Skip to main content
SpringerLink
Log in

Insulin resistance and hepatocarcinogenesis

  • Clinical Review
  • Published:
Clinical Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma (HCC) accounts for 85–90% of liver cancers and is one of the most frequent carcinomas in the world. HCCs classically develop against the background of chronic liver diseases. Common causes of such liver diseases are viral hepatitis, alcoholic hepatitis, or immune-related diseases; however, 15–50% of patients with HCCs have none of these classic antecedents, especially in developed countries. In this context, obesity and diabetes mellitus have been found to exhibit an increased risk of HCC. Both conditions are associated with insulin resistance. The tumorigenic effects of insulin resistance and complementary hyperinsulinemia could be mediated directly by insulin signaling, or indirectly related to changes in endogeneous hormone metabolism, particularly insulin-like growth factor I. Conversely, insulin resistance may be a consequence of obesity and hepatic inflammation, both of which can themselves promote tumorigenesis, mainly through cytokine production and/or generation of oxidative stress. Because the prevalence of obesity is now increasing throughout the world, insulin resistance is sure to be emphasized as a major factor in hepatocarcinogenesis in the foreseeable future.

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

Similar content being viewed by others

References

  1. World Health Organization. Mortality database. http://www.who.int/whosis/en. Accessed Feb 2010.

  2. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Moller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer. 1994;30A:344–50.

    Article  CAS  PubMed  Google Scholar 

  5. Wolk A, Gridley G, Svensson M, Nyren O, McLaughlin JK, Fraumeni JF, et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control. 2001;12:13–21.

    Article  CAS  PubMed  Google Scholar 

  6. Rapp K, Schroeder J, Klenk J, Stoehr S, Ulmer H, Concin H, et al. Obesity and incidence of cancer: a large cohort study of over 145,000 adults in Austria. Br J Cancer. 2005;93:1062–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Samanic C, Gridley G, Chow WH, Lubin J, Hoover RN, Fraumeni JF. Obesity and cancer risk among white and black United States veterans. Cancer Causes Control. 2004;15:35–43.

    Article  PubMed  Google Scholar 

  8. Calle EE, Rodriguez C, Walker-Thurmond K, Michael JT. Overweight, obesity and mortality from cancer in a prospective studied cohort of US adults. N Engl J Med. 2003;348:1625–38.

    Article  PubMed  Google Scholar 

  9. Lai MS, Hsieh MS, Chiu YH, Chen TH. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection. Hepatology. 2006;43:1295–302.

    Article  PubMed  Google Scholar 

  10. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case−control study among United States veterans. Am J Gastroenterol. 2001;96:2462–7.

    Article  CAS  PubMed  Google Scholar 

  11. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 2005;54:533–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Inoue M, Iwasaki M, Otani T, Sasazuki M. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med. 2006;166:1871–7.

    Article  PubMed  Google Scholar 

  13. Rajala MW, Scherer PE. Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144:3765–73.

    Article  CAS  PubMed  Google Scholar 

  14. Harrison SA. Liver disease in patients with diabetes mellitus. J Clin Gastroenterol. 2006;40:68–76.

    Article  PubMed  Google Scholar 

  15. McKeown-Eyssen G. Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol Biomarkers Prev. 1994;3:687–95.

    CAS  PubMed  Google Scholar 

  16. Giovannucci E. Insulin and colon cancer. Cancer Causes Control. 1995;6:164–79.

    Article  CAS  PubMed  Google Scholar 

  17. Kaaks R. Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes Control. 1996;7:605–25.

    Article  CAS  PubMed  Google Scholar 

  18. Stoll BA. Western nutrition and the insulin resistance syndrome: a link to breast cancer. Eur J Clin Nutr. 1999;53:83–7.

    Article  CAS  PubMed  Google Scholar 

  19. Weiderpass E. Occurrence, trends and environment etiology of pancreatic cancer. Scand J Work Environ Health. 1998;24:165–74.

