Tumor Biology

, Volume 36, Issue 8, pp 6265–6276 | Cite as

NFKB1/NFKBIa polymorphisms are associated with the progression of cervical carcinoma in HPV-infected postmenopausal women from rural area

  • Singhal Pallavi
  • Kumar Anoop
  • Hussain Showket
  • Nag Alo
  • Bharadwaj Mausumi
Research Article


Human papillomavirus (HPV) is considered as the major etiological agent for development of cervical cancer but alone is not sufficient enough. So, other environmental factors and host genetic background may play an important role in the development of cervical cancer. HPV carries a minimal amount of structural and regulatory proteins so it is apparently dependent on its host for survival. NF-κB/IkB system plays an important regulatory role in the apoptotic pathway. In the present study, a total of 575 consecutive subjects including 285 cases (45 cervical pre-cancerous and 240 invasive cervical carcinoma) and 290 age- and ethnicity-matched controls recruited from Lok Nayak Jai Prakash Hospital and Safdarjung Hospital, New Delhi between July 2009 to July 2013 were genotyped for NFKB1 -94 insertion/deletion (rs28362491) and NFKBIa 3′-UTR2758A > G (rs696) polymorphism by PCR-RFLP followed by sequencing. We observed a positive association of NFKB1 -94 insertion/insertion (II) and NFKBIa 3′-UTR 2758 GG genotypes with the progression of cervical carcinoma. Cervical cancer patients were found more pronounce to be a carrier of II + GG genotype of both the SNPs. We also noticed that HPV-infected postmenopausal women having higher parity along with the history of tobacco consumption and who carries insertion allele of NFKB1 -94 polymorphism in association of GG genotype of NFKBIa 3′-UTR polymorphism, were more susceptible to develop cervical carcinoma. II + GG genotype together were found to have direct proportionality with the aggressiveness of cervical carcinoma. In conclusion, alteration in the gene map of NFKB1/NFKBIa helps in the progression of cervical cancer accompanied by HPV infection in postmenopausal women from rural residential setup who had higher parity along with history of tobacco consumption.


NFKB1 NFKBIa Polymorphism HPV Cervical cancer 



We like to thank Dr. Sudha Salhan, Department of Obstetrics & Gynaecology, Safdarjung Hospital, New Delhi, and Dr. Swaraj Batra, Department of Obstetrics & Gynaecology, LNJP Hospital, New Delhi, India for providing clinical samples and valuable feedback for the manuscript. Dr. Suresh Bhambhani, Division of Cytopathology for pathological analysis of the clinical sample. PS is grateful to the Indian Council of Medical Research (ICMR) for Senior Research Fellowship and AK is for University Grant Commission for his Senior Research Fellowship. Core Facility of ICPO (ICMR) to MB is acknowledged. We also like to thank the patients and their family members.

Conflicts of interest


Supplementary material

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ESM 1 (DOC 45 kb)
13277_2015_3312_MOESM2_ESM.doc (38 kb)
ESM 2 (DOC 38 kb)


