Tumor Biology

, Volume 34, Issue 3, pp 1589–1594 | Cite as

Toll-like receptor 3 genetic variants and susceptibility to hepatocellular carcinoma and HBV-related hepatocellular carcinoma

  • Guanggang Li
  • Zhendong Zheng
Research Article


Hepatocellular carcinoma (HCC) is a highly aggressive cancer with few treatment options. Toll-like receptor 3 (TLR3) plays a key role in innate immunity and may affect the development of cancers. This study aimed to investigate whether TLR3 polymorphisms were associated with susceptibility to HCC. Two polymorphisms in the TLR3 gene, −976T/A and +1234C/T, were tested by polymerase chain reaction–restriction fragment length polymorphism in 466 HCC patients and 482 healthy controls. Results showed that the prevalence of +1234CT genotype and +1234TT genotype were significantly increased in the HCC cases than in controls (odds ratio [OR] = 1.51; 95 % confidence interval [CI]; 1.22–1.93; p = 0.004 and OR = 3.19; 95 % CI, 1.82–5.39; p = 1.99 × 10−5, respectively). The −976T/A polymorphism did not reveal any differences between cases and controls. When analyzing the TLR3 +1234C/T polymorphism with different clinical parameters in HCC patients, the cases who were hepatitis B virus (HBV) carriers had higher number of +1234CT genotype and +1234T allele than those without HBV infection (p = 0.032 and p = 0.043). These data indicate that TLR3 +1234C/T polymorphism could be a novel risk factor for HCC, especially the HBV-related HCC.


Toll-like receptor 3 Hepatocellular carcinoma 


Conflicts of interest



  1. 1.
    Tobe T, Uchino J, Endo Y, Oto M, Okamoto E, Kojiro M, et al. Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. The Liver Cancer Study Group of Japan. Cancer. 1994;74:2772–80.CrossRefGoogle Scholar
  2. 2.
    Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virusrelated hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene. 2006;25:3823–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. Immune pathogenesis of hepatocellular carcinoma. J Exp Med. 1998;188:341–50.PubMedCrossRefGoogle Scholar
  4. 4.
    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;317:121–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17:1–14.PubMedCrossRefGoogle Scholar
  7. 7.
    Beutler B, Jiang Z, Georgel P, et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu Rev Immunol. 2006;24:353–89.PubMedCrossRefGoogle Scholar
  8. 8.
    Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol. 2003;15:396–401.PubMedCrossRefGoogle Scholar
  9. 9.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.PubMedCrossRefGoogle Scholar
  10. 10.
    Horscroft NJ, Pryde DC, Bright H. Antiviral applications of Toll-like receptor agonists. J Antimicrob Chemother. 2012;67:789–7801.PubMedCrossRefGoogle Scholar
  11. 11.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, et al. Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531–7.PubMedGoogle Scholar
  12. 12.
    Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol. 2006;176:4894–901.PubMedGoogle Scholar
  13. 13.
    Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P. Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res. 2007;13:4565–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Harmey JH, Bucana CD, Lu W, et al. Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer. 2002;101:415–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Guo Z, Chen L, Zhu Y, Zhang Y, He S, Qin J, et al. Double-stranded RNA-induced TLR3 activation inhibits angiogenesis and triggers apoptosis of human hepatocellular carcinoma cells. Oncol Rep. 2012;27:396–402.PubMedGoogle Scholar
  16. 16.
    Shen P, Jiang T, Lu H, Han H, Luo R. Combination of Poly I:C and arsenic trioxide triggers apoptosis synergistically via activation of TLR3 and mitochondrial pathways in hepatocellular carcinoma cells. Cell Biol Int. 2011;35:803–10.PubMedCrossRefGoogle Scholar
  17. 17.
    Greene FL. AJCC cancer staging manual. Chicago: Springer; 2002. p. 435.Google Scholar
  18. 18.
    Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–35.PubMedCrossRefGoogle Scholar
  19. 19.
    Vercammen E, Staal J, Beyaert R. Sensing of viral infection and activation of innate immunity by toll-like receptor 3. Clin Microbiol Rev. 2008;21:13–25.PubMedCrossRefGoogle Scholar
  20. 20.
    Wu J, Lu M, Meng Z, Trippler M, Broering R, Szczeponek A, et al. Toll-like receptormediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology. 2007;46:1769–78.PubMedCrossRefGoogle Scholar
  21. 21.
    Yoneda K, Sugimoto K, Shiraki K, Tanaka J, Beppu T, Fuke H, et al. Dual topology of functional toll-like receptor 3 expression in human hepatocellular carcinoma: differential signaling mechanisms of TLR3-induced NFkappaB activation and apoptosis. Int J Oncol. 2008;33:929–36.PubMedGoogle Scholar
  22. 22.
    Berge M, Bonnin P, Sulpice E, Vilar J, Allanic D, et al. Small interfering RNAs induce target-independent inhibition of tumor growth and vasculature remodeling in a mouse model of hepatocellular carcinoma. Am J Pathol. 2012;177:3192–201.CrossRefGoogle Scholar
  23. 23.
    Dhiman N, Ovsyannikova IG, Vierkant RA, Ryan JE, Pankratz VS, Jacobson RM, et al. Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: preliminary results. Vaccine. 2008;26:1731–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Ranjith-Kumar CT, Miller W, Sun J, et al. Effects of single nucleotide polymorphisms on toll-like receptor 3 activity and expression in cultured cells. J Biol Chem. 2007;282:17696–705.PubMedCrossRefGoogle Scholar
  25. 25.
    Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188:818–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Mandal RK, George GP, Mittal RD. Association of toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population. Mol Biol Rep. 2012;39:7263–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Dai J, Hu Z, Dong J, et al. Host immune gene polymorphisms were associated with the prognosis of non-small-cell lung cancer in Chinese. Int J Cancer. 2012;130:671–6.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.Department of ICUGeneral Hospital of Beijing Military CommandBeijingChina
  2. 2.Department of OncologyGeneral Hospital of Shenyang Military RegionShenyangChina

Personalised recommendations