    Article  CAS  PubMed  Google Scholar 

  20. Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology. 2004;127:1044–50.

    Article  CAS  PubMed  Google Scholar 

  21. Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci. 2001;114:2903–10.

    Article  CAS  PubMed  Google Scholar 

  22. Weijzen S, Velders MP, Kast WM. Modulation of the immune response and tumor growth by activated Ras. Leukemia. 1999;13:502–13.

    Article  CAS  PubMed  Google Scholar 

  23. Goalstone ML, Draznin B. What does insulin do to Ras? Cell Signal. 1998;10:297–301.

    Article  CAS  PubMed  Google Scholar 

  24. Ito T, Sasaki Y, Wands JR. Overexpression of human insulin receptor substrate 1 induces cellular transformation with activation of mitogen-activated protein kinases. Mol Cell Biol. 1996;16:943–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tanaka S, Mohr L, Schmidt EV, Sugimachi K, Wands JR. Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. Hepatology. 1997;26:598–604.

    Article  CAS  PubMed  Google Scholar 

  26. Prisco M, Romano G, Peruzzi F, Valentinis B, Baserga R. Insulin and IGF-I receptors signaling in protection from apoptosis. Horm Metab Res. 1999;31:80–9.

    Article  CAS  PubMed  Google Scholar 

  27. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med. 1997;336:633–40.

    Article  CAS  PubMed  Google Scholar 

  28. Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab. 2000;85:4712–20.

    CAS  PubMed  Google Scholar 

  29. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92:1472–89.

    Article  CAS  PubMed  Google Scholar 

  30. Wu Y, Yakar S, Zhao L, Hennighausen L, LeRoith D. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res. 2002;62:1030–5.

    CAS  PubMed  Google Scholar 

  31. Bhalla V, Joshi K, Vohra H, Singh G, Ganguly NK. Effect of growth factors on proliferation of normal, borderline, and malignant breast epithelial cells. Exp Mol Pathol. 2000;68:124–32.

    Article  CAS  PubMed  Google Scholar 

  32. Hadsell DL, Murphy KL, Bonnette SG, Reece N, Laucirica R, Rosen JM. Cooperative interaction between mutant p53 and des (1–3)IGF-I accelerates mammary tumorigenesis. Oncogene. 2000;19:889–98.

    Article  CAS  PubMed  Google Scholar 

  33. Wu Y, Cui K, Miyoshi K, Hennighausen L, Green JE, Setser J, et al. Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res. 2003;63:4384–8.

    CAS  PubMed  Google Scholar 

  34. Ibrahim YH, Yee D. Insulin-like growth factor-I and cancer risk. Growth Horm IGF Res. 2004;14:261–9.

    Article  CAS  PubMed  Google Scholar 

  35. Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol. 2004;68:1003–15.

    Article  CAS  PubMed  Google Scholar 

  36. Mazziotti G, Sorvillo F, Morisco F, Carbone A, Rotondi M, Stornaiuolo G, et al. Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study. Cancer. 2002;95:2539–45.

    Article  CAS  PubMed  Google Scholar 

  37. Lukanova A. Prediagnostic levels of C-peptide, IGF-I, IGFBP-1, -2 and -3 and risk of endometrial cancer. Int J Cancer. 2004;108:262–8.

    Article  CAS  PubMed  Google Scholar 

  38. Somasundar P, McFadden DW, Hileman SM, Vona-Davis L. Leptin is a growth factor in cancer. J Surg Res. 2004;116:337–49.

    Article  CAS  PubMed  Google Scholar 

  39. Pessayre D, Fromenty B. NASH: a mitochondrial disease. J Hepatol. 2005;42:928–40.

    Article  CAS  PubMed  Google Scholar 

  40. Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ, et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology. 2002;181:43–7.

