Raunio H, Hakkola J. Cytochrome p450-mediated pulmonary metabolism of carcinogens: regulation and cross-talk in lung carcinogenesis. Am J Respir Cell Mol Biol. 2011;44:583–590.

    Article  CAS  Google Scholar 

  22. Su AI, Cooke MP, Ching KA, et al. Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA. 2002;99:4465–4470.

    Article  CAS  Google Scholar 

  23. Rice MC, O’Brien SJ. Genetic variance of laboratory outbred Swiss mice. Nature. 1980;283:157–161.

    Article  CAS  Google Scholar 

  24. McClain CJ, Hill DB, Song Z, Deaciuc I, Barve S. Monocyte activation in alcoholic liver disease. Alcohol. 2002;27:53–561.

    Article  CAS  Google Scholar 

  25. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–S50.

    Article  Google Scholar 

  26. Miller AM, Horiguchi N, Jeong WI, Radaeva S, Gao B. Molecular mechanisms of alcoholic liver disease: innate immunity and cytokines. Alcohol Clin Exp Res. 2011;35:787–793.

    Article  CAS  Google Scholar 

  27. Yam JW, Wong CM, Ng IO. Molecular and functional genetics of hepatocellular carcinoma. Front Biosci (Schol Ed). 2010;2:117–134.

    Article  Google Scholar 

  28. Beland FA, Benson RW, Mellick PW, et al. Effect of ethanol on the tumorigenicity of urethane (ethyl carbamate) in B6C3F1 mice. Food Chem Toxicol. 2005;43:1–19.

    Article  CAS  Google Scholar 

  29. Wu D, Cederbaum AI. Oxidative stress and alcoholic liver disease. Semin Liver Dis. 2009;29:141–154.

    Article  CAS  Google Scholar 

  30. Campbell JS, Hughes SD, Gilbertson DG, et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci USA. 2005;102:3389–3394.

    Article  CAS  Google Scholar 

  31. Cederbaum AI, Lu Y, Wu D. Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol. 2009;83:519–548.

    Article  CAS  Google Scholar 

  32. Amidi F, French BA, Chung D, Halsted CH, Medici V, French SW. M-30 and 4HNE are sequestered in different aggresomes in the same hepatocytes. Exp Mol Pathol. 2007;83:296–300.

    Article  CAS  Google Scholar 

  33. Maronpot RR, Haseman JK, Boorman GA, Eustis SE, Rao GN, Huff JE. Liver lesions in B6C3F1 mice: the national toxicology program, experience and position. Arch Toxicol Suppl. 1987;10:10–26.

    Article  CAS  Google Scholar 

  34. Baldrick P, Reeve L. Carcinogenicity evaluation: comparison of tumor data from dual control groups in the CD-1 mouse. Toxicol Pathol. 2007;35:562–569.

    Article  CAS  Google Scholar 

  35. Engelhardt JA, Gries CL, Long GG. Incidence of spontaneous neoplastic and nonneoplastic lesions in Charles River CD-1 mice varies with breeding origin. Toxicol Pathol. 1993;21:538–541.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant for specially promoted research from Kanazawa Medical University, Japan (SR 2012-04).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan

    Mutsumi Tsuchishima, Joseph George, Hisakazu Shiroeda, Tomiyasu Arisawa & Mikihiro Tsutsumi

  2. Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan

    Tsutomu Takegami

Authors
  1. Mutsumi Tsuchishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph George
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hisakazu Shiroeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomiyasu Arisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsutomu Takegami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mikihiro Tsutsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Joseph George or Mikihiro Tsutsumi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsuchishima, M., George, J., Shiroeda, H. et al. Chronic Ingestion of Ethanol Induces Hepatocellular Carcinoma in Mice Without Additional Hepatic Insult. Dig Dis Sci 58, 1923–1933 (2013). https://doi.org/10.1007/s10620-013-2574-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-013-2574-4

Keywords

Search

Navigation