  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11; 2013.Google Scholar
  2. 2.
    Zur HH. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2:342–50.CrossRefGoogle Scholar
  3. 3.
    Kohaar I, Thakur N, Salhan S, Batra S, Singh V, Sharma A, et al. TNFalpha-308G/A polymorphism as a risk factor for HPV associated cervical cancer in Indian population. Cell Oncol. 2007;29:249–56.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Hinkula M, Pukkala E, Kyyronen P, Laukkanen P, Koskela P, Paavonen J, et al. A population-based study on the risk of cervical cancer and cervical intraepithelial neoplasia among grand multiparous women in Finland. Br J Cancer. 2004;90:1025–9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kjellberg L, Hallmans G, Ahren AM, Johansson R, Bergman F, Wadell G, et al. Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer. 2000;82:1332–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Santoro MG, Rossi A, Amici C. NF-kappaB and virus infection: who controls whom. EMBO J. 2003;22:2552–60.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–10.CrossRefPubMedGoogle Scholar
  8. 8.
    Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2:725–34.CrossRefPubMedGoogle Scholar
  9. 9.
    Sethi G, Sung B, Aggarwal BB. Nuclear factor-kappaB activation: from bench to bedside. Exp Biol Med (Maywood). 2008;233:21–31.CrossRefGoogle Scholar
  10. 10.
    Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–6.CrossRefPubMedGoogle Scholar
  11. 11.
    James MA, Lee JH, Klingelhutz AJ. Human papillomavirus type 16 E6 activates NF-kappaB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J Virol. 2006;80:5301–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Du CX, Wang Y. Expression of P-Akt, NFkappaB and their correlation with human papillomavirus infection in cervical carcinoma. Eur J Gynaecol Oncol. 2012;33:274–7.PubMedGoogle Scholar
  13. 13.
    Nair A, Venkatraman M, Maliekal TT, Nair B, Karunagaran D. NF-kappaB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix. Oncogene. 2003;22:50–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Sambrook Ra. Molecular Cloninig: a laboratory manual; Cold Spring Harbor Laboratory Press 3, 2001.Google Scholar
  15. 15.
    Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239:487–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Senol TS, Okyay P, Bardakci F. Identification of NF-kappaB1 and NF-kappaBIAlpha polymorphisms using PCR-RFLP assay in a Turkish population. Biochem Genet. 2010;48:104–12.CrossRefGoogle Scholar
  17. 17.
    Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986;46:705–16.CrossRefPubMedGoogle Scholar
  18. 18.
    Karban AS, Okazaki T, Panhuysen CI, Gallegos T, Potter JJ, Bailey-Wilson JE, et al. Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet. 2004;13:35–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa] B activity. Annu Rev Immunol. 2000;18:621–63.CrossRefPubMedGoogle Scholar
  20. 20.
    Bianco B, Lerner TG, Trevisan CM, Cavalcanti V, Christofolini DM, Barbosa CP. The nuclear factor-kB functional promoter polymorphism is associated with endometriosis and infertility. Hum Immunol. 2012;73:1190–3.CrossRefPubMedGoogle Scholar
  21. 21.
    Burnik FS, Yalcin S. NFKB1–94 insertion/deletion ATTG polymorphism in gastroenteropancreatic neuroendocrine tumors. Chemotherapy. 2009;55:381–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Cheng CW, Su JL, Lin CW, Su CW, Shih CH, Yang SF, et al. Effects of NFKB1 and NFKBIA gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathological features. PLoS One. 2013;8:e56130.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lin CW, Hsieh YS, Hsin CH, Su CW, Lin CH, Wei LH, et al. Effects of NFKB1 and NFKBIA gene polymorphisms on susceptibility to environmental factors and the clinicopathologic development of oral cancer. PLoS One. 2012;7:e35078.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Mishra A, Srivastava A, Mittal T, Garg N, Mittal B. Role of inflammatory gene polymorphisms in left ventricular dysfunction (LVD) susceptibility in coronary artery disease (CAD) patients. Cytokine. 2013;61:856–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Mohd Suzairi MS. Tan SC, hmad Aizat AA, Mohd AM, Siti Nurfatimah MS, Andee ZD, Ankathil R: The functional −94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer. Cancer Epidemiol. 2013;37:634–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Tang T, Cui S, Deng X, Gong Z, Jiang G, Wang P, et al. Insertion/deletion polymorphism in the promoter region of NFKB1 gene increases susceptibility for superficial bladder cancer in Chinese. DNA Cell Biol. 2010;29:9–12.CrossRefPubMedGoogle Scholar
