Interleukin-12 and Interleukin-6 Gene Polymorphisms and Risk of Bladder Cancer in the Iranian Population

  • Ebadi, Nader (Department of Medical Genetics, School of Medicine Tehran University of Medical Sciences) ;
  • Jahed, Marzieh (Varamin) ;
  • Mivehchi, Mohamad (Young Researchers' Club, Varamin - Pishva Branch, Islamic Azad University) ;
  • Majidizadeh, Tayebeh (Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology) ;
  • Asgary, Mojgan (Department of Pathology-Hasheminejad Clinical Research Developing Center, School of Medicine Tehran University of Medical Sciences) ;
  • Hosseini, Seyed Ali (Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology)
  • 발행 : 2014.10.11


Interleukin-12 (IL-12) as an antitumor and interleukin-6 (IL-6) as an inflammatory cytokine, are immunomodulatory products that play important roles in responses in cancers and inflammation. We tested the association between two polymorphisms of IL-12(1188A>C; rs3212227) and IL-6 (-174 C>G) and the risk of bladder cancer in 261 patients and 251 healthy individuals. We also investigated the possible association of these SNPs in patients with high-risk jobs and smoking habits with the incidence of bladder cancer. The genotype distributions of IL-6 (-174 C/G) genotype were similar between the cases and the control groups; however, among patients with smoking habits, the association between IL-6 gene polymorphism and incidence of bladder cancer was significant. After a control adjustment for age and sex, the following results were recorded: CC genotype (OR= 2.11, 95%CI=1.56-2.87, p=0.007), GC genotype (OR=2.18, 95%CI=1.16-4.12, p=0.014) and GC+CC (OR=2.6, 95%CI=1.43-4.47, p=0.011). A significant risk of bladder cancer was observed for the heterozygous genotype (AC) of IL-12 (OR=1.47, 95%CI=1.01-2.14, p=0.045) in all cases, and among smokers (AC) (OR=3.13, 95%CI=1.82-5.37, p=0.00014), combined AC+CC (OR=3.05, 95%CI=1.8-5.18, p=0.000015). Moreover among high risk job patients, there was more than a 3-fold increased risk of cancer in the carriers of IL-12 beta heterozygous (OR=3.7, 95%CI=2.04-6.57, p=0.000056) and combined AC+CC(OR=3.29, 95%CI=1.58-5.86, p=0.00002) genotypes as compared with the AA genotype with low-risk jobs. As a conclusion, this study suggests that IL-12(3'UTR A>C) and IL-6 (-174 C>G) genotypes are significantly associated with an increased risk of bladder cancer in the Iranian population with smoking habits and/or performing high-risk jobs.


