Tumor Biology

, Volume 36, Issue 5, pp 3985–3993 | Cite as

Association between the genetic variations within TBX21 gene promoter and the clinicopathological characteristics of esophageal squamous cell carcinoma in a high-risk Chinese population

  • Huihui Li
  • Hongchao Zhen
  • Lei Han
  • Bo Yan
  • Jing Yu
  • Shengtao Zhu
  • Bangwei Cao
Research Article


The correlation between TBX21 gene (T-box transcription factor protein 21; T-bet), which was a pivotal transcriptional regulation gene for Th1/Th2 polarization, and the development risk of esophagus squamous cell carcinoma (ESCC) was assessed in a high-risk Chinese population. A total of 302 ESCC cases and 311 normal controls coming from the highest incidence area of China were enrolled in this study. Three polymorphisms at −1499, −1514, and −1993 located in the TBX21 promoter were identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Logistic regression was used to determine whether the inherited variations of the TBX21 gene would associate with the risk and the clinicopathological characteristics of ESCC. Among the ESCC patients, an association between the TBX21 −1514T/C or −1993T/C polymorphisms and the lymph node or distant metastasis was found (odds ratios (ORs) were 9.46 and 4.35, respectively, all P < 0.01). By the log-additive model analysis, the results exhibited that three haplotypes, ACC, ACT, and ATC, were significantly related to the development risk of ESCC (OR = 11.81, 3.44, 2.37, respectively, all P < 0.05). TBX21 gene −1514 and −1993 polymorphisms might be counted as the influential factors for lymph node and distant metastasis to ESCC. Especially, the ACC, ACT, and ATC haplotypes derived from the TBX21 gene would increase the susceptibility to ESCC in the high-risk Chinese population.


TBX21 gene Genetic variations ESCC 



This work was supported by grants from the National High Technology Research and Development Program of China (863 Program, No. SS2014AA020601), by Grant No. 2011-3-007 from the Beijing Municipal Health System High-Level Health Person Foundation Project (to Bangwei Cao), by grants from Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases Foundation Project (2013–2014), and by grants from the National Key Basic Research Program of China (973 Program, No. 2012CB526600).

