Tumor Biology

, Volume 34, Issue 2, pp 805–809 | Cite as

T-cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and prognosis of non-small-cell lung cancer

  • Jianwen Bai
  • Xiaoyan Li
  • Danian Tong
  • Weiwei Shi
  • Haihan Song
  • Qinchuan Li
Research Article


Lung cancer is the leading cause of death worldwide. Non-small-cell lung cancer (NSCLC) accounts for most of these cases. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule and plays a critical role in immune tolerance. Studies have shown that polymorphisms in TIM-3 gene can be associated with various diseases. The aim of this study was to investigate whether polymorphisms in the TIM-3 gene were associated with susceptibility to NSCLC. Three polymorphisms in TIM-3 gene (−1516G/T, −574G/T, and +4259T/G) were identified by polymerase chain reaction–restriction fragment length polymorphism in 432 NSCLC patients and 466 healthy controls. Results showed that frequencies of TIM-3 +4259TG genotype for cases and controls were 10.9 and 4.1 %, respectively; subjects carrying the +4259TG genotype had a 2.81-fold increased risk of NSCLC compared to the wild-type genotype (P < 0.0001). The TIM-3 −1516G/T and −574G/T polymorphisms did not show any correlation with NSCLC. In addition, when analyzing the survival time of NSCLC patients with TIM-3 +4259T/G polymorphism, cases with +4259TG genotype had significantly shorter survival time compared to the wild-type patients (15.2 months vs. 26.7 months, P = 0.007). These results suggested polymorphism in TIM-3 gene is associated with increased susceptibility to NSCLC and could be used as prognostic factor for this malignancy.


TIM-3 Polymorphism Lung cancer 


Conflicts of interest



  1. 1.
    Ishikawa M, Kitayama J, Yamauchi T, Kadowaki T, Maki T, Miyato H. Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2. Cancer Sci. 2007;98:1120–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Lawrence RE, Salgia R. MET molecular mechanisms and therapies in lung cancer. Cell Adh Migr. 2010;4:146–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science. 2007;318:1141–3.PubMedCrossRefGoogle Scholar
  4. 4.
    Hastings WD, Anderson DE, Kassam N, Koguchi K, Greenfield EA, et al. TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur J Immunol. 2009;39:2492–501.PubMedCrossRefGoogle Scholar
  5. 5.
    Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–41.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 2003;4:1102–10.PubMedCrossRefGoogle Scholar
  8. 8.
    Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol. 2003;4:1093–101.PubMedCrossRefGoogle Scholar
  9. 9.
    Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205:2763–79.PubMedCrossRefGoogle Scholar
  10. 10.
    Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction inmelanoma patients. J Exp Med. 2010;207:2175–86.PubMedCrossRefGoogle Scholar
  11. 11.
    Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187–94.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhuang X, Zhang X, Xia X, Zhang C, Liang X, Gao L, et al. Ectopic expression of TIM-3 in lung cancers: a potential independent prognostic factor for patients with NSCLC. Am J Clin Pathol. 2012;137(6):978–85.PubMedCrossRefGoogle Scholar
  13. 13.
    Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F, et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One. 2012. doi: 10.1371/journal.pone.0030676.
  14. 14.
    Groome PA, Bolejack V, Crowley JJ, Kennedy C, Krasnik M, Sobin LH, et al. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumors. J Thorac Oncol. 2007;2:694–705.PubMedCrossRefGoogle Scholar
  15. 15.
    Chae SC, Song JH, Pounsambath P, Yuan HY, Lee JH, Kim JJ, et al. Molecular variations in Th1-specific cell surface gene Tim-3. Exp Mol Med. 2004;36:274–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Frisancho-Kiss S, Nyland JF, Davis SE, Barrett MA, Gatewood SJ, Njoku DB, et al. Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J Immunol. 2006;176:6411–5.PubMedGoogle Scholar
  17. 17.
    Chae SC, Park YR, Shim SC, Yoon KS, Chung HT. The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population with rheumatoid arthritis. Immunol Lett. 2004;95:91–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Chae SC, Park YR, Lee YC, Lee JH, Chung HT. The association of TIM-3 gene polymorphism with atopic disease in Korean population. Hum Immunol. 2004;65:1427–31.PubMedCrossRefGoogle Scholar
  19. 19.
    Cao B, Zhu L, Zhu S, Li D, Zhang C, Xu C, et al. Genetic variations and haplotypes in TIM-3 gene and the risk of gastric cancer. Cancer Immunol Immunother. 2010;59:1851–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Boenisch O, D’Addio F, Watanabe T, Elyaman W, Magee CN, et al. TIM-3: a novel regulatory molecule of alloimmune activation. J Immunol. 2010;185:5806–19.PubMedCrossRefGoogle Scholar
  21. 21.
    Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, et al. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A. 2008;105:9331–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127:78–88.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhuang X, Zhang X, Xia X, Zhang C, Liang X, et al. Ectopic expression of TIM-3 in lung cancers: a potential independent prognostic factor for patients with NSCLC. Am J Clin Pathol. 2012;137:978–85.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.Internal Medicine Division of the Emergency Center, Shanghai East HospitalTongji UniversityShanghaiChina
  2. 2.Department of Lung CancerAffiliated Hospital of Academy of Military Medical Sciences of PLABeijingChina
  3. 3.Department of Surgery, The Sixth People’s HospitalShanghai Jiao Tong UniversityShanghaiChina
  4. 4.Department of OncologyPLA General HospitalBeijingChina
  5. 5.Department of Cardiovascular and Thoracic Surgery, Shanghai East HospitalTongji UniversityShanghaiChina

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