  1. Bozcuk H, Uslu G, Samur M, et al (2004). Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. Cytokine, 27, 58-65.
  2. Arnson Y, Shoenfeld Y, Amital H (2010). Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun, 34, 258-65.
  3. Belluco C, Olivieri F, Bonafe M, et al (2003). -174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clin Cancer Res, 9, 2173-6.
  4. Bergholdt R, Ghandil P, Johannesen J, et al (2004). Genetic and functional evaluation of an interleukin-12 polymorphism (IDDM18) in families with type 1 diabetes. J Med Genet, 41, 39.
  5. Chen H, Cheng S, Wang J, et al (2012). Interleukin-12B rs3212227 polymorphism and cancer risk: a meta-analysis. Mol Biol Rep, 39, 10235-42.
  6. Chen MF, Lin PY, Wu CF, et al (2013). IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. PLoS One, 8, 61901.
  7. Colombo MP, Trinchieri G (2002). Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev, 13, 155-68.
  8. Enewold L, Mechanic LE, Bowman ED, et al (2009). Serum concentrations of cytokines and lung cancer survival in African Americans and Caucasians. Cancer Epidemiol Biomarkers Prev, 18, 215-22.
  9. George DJ, Halabi S, Shepard TF, et al (2005). The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res, 11, 1815-20.
  10. Iliopoulos D, Jaeger SA, Hirsch HA, et al (2010). STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell, 39, 493-506.
  11. Grivennikov S, Karin M (2008). Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell, 13, 7-9.
  12. Hagiwara E, Takahashi KI, Okubo T, et al (2001). Cigarette smoking depletes cells spontaneously secreting Th(1) cytokines in the human airway. Cytokine, 14, 121-6.
  13. Iliopoulos D, Hirsch HA, Struhl K (2009). An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell, 139, 693-706.
  14. Iranian Ministry of Health and Medical Education HD, Department of Prevention of Non Contagious Diseases (2012). Iranian annual of national cancer registration report 2009/2010, (In Persian).
  15. Jaiswal PK, Singh V, Srivastava P, et al (2013). Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population. Gene, 519, 128-34.
  16. Kishimoto T (2005). Interleukin-6: from basic science to medicine--40 years in immunology. Annu Rev Immunol, 23, 1-21.
  17. Kobeissi LH, Yassine IA, Jabbour ME, et al (2013). Urinary bladder cancer risk factors: a Lebanese case- control study. Asian Pac J Cancer Prev, 14, 3205-11.
  18. Lagmay JP, London WB, Gross TG, et al (2009). Prognostic significance of interleukin-6 single nucleotide polymorphism genotypes in neuroblastoma: rs1800795 (promoter) and rs8192284 (receptor). Clin Cancer Res, 15, 5234-9.
  19. Letasiova S, Medve'ova A, Sovcikova A, et al (2012). Bladder cancer, a review of the environmental risk factors. Environ Health, 11, 11.
  20. Morgan L, Cooper J, Montgomery H, et al (2006). The interleukin-6 gene -174G>C and -572G>C pro- moter polymorphisms are related to cerebral aneurysms. J Neurol Neurosurg Psychiatry, 77, 915-7.
  21. Lin CY, Chien JW (2004). Increased interleukin-12 release from peripheral blood mononuclear cells in nephrotic phase of minimal change nephrotic syndrome. Acta Paediatr Taiwan, 45, 77-80.
  22. Liu RY, Song X, Chen P, et al (2012). Association between IL6 -174G/C and cancer: A meta-analysis of 105,482 individuals. Exp Ther Med, 3, 655-64.
  23. Machado JC, Figueiredo C, Canedo P, et al (2003). A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology, 125, 364-71.
  24. Murakami S, Okubo K, Tsuji Y, et al (2004). Serum interleukin-12 levels in patients with gastric cancer. Surg Today, 34, 1014-9.
  25. Noguchi Y, Jungbluth A, Richards EC, et al (1996). Effect of interleukin 12 on tumor induction by 3-methylcholanthrene. Proc Natl Acad Sci U S A, 93, 11798-801.
  26. Otunctemur A, Koklu I, Ozbek E, et al (2014). Are Bladder Neoplasms More Aggresive in Patients with a Smokingrelated Second Malignancy? Asian Pac J Cancer Prev, 15, 4025-8.
  27. Qin Q, Xu X, Wang X, et al (2013). Obesity and risk of bladder cancer: a meta-analysis of cohort studies. Asian Pac J Cancer Prev, 14, 3117-21.
  28. Rakoff-Nahoum S (2006). Why cancer and inflammation? Yale J Biol Med, 79, 123-30.
  29. Sangro B, Melero I, Qian C, et al (2005). Gene therapy of cancer based on interleukin 12. Curr Gene Ther, 5, 573-81.
  30. Schafer ZT, Brugge JS (2007). IL-6 involvement in epithelial cancers. J Clin Invest, 117, 3660-3.
  31. Smyth MJ, Dunn GP, Schreiber RD (2006). Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol, 90, 1-50.
  32. Šery O, Hladilová R, Novotny M, et al (2003). Association between -174 G/C polymorphism of interleukin-6 gene and alcoholism. Acta Neuropsychiatrica, 15, 257-61.
  33. Siegel R, Naishadham D, Jemal A (2013). Cancer statistics, 2013. CA Cancer J Clin, 63, 11-30.
  34. Smith AJ, D'Aiuto F, Palmen J, et al (2008). Association of serum interleukin-6 concentration with a functional IL6 -6331T>C polymorphism. Clin Chem, 54, 841-50.
  35. Sopori M (2002). Effects of cigarette smoke on the immune system. Nat Rev Immunol, 2, 372-7.
  36. Tahara E (1990). Growth factors and oncogenes in human gastrointestinal carcinomas. J Cancer Res Clin Oncol, 116, 121-31.
  37. Tamandani DM, Shekari M, Suri V (2009). Interleukin-12 gene polymorphism and cervical cancer risk. Am J Clin Oncol, 32, 524-8.
  38. Tan D, Wu X, Hou M, et al (2005). Interleukin-6 polymorphism is associated with more aggressive prostate cancer. J Urol, 174, 753-6.
  39. Terry CF, Loukaci V, Green FR (2000). Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem, 275, 18138-44.
  40. Waldner MJ, Foersch S, Neurath MF (2012). Interleukin-6--a key regulator of colorectal cancer development. Int J Biol Sci, 8, 1248-53.
  41. Wolf SF, Temple PA, Kobayashi M, et al (1991). Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol, 146, 3074-81.
  42. Zhang H, Xu Y, Li L, et al (2012). The interleukin-6 -174G/C polymorphism and prostate cancer risk: a systematic review and meta-analysis. Urol Int, 88, 447-53.
  43. Xu B, Niu XB, Wang ZD, et al (2011). IL-6 -174G>C polymorphism and cancer risk: a meta-analysis involving 29,377 cases and 37,739 controls. Mol Biol Rep, 38, 2589-96.
  44. Yang XQ, Xu C, Sun Y, et al (2013). Diabetes mellitus increases the risk of bladder cancer: an updated meta-analysis. Asian Pac J Cancer Prev, 14, 2583-9.
  45. Yu Y, Wang W, Zhai S, et al (2012). IL6 gene polymorphisms and susceptibility to colorectal cancer: a meta-analysis and review. Mol Biol Rep, 39, 8457-63.
  46. Zhang T, Wang H (2013). Variants of interleukin-16 associated with gastric cancer risk. Asian Pac J Cancer Prev, 14, 5269-73.
  47. Zhou L, Yao F, Luan H, et al (2012). Functional polymorphisms in the interleukin-12 gene contribute to cancer risk: evidence from a meta-analysis of 18 case-control studies. Gene, 510, 71-7.
  48. Zhu Z, Shen Z, Xu C (2012). Inflammatory pathways as promising targets to increase chemotherapy response in bladder cancer. Mediators Inflamm, 2012, 528690.

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