Conflicts of interest



  1. 1.
    Rasool S, Ganai BA, Syed Sameer A, Masood A. Esophageal cancer: associated factors with special reference to the Kashmir Valley. Tumori. 2012;98:191–203. PubMed: 22677984.PubMedGoogle Scholar
  2. 2.
    Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400–12. PubMed: 23374478.CrossRefPubMedGoogle Scholar
  3. 3.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin. 2009;59:225–49. PubMed: 19474385.CrossRefPubMedGoogle Scholar
  4. 4.
    Kumagai Y, Kawada K, Yamazaki S, Iida M, Ochiai T, Momma K, et al. Endocytoscopic observation of esophageal squamous cell carcinoma. Dig Endosc. 2010;22:10–6. PubMed: 20078658.CrossRefPubMedGoogle Scholar
  5. 5.
    Shammas MA. Repetitive sequences, genomic instability and Barrett’s esophageal adenocarcinoma. Mob Genet Elem. 2011;1:208–12. PubMed: 22479688.CrossRefGoogle Scholar
  6. 6.
    Mao WM, Zheng WH, Ling ZQ. Epidemiologic risk factors for esophageal cancer development. Asian Pac J Cancer Prev. 2011;12:2461–6. PubMed: 22320939.PubMedGoogle Scholar
  7. 7.
    Uedo N, Jung HY, Fujishiro M, Lee IL, Zhou PH, Chiu PW, et al. Current situation of endoscopic submucosal dissection for superficial neoplasms in the upper digestive tract in East Asian countries: a questionnaire survey. Dig Endosc. 2012;24 Suppl 1:124–8. PubMed: 22533767.CrossRefPubMedGoogle Scholar
  8. 8.
    Roshandel G, Sadjadi A, Aarabi M, Keshtkar A, Sedaghat SM, Nouraie SM, et al. Cancer incidence in Golestan Province: report of an ongoing population-based cancer registry in Iran between 2004 and 2008. Arch Iran Med. 2012;15:196–200. PubMed: 22424034.PubMedGoogle Scholar
  9. 9.
    Lone GN, Sheikh AA, Sheikh ZA, Baba KM, Qurieshi MA, Mufti GN, et al. Role of preoperative chemotherapy in squamous cell carcinoma of esophagus in Kashmir, a cancer belt—a pilot study. Asian Pac J Cancer Prev. 2011;12:465–70. PubMed: 21545214.PubMedGoogle Scholar
  10. 10.
    Cao B, Tian X, Li Y, Jiang P, Ning T, Xing H, et al. LMP7/TAP2 gene polymorphisms and HPV infection in esophageal carcinoma patients from a high incidence area in China. Carcinogenesis. 2005;26:1280–4. PubMed: 15774487.CrossRefPubMedGoogle Scholar
  11. 11.
    Zandberg DP, Bhargava R, Badin S, Cullen KJ. The role of human papillomavirus in nongenital cancers. CA Cancer J Clin. 2013;63:57–81. PubMed: 23258613.CrossRefPubMedGoogle Scholar
  12. 12.
    Alizadeh AM, Rohandel G, Roudbarmohammadi S, Roudbary M, Sohanaki H, Ghiasian SA, et al. Fumonisin B1 contamination of cereals and risk of esophageal cancer in a high risk area in northeastern Iran. Asian Pac J Cancer Prev. 2012;13:2625–8. PubMed: 22938431.CrossRefPubMedGoogle Scholar
  13. 13.
    Conteduca V, Sansonno D, Ingravallo G, Marangi S, Russi S, Lauletta G, et al. Barrett’s esophagus and esophageal cancer: an overview. Int J Oncol. 2012;41:414–24. PubMed: 22615011.PubMedGoogle Scholar
  14. 14.
    Joshi NS, Cui W, Dominguez CX, Chen JH, Hand TW, Kaech SM. Increased numbers of preexisting memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. J Immunol. 2011;187:4068–76. PubMed: 21930973.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bending D, Newland S, Krejci A, Phillips JM, Bray S, Cooke A. Epigenetic changes at Il12rb2 and Tbx21 in relation to plasticity behavior of Th17 cells. J Immunol. 2011;186:3373–82. PubMed: 21307296.CrossRefPubMedGoogle Scholar
  16. 16.
    Qu Y, Chen L, Lowe DB, Storkus WJ, Taylor JL. Combined Tbet and IL12 gene therapy elicits and recruits superior antitumor immunity in vivo. Mol Ther. 2012;20:644–51. PubMed: 22215017.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Reppert S, Boross I, Koslowski M, Türeci Ö, Koch S, Lehr HA, et al. A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer. Nat Commun. 2011;2:600. PubMed: 22186896.CrossRefPubMedGoogle Scholar
  18. 18.
    Ladoire S, Arnould L, Mignot G, Apetoh L, Rébé C, Martin F, et al. T-bet expression in intratumoral lymphoid structures after neoadjuvant trastuzumab plus docetaxel for HER2-overexpressing breast carcinoma predicts survival. Br J Cancer. 2011;105:366–71. PubMed: 21750556.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chen LJ, Zheng X, Shen YP, Zhu YB, Li Q, Chen J, et al. Higher numbers of T-bet(+) intratumoral lymphoid cells correlate with better survival in gastric cancer. Cancer Immunol Immunother. 2013;62:553–61. PubMed: 23090288.CrossRefPubMedGoogle Scholar
  20. 20.
    Morita M, Watanabe M, Inoue N, Inaoka C, Akamizu T, Tatsumi KI, et al. Functional polymorphisms in TBX21 and HLX are associated with development and prognosis of Graves’ disease. Autoimmunity. 2012;45:129–36. PubMed: 22014209.CrossRefPubMedGoogle Scholar
