Tumor Biology

, Volume 35, Issue 8, pp 7837–7846 | Cite as

Association between Toll-like receptor 3 polymorphisms and cancer risk: a meta-analysis

  • Daye Cheng
  • Yiwen Hao
  • Wenling Zhou
  • Yiran Ma
Research Article


Toll-like receptors (TLRs) are well known as molecular sensors of pathogen-associated molecular patterns. They control activation of the innate immune response and subsequently shape the adaptive immune response. Polymorphisms in TLR3 gene associated with cancer have been studied extensively. However, the results remain controversial. A literature search was performed among PubMed, Embase, Web of Science, Science Direct, Wanfang, and Chinese National Knowledge Infrastructure databases to identify eligible studies on the association between TLR3 polymorphisms and cancer risk. A total of 12 studies in 11 articles were included in the meta-analysis including 5,861 cases and 6,339 controls. Significant associations with cancer risk were observed for single nucleotide polymorphisms (SNPs) rs3775291 (allele model: odds ratio (OR) = 1.12, 95 % confidence interval (95 % CI) = 1.00–1.25, P = 0.04), rs3775290 (allele model: OR = 1.12, 95 % CI = 1.00–1.25, P = 0.04; dominant model: OR = 1.30, 95 % CI = 1.05–1.60, P = 0.01; homozygous comparison: OR = 1.68, 95 % CI = 1.06–2.68, P = 0.03; heterozygous comparison: OR = 1.25, 95 % CI = 1.01–1.55, P = 0.04), rs5743305 (allele model: OR = 1.07, 95 % CI = 1.01–1.15, P = 0.03; dominant model: OR = 1.11, 95 % CI = 1.01–1.22, P = 0.03), and rs5743312 (allele model: OR = 1.13, 95 % CI = 1.01–1.27, P = 0.03; recessive model: OR = 1.86, 95 % CI = 1.31–2.63, P < 0.01; homozygous comparison: OR = 1.88, 95 % CI = 1.33–2.67, P < 0.01), respectively. Meanwhile, we did not find any significant association with cancer risk for rs7657186 and rs7668666. In conclusion, this meta-analysis indicates a significant association of four TLR3 gene polymorphisms with cancer risk. However, because the study size was limited, further studies are essential to confirm our results.


Toll-like receptor Polymorphism Cancer risk Meta-analysis 



This work has been supported by a grant from the National Natural Science Foundation of China (No. 81301835).

Conflicts of interest



  1. 1.
    Kutikhin AG. Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk. Hum Immunol. 2011;72(11):1095–116.PubMedCrossRefGoogle Scholar
  2. 2.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–80.PubMedCrossRefGoogle Scholar
  4. 4.
    Oblak A, Jerala R. Toll-like receptor 4 activation in cancer progression and therapy. Clin Dev Immunol. 2011;2011:609579.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Rogers EN, Jones DZ, Kidd NC, Yeyeodu S, Brock G, Ragin C, et al. Toll-like receptor-associated sequence variants and prostate cancer risk among men of African descent. Genes Immun. 2013;14(6):347–55.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Yamamoto M, Takeda K, Akira S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol. 2004;40(12):861–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Takeuchi O, Akira S. Toll-like receptors; their physiological role and signal transduction system. Int Immunopharmacol. 2001;1(4):625–35.PubMedCrossRefGoogle Scholar
  8. 8.
    Honda K, Taniguchi T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol. 2006;6(9):644–58.PubMedCrossRefGoogle Scholar
  9. 9.
    Wong Y, Sethu C, Louafi F, Hossain P. Lipopolysaccharide regulation of toll-like receptor-4 and matrix metalloprotease-9 in human primary corneal fibroblasts. Invest Ophthalmol Vis Sci. 2011;52(5):2796–803.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhu J, Mohan C. Toll-like receptor signaling pathways—therapeutic opportunities. Mediat Inflamm. 2010;2010:781235.CrossRefGoogle Scholar
  11. 11.
    Shime H, Matsumoto M, Oshiumi H, Tanaka S, Nakane A, Iwakura Y, et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc Natl Acad Sci U S A. 2012;109(6):2066–71.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413(6857):732–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Matsumoto M, Funami K, Tanabe M, Oshiumi H, Shingai M, Seto Y, et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol. 2003;171(6):3154–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Pisegna S, Pirozzi G, Piccoli M, Frati L, Santoni A, Palmieri G. p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells. Blood. 2004;104(13):4157–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Farina GA, York MR, Di Marzio M, Collins CA, Meller S, Homey B, et al. Poly(I:C) drives type I IFN- and TGFbeta-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Investig Dermatol. 2010;130(11):2583–93.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Guillot L, Le Goffic R, Bloch S, Escriou N, Akira S, Chignard M, et al. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. J Biol Chem. 2005;280(7):5571–80.PubMedCrossRefGoogle Scholar
  17. 17.
    Li K, Chen Z, Kato N, Gale Jr M, Lemon SM. Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes. J Biol Chem. 2005;280(17):16739–47.PubMedCrossRefGoogle Scholar
  18. 18.
    Sheyhidin I, Nabi G, Hasim A, Zhang RP, Ainiwaer J, Ma H, et al. Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma. World J Gastroenterol: WJG. 2011;17(32):3745–51.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Gonzalez-Reyes S, Marin L, Gonzalez L, Gonzalez LO, del Casar JM, Lamelas ML, et al. Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer. 2010;10:665.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    McCall KD, Harii N, Lewis CJ, Malgor R, Kim WB, Saji M, et al. High basal levels of functional toll-like receptor 3 (TLR3) and noncanonical Wnt5a are expressed in papillary thyroid cancer and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology. 2007;148(9):4226–37.PubMedCrossRefGoogle Scholar
  21. 21.
    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: Off J Am Assoc Cancer Res. 2007;13(15 Pt 1):4565–74.CrossRefGoogle Scholar
  22. 22.
    Lamba V, Lamba J, Yasuda K, Strom S, Davila J, Hancock ML, et al. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp ther. 2003;307(3):906–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Tierney MJ, Medcalf RL. Plasminogen activator inhibitor type 2 contains mRNA instability elements within exon 4 of the coding region. Sequence homology to coding region instability determinants in other mRNAs. J Biol Chem. 2001;276(17):13675–84.PubMedGoogle Scholar
  24. 24.
    Thomas KH, Meyn P, Suttorp N. Single nucleotide polymorphism in 5′-flanking region reduces transcription of surfactant protein B gene in H441 cells. Am J Physiol Lung Cell Mol Physiol. 2006;291(3):L386–90.PubMedCrossRefGoogle Scholar
  25. 25.
    Zysow BR, Lindahl GE, Wade DP, Knight BL, Lawn RM. C/T polymorphism in the 5′ untranslated region of the apolipoprotein(a) gene introduces an upstream ATG and reduces in vitro translation. Arterioscler Thromb Vasc Biol. 1995;15(1):58–64.PubMedCrossRefGoogle Scholar
  26. 26.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.PubMedCrossRefGoogle Scholar
  27. 27.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.PubMedCrossRefGoogle Scholar
