Advertisement

Hepatology International

, Volume 8, Supplement 2, pp 408–412 | Cite as

Alcohol, TLR4-TGF-β antagonism, and liver cancer

  • Hidekazu TsukamotoEmail author
  • Lopa Mishra
  • Keigo Machida
Supplement Issue: ALPD

Abstract

Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also synergistically promote HBV/HCV-related carcinogenesis. TLR4, the receptor for endotoxin, participates in inflammatory processes such as M1 activation of hepatic macrophages in alcoholic liver disease. However, its role in liver carcinogenesis via ectopic expression and activation has only recently been revealed in alcohol/HCV-associated HCC models. Alcohol feeding to mice expressing the HCV Ns5a in a hepatocyte specific manner aggravates liver inflammation via activation of overexpressed TLR4 in the parenchymal cells. Long-term alcohol feeding produces liver tumors in these transgenic mice in a manner dependent on TLR4. From these mice, CD133+/CD49f+ tumor-initiating stem cell-like cells (TICs) have been isolated. These TICs exhibit self-renewal and tumorigenic activities driven by TLR4-dependent upregulation of the stem cell factor NANOG. A defective TGF-β tumor suppressor pathway is identified in the TICs and mediated by NANOG target genes Igf2bp3 and Yap1. This TGF-β pathway antagonism is responsible in part for the TICs’ tumorigenic activity and chemoresistance. Conversely, mice with an attenuated TGF-β pathway due to haploinsufficiency of β2-Spectrin, spontaneously develop liver tumors and alcohol feeding increases tumor incidence in a TLR4-dependent manner. This reciprocal antagonism between TLR4 and TGF-β pathways may serve as a novel therapeutic target for HCC.

Keywords

TLR4 Cancer stem cells NANOG TGF-β 

Notes

Acknowledgements

The authors’ research described in this review was supported by NIH Grants 1R01AA018857, 5RC2AA019392, and P50AA011999, and Department of Veterans Affairs.

Compliance with ethical requirements and Conflict of interest

The studies were also conducted following full approval of IRB and IACUC protocols by respective institutions for appropriate involvement of human and animal subjects. Hidekazu Tsukamoto, Lopa Mishra, and Keigo Machida declare no conflict of interest.

References

  1. 1.
    Okuda K. Hepatocellular carcinoma. J Hepatol 2000;32(1 Suppl):225–237PubMedCrossRefGoogle Scholar
  2. 2.
    Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 2002;122(2):366–375PubMedCrossRefGoogle Scholar
  3. 3.
    Yao F, Terrault N. Hepatitis C and hepatocellular carcinoma. Curr Treat Options Oncol 2001;2(6):473–483PubMedCrossRefGoogle Scholar
  4. 4.
    Korenaga M, Wang T, Li Y, Showalter LA, Chan T, Sun J, et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem 2005;280(45):37481–37488PubMedCrossRefGoogle Scholar
  5. 5.
    Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001;61(11):4365–4370PubMedGoogle Scholar
  6. 6.
    Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chretien Y, et al. 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 2002;16(2):185–194PubMedCrossRefGoogle Scholar
  7. 7.
    Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol 2004;165(5):1499–1508PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Banerjee S, Saito K, it-Goughoulte M, Meyer K, Ray RB, Ray R. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol 2008;82(6):2606–2612PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J, Das D, et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2013; doi: 10.1016/j.jhep.2013.08.011 PubMedGoogle Scholar
  10. 10.
    Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002;36(5):1206–1213PubMedCrossRefGoogle Scholar
  11. 11.
    Yuan JM, Govindarajan S, Arakawa K, Yu MC. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the US. Cancer 2004;101(5):1009–1017PubMedCrossRefGoogle Scholar
  12. 12.
    Tsukamoto H. Conceptual importance of identifying alcoholic liver disease as a lifestyle disease. J Gastroenterol 2007;42(8):603–609PubMedCrossRefGoogle Scholar
  13. 13.
    Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357(9255):539–545PubMedCrossRefGoogle Scholar
  14. 14.
    Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420(6917):860–867PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Parkin DM, Pisani P, Munoz N, Ferley F. Infections and human cancer microbes and malignancy infection as a cause of human cancers. New York: Cold Spring Harbor Laboratory Press; 1999Google Scholar
  16. 16.
    Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH. A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 1999;190(10):1375–1382PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Sakurai T, Maeda S, Chang L, Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci USA 2006;103(28):10544–10551PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317(5834):121–124PubMedCrossRefGoogle Scholar
  19. 19.
    Jamieson T, Clarke M, Steele CW, Samuel MS, Neumann J, Jung A, et al. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J Clin Invest 2012;122(9):3127–3144PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 2001;34(1):101–108PubMedCrossRefGoogle Scholar
  21. 21.
    Mathurin P, Deng QG, Keshavarzian A, Choudhary S, Holmes EW, Tsukamoto H. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 2000;32(5):1008–1017PubMedCrossRefGoogle Scholar
  22. 22.
    Enomoto N, Ikejima K, Yamashina S, Hirose M, Shimizu H, Kitamura T, et al. Kupffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin. Alcohol Clin Exp Res 2001;25(6 Suppl):51S–54SPubMedCrossRefGoogle Scholar
  23. 23.
    Tsukamoto H, Lu SC. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J 2001;15(8):1335–1349PubMedCrossRefGoogle Scholar
  24. 24.
    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(5):1548–1553PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Chen CL, Tsukamoto H, Liu JC, Kashiwabara C, Feldman D, Sher L, et al. Reciprocal regulation by TLR4 and TGF-beta in tumor-initiating stem-like cells. J Clin Invest 2013;123(7):2832–2849PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Bauer AK, Dixon D, DeGraff LM, Cho HY, Walker CR, Malkinson AM, et al. Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst 2005;97(23):1778–1781PubMedCrossRefGoogle Scholar
  27. 27.
    Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S, et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 2007;133(6):1869–1881PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Mittal D, Saccheri F, Venereau E, Pusterla T, Bianchi ME, Rescigno M. TLR4-mediated skin carcinogenesis is dependent on immune and radioresistant cells. EMBO J 2010;29(13):2242–2252PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Fukata M, Shang L, Santaolalla R, Sotolongo J, Pastorini C, Espana C, et al. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm Bowel Dis 2011;17(7):1464–1473PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012;21(4):504–516PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology 2012;143(5):1158–1172PubMedCrossRefGoogle Scholar
  32. 32.
    Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 2012;122(10):3476–3489PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Negash AA, Ramos HJ, Crochet N, Lau DT, Doehle B, Papic N, et al. IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog 2013;9(4):e1003330PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013;155(2):384–396PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2013

Authors and Affiliations

  • Hidekazu Tsukamoto
    • 1
    • 2
    • 4
    Email author
  • Lopa Mishra
    • 5
  • Keigo Machida
    • 1
    • 3
  1. 1.Southern California Research Center for ALPD and CirrhosisKeck School of Medicine of the University of Southern CaliforniaLos AngelesUSA
  2. 2.Department of PathologyKeck School of Medicine of the University of Southern CaliforniaLos AngelesUSA
  3. 3.Department of Molecular Microbiology and ImmunologyKeck School of Medicine of the University of Southern CaliforniaLos AngelesUSA
  4. 4.Department of Veterans Affairs Greater Los Angeles Healthcare SystemLos AngelesUSA
  5. 5.Department of Gastroenterology, Hepatology, and NutritionThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations