Relationship between rs4073 polymorphism of interleukin 8 gene and cervical cancer by arms-PCR Tetra-primer

Document Type : Original Article


1 M.Sc. of Cellular and Molecular, School of Basic Sciences, Yadegar-e-Imam Khomeini (RAH) Islamic Azad University, Shahre Rey Branch, Tehran, Iran.

2 Assistant Professor, Department of Biology, School of Basic Sciences, Yadegar-e-Imam Khomeini (RAH) Islamic Azad University, Shahre Rey Branch, Tehran, Iran.

3 Associate Professor, Department of Biology, School of Basic Sciences, Islamic Azad University, Saveh Branch, Saveh, Iran.


Introduction: Cervical cancer is the second most common cancer among women. Interleukin-8 (IL-8) is a member of the chemokine family and is involved in initiating inflammatory reactions. Previous studies have shown that polymorphisms in the IL-8 gene are associated with an increased risk of various types of cancer. This study was performed with aim to investigate the association between IL-8 -251A> T polymorphism (rs4073) with cervical cancer in the female population in Tehran using Tetra primer arms-PCR.
Methods: In this case-control study which was performed in 2018, a total of 100 blood samples were examined, of which 50 samples were related to women with cervical cancer and another 50 samples belonged to healthy women as a control group. After DNA extraction from all samples, the frequency of IL-8 -251A> T polymorphism (rs4073) was evaluated using Tetra primer arms-PCR technique. Data were analyzed by SPSS statistical software (version 21) and chi-square test. P<0.05 was considered statistically significant.
Results: The frequency of TT, AT, AA genotypes was 42%, 50% and 8%, respectively in the patient group and 24%, 70% and 6%, respectively in the control group. The frequency of A and T alleles in the patients was 33% and 67% and in the healthy individuals was 41% and 59%, respectively. There was no significant difference between the control and patient groups in allelic distribution (P = 0.24) and genotype in all three codominant models (p=0.16), dominant (p=0.055) and recessive (P = 0.6).
Conclusion: There was no relationship between IL-8 gene T-251A polymorphism and cervical cancer in the population of women studied in Tehran.