  28. 28.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Moumad K, Lascorz J, Bevier M, Khyatti M, Ennaji MM, Benider A et al. Genetic polymorphisms in host innate immune sensor genes and the risk of nasopharyngeal carcinoma in North Africa. G3 (Bethesda). 2013;3(6):971-7.Google Scholar
  30. 30.
    Li G, Zheng Z. Toll-like receptor 3 genetic variants and susceptibility to hepatocellular carcinoma and HBV-related hepatocellular carcinoma. Tumour Biol: J Int Soc Oncodev Biol Med. 2013;34(3):1589–94.CrossRefGoogle Scholar
  31. 31.
    Etokebe GE, Knezevic J, Petricevic B, Pavelic J, Vrbanec D, Dembic Z. Single-nucleotide polymorphisms in genes encoding toll-like receptor -2, -3, -4, and -9 in case-control study with breast cancer. Genet Test Mol Biomark. 2009;13(6):729–34.CrossRefGoogle Scholar
  32. 32.
    Resler AJ, Malone KE, Johnson LG, Malkki M, Petersdorf EW, McKnight B, et al. Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study. BMC Cancer. 2013;13:219.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Fan L. The genetic contribution of TLR3-mediated signaling genes susceptibility and progress of breast cancer. Fudan University; 2010.Google Scholar
  34. 34.
    Gast A, Bermejo JL, Claus R, Brandt A, Weires M, Weber A, et al. Association of inherited variation in Toll-like receptor genes with malignant melanoma susceptibility and survival. PLoS One. 2011;6(9):e24370.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Slattery ML, Herrick JS, Bondurant KL, Wolff RK. Toll-like receptor genes and their association with colon and rectal cancer development and prognosis. Int J Cancer J Int Cancer. 2012;130(12):2974–80.CrossRefGoogle Scholar
  36. 36.
    Zeljic K, Supic G, Jovic N, Kozomara R, Brankovic-Magic M, Obrenovic M et al. Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival. Oral diseases. 2013.Google Scholar
  37. 37.
    Pandey S, Mittal B, Srivastava M, Singh S, Srivastava K, Lal P, et al. Evaluation of Toll-like receptors 3 (c.1377C/T) and 9 (G2848A) gene polymorphisms in cervical cancer susceptibility. Mol Biol Rep. 2011;38(7):4715–21.PubMedCrossRefGoogle Scholar
  38. 38.
    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(7):7263–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Singh V, Srivastava N, Kapoor R, Mittal RD. Single-nucleotide polymorphisms in genes encoding toll-like receptor -2, -3, -4, and -9 in a case-control study with bladder cancer susceptibility in a North Indian population. Arch Med Res. 2013;44(1):54–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48(1):322–35.PubMedCrossRefGoogle Scholar
  41. 41.
    Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72(11):1605–21.PubMedCrossRefGoogle Scholar
  42. 42.
    Killeen SD, Wang JH, Andrews EJ, Redmond HP. Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword? Br J Cancer. 2006;95(3):247–52.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol. 2006;176(8):4894–901.PubMedCrossRefGoogle Scholar
  44. 44.
    Morikawa T, Sugiyama A, Kume H, Ota S, Kashima T, Tomita K, et al. Identification of Toll-like receptor 3 as a potential therapeutic target in clear cell renal cell carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13(19):5703–9.CrossRefGoogle Scholar
  45. 45.
    Jiang Q, Wei H, Tian Z. Poly I:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway. BMC Cancer. 2008;8:12.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Paone A, Starace D, Galli R, Padula F, De Cesaris P, Filippini A, et al. Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis. 2008;29(7):1334–42.PubMedCrossRefGoogle Scholar
  47. 47.
    Galli R, Paone A, Fabbri M, Zanesi N, Calore F, Cascione L, et al. Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARbeta and tumor regression. Proc Natl Acad Sci U S A. 2013;110(24):9812–7.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Chin AI, Miyahira AK, Covarrubias A, Teague J, Guo B, Dempsey PW, et al. Toll-like receptor 3-mediated suppression of TRAMP prostate cancer shows the critical role of type I interferons in tumor immune surveillance. Cancer Res. 2010;70(7):2595–603.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Chew V, Tow C, Huang C, Bard-Chapeau E, Copeland NG, Jenkins NA, et al. Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. J Natl Cancer Inst 2012;104(23):1796–807.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    He JF, Jia WH, Fan Q, Zhou XX, Qin HD, Shugart YY, et al. Genetic polymorphisms of TLR3 are associated with nasopharyngeal carcinoma risk in Cantonese population. BMC Cancer. 2007;7:194.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Ranjith-Kumar CT, Miller W, Sun J, Xiong J, Santos J, Yarbrough I, et al. Effects of single nucleotide polymorphisms on Toll-like receptor 3 activity and expression in cultured cells. J Biol Chem. 2007;282(24):17696–705.PubMedCrossRefGoogle Scholar
  52. 52.
    Yang CA, Raftery MJ, Hamann L, Guerreiro M, Grutz G, Haase D, et al. Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis. Hum Immunol. 2012;73(8):844–51.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of TransfusionThe First Hospital of China Medical UniversityShenyangPeople’s Republic of China

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