  27. 27.
    Yalcin B, Atakan N, Alli N. The functional role of nuclear factor kappa-kappaB1–94 ins/del ATTG promotor gene polymorphism in Behcet’s disease: an exploratory study. Clin Exp Dermatol. 2008;33:629–33.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang D, Li L, Zhu Y, Zhao L, Wan L, Lv J, et al. The NFKB1–94 ATTG insertion/deletion polymorphism (rs28362491) contributes to the susceptibility of congenital heart disease in a Chinese population. Gene. 2013;516:307–10.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhou B, Rao L, Li Y, Gao L, Wang Y, Chen Y, et al. A functional insertion/deletion polymorphism in the promoter region of NFKB1 gene increases susceptibility for nasopharyngeal carcinoma. Cancer Lett. 2009;275:72–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhou B, Qie M, Wang Y, Yan L, Zhang Z, Liang A, et al. Relationship between NFKB1–94 insertion/deletion ATTG polymorphism and susceptibility of cervical squamous cell carcinoma risk. Ann Oncol. 2010;21:506–11.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhou B, Rao L, Peng Y, Wang Y, Qie M, Zhang Z, et al. A functional promoter polymorphism in NFKB1 increases susceptibility to endometriosis. DNA Cell Biol. 2010;29:235–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Arisawa T, Tahara T, Shiroeda H, Yamada H, Nomura T, Hayashi R, et al. NFKB1 polymorphism is associated with age-related gene methylation in Helicobacter pylori-infected subjects. Int J Mol Med. 2012;30:255–62.PubMedGoogle Scholar
  33. 33.
    Arisawa T, Tahara T, Shiroeda H, Yamada K, Nomura T, Yamada H, et al. Functional promoter polymorphisms of NFKB1 influence susceptibility to the diffuse type of gastric cancer. Oncol Rep. 2013;30:3013–9.PubMedGoogle Scholar
  34. 34.
    Gao J, Xu HL, Gao S, Zhang W, Tan YT, Rothman N, et al. Genetic polymorphism of NFKB1 and NFKBIA genes and liver cancer risk: a nested case–control study in Shanghai. China BMJ Open. 2014;4:e004427.CrossRefPubMedGoogle Scholar
  35. 35.
    Bu H, Rosdahl I, Sun XF, Zhang H. Importance of polymorphisms in NF-kappaB1 and NF-kappaBIalpha genes for melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients. J Cancer Res Clin Oncol. 2007;133:859–66.CrossRefPubMedGoogle Scholar
  36. 36.
    Gao J, Pfeifer D, He LJ, Qiao F, Zhang Z, Arbman G, et al. Association of NFKBIA polymorphism with colorectal cancer risk and prognosis in Swedish and Chinese populations. Scand J Gastroenterol. 2007;42:345–50.CrossRefPubMedGoogle Scholar
  37. 37.
    Huang D, Yang L, Liu Y, Zhou Y, Guo Y, Pan M, et al. Functional polymorphisms in NFkappaB1/IkappaBalpha predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese. Hum Genet. 2013;132:451–60.CrossRefPubMedGoogle Scholar
  38. 38.
    Song S, Chen D, Lu J, Liao J, Luo Y, Yang Z, et al. NFkappaB1 and NFkappaBIA polymorphisms are associated with increased risk for sporadic colorectal cancer in a southern Chinese population. PLoS One. 2011;6:e21726.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. Association of common polymorphisms inTNFA, NFkB1 and NFKBIA with risk and prognosis of esophageal squamous cell carcinoma. PLoS One. 2013;8:e81999.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Koc A, Batar B, Celik O, Onaran I, Tasan E, Sultuybek GK. Polymorphism of the NFKB1 affects the serum inflammatory levels of IL-6 in Hashimoto thyroiditis in a Turkish population. Immunobiology. 2014;219:531–6.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Singhal Pallavi
    • 1
    • 2
  • Kumar Anoop
    • 1
  • Hussain Showket
    • 1
  • Nag Alo
    • 2
  • Bharadwaj Mausumi
    • 1
  1. 1.Division of Molecular Genetics and BiochemistryInstitute of Cytology and Preventive OncologyNoidaIndia
  2. 2.Department of BiochemistryUniversity of Delhi South campus (UDSC)New DelhiIndia

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