  1. Bal MS, Bodal VK, Kaur J, Kaur M, Sharma S. Patterns of cancer: a study of 500 Punjabi patients. Asian Pacific Journal of Cancer Prevention 2015; 16(12):5107-10.
  2. Xu XC. Risk factors and gene expression in esophageal cancer. Cancer epidemiology 2009: 335-60.
  3. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International journal of cancer 2010; 127(12):2893-917.
  4. Wright Jr TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. New England Journal of Medicine 2003; 348(6):489-90.
  5. Munoz N. Human papillomavirus and cancer: the epidemiological evidence. Journal of clinical virology. 2000; 19(1-2):1-5.
  6. Liu ZC, Liu WD, Liu YH, Ye XH, Chen SD. Multiple sexual partners as a potential independent risk factor for cervical cancer: a meta-analysis of epidemiological studies. Asian Pacific Journal of Cancer Prevention 2015; 16(9):3893-900.
  7. Iversen L, Sivasubramaniam S, Lee AJ, Fielding S, Hannaford PC. Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ Oral Contraception Study. American journal of obstetrics and gynecology 2017; 216(6):580-e1.
  8. Gu W, Chen C, Zhao KN. Obesity-associated endometrial and cervical cancers. Front Biosci (Elite Ed). 2013; 5(1):109-8.
  9. Leyden WA, Manos MM, Geiger AM, Weinmann S, Mouchawar J, Bischoff K, et al. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. Journal of the National Cancer Institute 2005; 97(9):675-83.
  10. Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J. Screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin 2012; 62(3):147-72.
  11. Brumfield RT, Beerli P, Nickerson DA, Edwards SV. The utility of single nucleotide polymorphisms in inferences of population history. Trends in Ecology & Evolution 2003; 18(5):249-56.
  12. Mitani Y, Lezhava A, Kawai Y, Kikuchi T, Oguchi-Katayama A, Kogo Y, et al. Rapid SNP diagnostics using asymmetric isothermal amplification and a new mismatch-suppression technology. Nature Methods 2007; 4(3):257-62.
  13. Wang Y, Liu XH, Li YH, Li O. The paradox of IL‑10‑mediated modulation in cervical cancer. Biomedical Reports 2013; 1(3):347-51.
  14. Sims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ, et al. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science 1988; 241(4865):585-9.
  15. Zafari Zangeneh F, Abdollahi A, Naghizadeh MM, Bagheri M. A low-grade chronic inflammation in polycystic ovary syndrome: Role of interleukin-1 alpha, 1 beta, 17A and TNFα. Iran J Obstet Gynecol Infertil 2015; 17(135):9-15.
  16. Baggiolini M, Walz A, Kunkel SL. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. The Journal of clinical investigation 1989; 84(4):1045-9.
  17. Yoshimura T, Matsushima K, Oppenheim JJ, Leonard EJ. Neutrophil chemotactic factor produced by lipopolysaccharide (LPS)-stimulated human blood mononuclear leukocytes: partial characterization and separation from interleukin 1 (IL 1). The Journal of Immunology 1987; 139(3):788-93.
  18. Li MQ, Luo XZ, Meng YH, Mei J, Zhu XY, Jin LP, et al. CXCL8 enhances proliferation and growth and reduces apoptosis in endometrial stromal cells in an autocrine manner via a CXCR1-triggered PTEN/AKT signal pathway. Human reproduction 2012; 27(7):2107-16.
  19. Xie F, Meng YH, Liu LB, Chang KK, Li H, Li MQ, et al. Cervical carcinoma cells stimulate the angiogenesis through TSLP promoting growth and activation of vascular endothelial cells. American Journal of Reproductive Immunology 2013; 70(1):69-79.
  20. Marshall RM, Salerno D, Garriga J, Graña X. Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes. The Journal of Immunology 2005; 175(10):6402-11.
  21. Araki S, Omori Y, Lyn D, Singh RK, Meinbach DM, Sandman Y, et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer research 2007; 67(14):6854-62.
  22. Russo RC, Garcia CC, Teixeira MM, Amaral FA. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert review of clinical immunology 2014; 10(5):593-619.
  23. Jia L, Li F, Shao M, Zhang W, Zhang C, Zhao X, et al. IL‑8 is upregulated in cervical cancer tissues and is associated with the proliferation and migration of HeLa cervical cancer cells. Oncology letters 2018; 15(1):1350-6.
  24. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. The Journal of Immunology 2003; 170(6):3369-76.
  25. Wu S, Lu S, Tao H, Zhang L, Lin W, Shang H, et al. Correlation of polymorphism of IL-8 and MMP-7 with occurrence and lymph node metastasis of early stage cervical cancer. Journal of Huazhong University of Science and Technology [Medical Sciences] 2011; 31(1):114-9.
  26. Garza-Gonzalez E, Bosques-Padilla FJ, Mendoza-Ibarra SI, Flores-Gutierrez JP, Maldonado-Garza HJ, Perez-Perez GI. Assessment of the toll-like receptor 4 Asp299Gly, Thr399Ile and interleukin-8-251 polymorphisms in the risk for the development of distal gastric cancer. BMC cancer 2007; 7(1):1-5.
  27. Snoussi K, Mahfoudh W, Bouaouina N, Fekih M, Khairi H, Helal AN, et al. Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. BMC cancer 2010; 10(1):1-2.