  21. 21.
    Cao B, Yang H, Ding H, Qi S, Gao L, Cui H, et al. Association analysis of hepatitis virus B infection with haplotypes of the TBX21 gene promoter region in the Chinese population. Clin Chem Lab Med. 2007;45:333–8. PubMed: 17378728.CrossRefPubMedGoogle Scholar
  22. 22.
    Li J, You Y, Chen S. The role of upstream stimulatory factor 1 in the transcriptional regulation of the human TBX21 promoter mediated by the T-1514C polymorphism associated with systemic lupus erythematosus. Immunogenetics. 2012;64:361–70. PubMed: 22258560.CrossRefPubMedGoogle Scholar
  23. 23.
    Akahoshi M, Obara K, Hirota T, Matsuda A, Hasegawa K, Takahashi N, et al. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet. 2005;17:16–26. PubMed: 15806396.CrossRefGoogle Scholar
  24. 24.
    Rice TW, Blackstone EH, Rusch VW. 7th Edition of the AJCC cancer staging manual: esophagus and esophagogastric junction. Ann Surg Oncol. 2010;17:1721–4. PubMed: 20369299.CrossRefPubMedGoogle Scholar
  25. 25.
    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. PubMed: 20811886.CrossRefPubMedGoogle Scholar
  26. 26.
    Cao B, Dong S, Su Q, Yan B, Zhen H, Yuan Z, et al. Lack of association between the unique LMP2 gene polymorphism and the outcome of lung cancer in a population of Chinese Han nationality. Hum Immunol. 2012;73:580–4. PubMed: 22261389.CrossRefPubMedGoogle Scholar
  27. 27.
    Li Z, Zhang Z, He Z, Tang W, Li T, Zeng Z, et al. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis ( Cell Res. 2009;19:519–23. PubMed: 19290020.CrossRefPubMedGoogle Scholar
  28. 28.
    Enomoto K, Sho M, Wakatsuki K, Takayama T, Matsumoto S, Nakamura S, et al. Prognostic importance of tumour-infiltrating memory T cells in oesophageal squamous cell carcinoma. Clin Exp Immunol. 2012;168:186–91. PubMed: 22471279.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ichiki Y, Hanagiri T, Takenoyama M, Baba T, Nagata Y, Mizukami M, et al. Differences in sensitivity to tumor-specific CTLs between primary and metastatic esophageal cancer cell lines derived from the same patient. Surg Today. 2012;42:272–9. PubMed: 22234743.CrossRefPubMedGoogle Scholar
  30. 30.
    Yeo CJ, Fearon DT. T-bet-mediated differentiation of the activated CD8+ T cell. Eur J Immunol. 2011;41:60–6. PubMed: 21182077.CrossRefPubMedGoogle Scholar
  31. 31.
    Mohr E, Cunningham AF, Toellner KM, Bobat S, Coughlan RE, Bird RA, et al. IFN-{gamma} produced by CD8 T cells induces T-bet-dependent and -independent class switching in B cells in responses to alum-precipitated protein vaccine. Proc Natl Acad Sci U S A. 2010;107:17292–7. PubMed: 20855629.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lee K, Min HJ, Jang EJ, Hong JH, Hwang ES. In vivo tumor suppression activity by T cell-specific T-bet restoration. Int J Cancer. 2010;127:2129–37. PubMed: 20143391.CrossRefPubMedGoogle Scholar
  33. 33.
    Li JR, Li JG, Deng GH, Zhao WL, Dan YJ, Wang YM, et al. A common promoter variant of TBX21 is associated with allele specific binding to Yin-Yang 1 and reduced gene expression. Scand J Immunol. 2011;73:449–58. PubMed: 21272048.CrossRefPubMedGoogle Scholar
  34. 34.
    Oestreich KJ, Huang AC, Weinmann AS. The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J Exp Med. 2011;208:1001–13. PubMed: 21518797.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Garrett WS, Punit S, Gallini CA, Michaud M, Zhang D, Sigrist KS, et al. Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell. 2009;16:208–19. PubMed: 19732721.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lin TC, Chen SU, Chen YF, Chang YC, Lin CW. Intramucosal variant of nasal natural killer (NK)/T cell lymphoma has a better survival than does invasive variant: implication on loss of E26 transformation-specific sequence 1 (ETS-1) and T-box expressed in T cells (T-bet) with invasion. Histopathology. 2012;60:287–95. PubMed: 22211287.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Huihui Li
    • 1
  • Hongchao Zhen
    • 1
  • Lei Han
    • 2
  • Bo Yan
    • 3
  • Jing Yu
    • 1
  • Shengtao Zhu
    • 4
    • 5
  • Bangwei Cao
    • 1
    • 4
    • 5
  1. 1.Department of Oncology, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
  2. 2.Department of Oncology, People’s Hospital of Beijing Daxing DistrictCapital Medical UniversityBeijingChina
  3. 3.Department of Microbiology and ImmunologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  4. 4.Department of Gastroenterology, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
  5. 5.Beijing Key Laboratory for Precancerous Lesion of Digestive DiseasesBeijing Digestive Diseases CenterBeijingChina

Personalised recommendations