    Article  PubMed  Google Scholar 

  41. Cowe S, Hardy RW. The metabolic syndrome; a high-risk state for cancer? Am J Pathol. 2006;169:1505–22.

    Google Scholar 

  42. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lloyd RV, Hanna PM, Mason RP. The origin of the hydroxyl radical oxygen in the fenton reaction. Free Radic Biol Med. 1997;22:885–8.

    Article  CAS  PubMed  Google Scholar 

  44. Sasaki Y. Does oxidative stress participate in the development of hepatocellular carcinoma? J Gastroenterol. 2006;41:1135–48.

    Article  CAS  PubMed  Google Scholar 

  45. Hussain SP, Haris CC. Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res. 1998;58:4023–37.

    CAS  PubMed  Google Scholar 

  46. Zhang H, Kamendulis LM, Xu Y, Klaunig JE. The role of 8-hydroxy-2′-deoxyguanosine in morphological transformation of Syrian hamster embryo (SHE) cells. Toxicol Sci. 2000;56:303–12.

    Article  CAS  PubMed  Google Scholar 

  47. Baylin S, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–96.

    Article  CAS  PubMed  Google Scholar 

  48. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21:163–7.

    Article  CAS  PubMed  Google Scholar 

  49. Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation oxidants or alkylating agents. EMBO J. 1996;15:5314–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, et al. Regulation of JNK signaling by GSTp. EMBO J. 1999;18:1321–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Iyoda K, Sasaki Y, Horimoto M, Toyama T, Yakushijin T, Sakakibara M, et al. Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer. 2003;97:3017–26.

    Article  CAS  PubMed  Google Scholar 

  52. Nemoto S, Xiang J, Huang S, Lin A. Induction of apoptosis by SB202190 through inhibition of p38beta mitogen-activated protein kinase. J Biol Chem. 1998;273:16415–20.

    Article  CAS  PubMed  Google Scholar 

  53. Muller JM, Cahill MA, Rupee RA, Baeuerle PA, Nordheim A. Antioxidants as well as oxidants activate c-fos via RAS-dependent activation of extracellular signal-regulated kinase 2 and Elk-1. Eur J Biochem. 1997;244:45–52.

    Article  CAS  PubMed  Google Scholar 

  54. Brown JR, Nigh E, Lee RJ, Ye H, Thompson MA, Saudou F, et al. Fos family members induce cell cycle entry by activating cyclin D1. Mol Cell Biol. 1998;18:5609–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schutte J, Minna JD, Birer MI. Deregulated expression of human c-jun transforms primary rat embryo cells in cooperation with an activated c-Ha-ras gene and transforms rat-1a cells as a single gene. Proc Natl Acad Sci USA. 1989;86:2257–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen F, Castranova V, Shi X. New insights into the role of nuclear factor-κB in cell growth regulation. Am J Pathol. 2001;159:387–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Flohe L, Brigelius-Flohe B, Saliou C, Traber MG, Packer L. Redox regulation of NF-κB activation. Free Radic Biol Med. 1997;22:1115–26.

    Article  CAS  PubMed  Google Scholar 

  58. Baldwin AS Jr. The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–83.

    Article  CAS  PubMed  Google Scholar 

  59. Pahl HL. Activators and target genes of Rel/NF-κB transcriptional factors. Oncogene. 1999;18:6853–66.

    Article  CAS  PubMed  Google Scholar 

  60. Taylor WR, Stark GR. Regulation of the G2/M transition by p53. Oncogene. 2001;20:1803–15.

    Article  CAS  PubMed  Google Scholar 

  61. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–31.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, Kumamoto, 860-8556, Japan

    Yutaka Sasaki

Authors
  1. Yutaka Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yutaka Sasaki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sasaki, Y. Insulin resistance and hepatocarcinogenesis. Clin J Gastroenterol 3, 271–278 (2010). https://doi.org/10.1007/s12328-010-0177-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12328-010-0177-6

Keywords

Search

Navigation