  28. Matheson MC, Ellis JA, Raven J, Walters EH, Abramson MJ. Association of IL8, CXCR2 and TNF-α polymorphisms and airway disease. Journal of Human Genetics 2006; 51(3):196-203.
  29. Siasi E, Ghane B, Ashrafi F. Study of relation on breast cancer and rs3803662 polymorphism of TOX3 gene in Iranian female population by Tetra Arms PCR. Journal of Developmental Biology 2019; 11(3):62-74 (Persian).
  30. Allafan S, Hasanzadeh Nazarabadi M, Enghelabifar M, Khayatzadeh J, Shahrokh Abadi K, Jalali M, et al. No association between recurrent implantation failure (RIF) following in vitro Fertilization (IVF) with gene Polymorphism (P53 Arg72Pro). Iran J Obstet Gynecol Infertil 2015; 18(172):18-25.
  31. La Vecchia C, Boccia S. Oral contraceptives, human papillomavirus and cervical cancer. European journal of cancer prevention 2014; 23(2):110-2.
  32. Xie K. Interleukin-8 and human cancer biology. Cytokine & growth factor reviews 2001; 12(4):375-91.
  33. Hull J, Thomson A, Kwiatkowski D. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 2000; 55(12):1023-7.
  34. Ren YI, Poon RT, Tsui HT, Chen WH, Li Z, Lau C, et al. Interleukin-8 serum levels in patients with hepatocellular carcinoma: correlations with clinicopathological features and prognosis. Clinical Cancer Research 2003; 9(16):5996-6001.
  35. Siasi E, Gholami M, Ashrafi F. Study of relation on breast cancer and A/T 251 polymorphism of IL-8 gene in Iranian female populations by Tetra Arms PCR. Journal of Cell & Tissue 2019; 10(1):12-23.
  36. Vairaktaris E, Yapijakis C, Serefoglou Z, Derka S, Vassiliou S, Nkenke E, et al. The interleukin-8 (− 251A/T) polymorphism is associated with increased risk for oral squamous cell carcinoma. European Journal of Surgical Oncology (EJSO) 2007; 33(4):504-7.
  37. Huang CY, Chang WS, Tsai CW, Hsia TC, Shen TC, Bau DT, et al. The contribution of interleukin-8 genotypes and expression to nasopharyngeal cancer susceptibility in Taiwan. Medicine 2018; 97(36):e12135.
  38. Lima SF, Tavares MM, Macedo JL, Oliveira RS, Heráclio SD, Maia MD, et al. Influence of IL-6, IL-8, and TGF-β1 gene polymorphisms on the risk of human papillomavirus-infection in women from Pernambuco, Brazil. Memórias do Instituto Oswaldo Cruz 2016; 111(11):663-9.
  39. Gupta MK, Singh R, Banerjee M. Cytokine gene polymorphisms and their association with cervical cancer: A North Indian study. Egyptian Journal of Medical Human Genetics 2016; 17(2):155-63.
  40. Guo C, Wen L, Song JK, Zeng WJ, Dan C, Niu YM, et al. Significant association between interleukin-10 gene polymorphisms and cervical cancer risk: a meta-analysis. Oncotarget 2018; 9(15):12365-75.
  41. Kim W, Pyo J, Noh BJ, Jeong JW, Lee J, Kim JE. CCAR2 negatively regulates IL-8 production in cervical cancer cells. Oncotarget 2018; 9(1):1143-55.
  42. Lee YS, Choi I, Ning Y, Kim NY, Khatchadourian V, Yang D, et al. Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis. British journal of cancer 2012; 106(11):1833-41.
  43. Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK. Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis 2005; 8(1):63-71.
  44. Park SY, Han J, Kim JB, Yang MG, Kim YJ, Lim HJ, et al. Interleukin-8 is related to poor chemotherapeutic response and tumourigenicity in hepatocellular carcinoma. European Journal of Cancer 2014; 50(2):341-50.
  45. Haukim N, Bidwell JL, Smith AJ, Keen LJ, Gallagher G, Kimberly R, et al. Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes & Immunity 2002; 3(6):313-30.
  46. de Matos FR, de Moura Santos E, de Pontes Santos HB, Machado RA, Lemos TM, Coletta RD, et al. Association of polymorphisms in IL-8, MMP-1 and MMP-13 with the risk and prognosis of oral and oropharyngeal squamous cell carcinoma. Archives of oral biology 2019; 108:104547.
  47. Gonzalez-Hormazabal P, Romero S, Musleh M, Bustamante M, Stambuk J, Pisano R, et al. IL-8-251T> A (rs4073) polymorphism is associated with prognosis in gastric cancer patients. Anticancer research 2018; 38(10):5703-8.
  48. Moghimi M, Dastgheib SA, Heiranizadeh N, Zare M, Sheikhpour E, Neamatzadeh H. Association of IL-8-251T> A (rs4073) polymorphism with susceptibility to gastric cancer: a systematic review and meta-analysis based on 33 case-control studies. Arquivos de gastroenterologia 2020; 57:91-9.
  49. Wu S, Hu G, Chen J, Xie G. Interleukin 1β and interleukin 1 receptor antagonist gene polymorphisms and cervical cancer: a meta-analysis. International Journal of Gynecologic Cancer 2014; 24(6):984-990.
  50. Gao B, Yang S, Li N. Relationship of IL-18 genetic polymorphism to cervical cancer risk: A metaanalysis. Biomedical Research (0970-938X) 2017; 28(22):10020-25.
  51. Pereira AP, Trugilo KP, Okuyama NC, Sena MM, Couto-filho JD, Watanabe MA, et al. IL-10 c.-592C> A (rs1800872) polymorphism is associated with cervical cancer. Journal of Cancer Research and Clinical Oncology 2020; 146:1971-8.