Skip to main content
SpringerLink
Log in

Influence of IL1B polymorphism on CpG island hypermethylation in Helicobacter pylori-infected gastric cancer

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Helicobacter pylori infection can induce aberrant CpG island hypermethylation in gastric mucosal epithelial cells. Single nucleotide polymorphisms of proinflammatory cytokine genes encoding for interleukin 1B (IL1B), IL6, and IL8 have been demonstrated to be associated with an increased risk of gastric cancer. To identify the influence of host genetic factors in CpG island hypermethylation induced by H. pylori infection, we analyzed H. pylori-infected chronic gastritis (n = 111) and gastric cancer samples (n = 78) for the methylation status of eight genes previously shown to be hypermethylated in chronic gastritis and single nucleotide polymorphisms of IL1B, IL6, and IL8. The methylation levels were then compared between different genotypes. Gastric cancers from patients with the IL1B-511T/T allele showed significantly higher methylation levels in five genes as compared with gastric cancers from IL1B-511 C carriers (P < 0.05). An increased level of hypermethylation in association with the IL1B-511T/T allele was observed in chronic gastritis samples, but the association was not statistically significant. These findings suggest that the IL1B-511T/T allele is associated with enhanced hypermethylation of multiple CpG island loci, which might contribute to an increase in the risk for gastric cancer in individuals with H. pylori infection and IL1B-511T/T allele.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167

    Article  CAS  PubMed  Google Scholar 

  2. IARC working group on the evaluation of carcinogenic risks to humans, schistosomes, liver flukes, Helicobacter pylori (1994) IARC monographs on the evaluation of carcinogenic risks to humans, vol 61. International Agency for Research on Cancer, Lyon, pp 1–241

    Google Scholar 

  3. Maekita T, Nakazawa K, Mihara M et al (2006) High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res 12:989–995

    Article  CAS  PubMed  Google Scholar 

  4. Chan AO, Lam SK, Wong BC et al (2003) Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut 52:502–506

    Article  CAS  PubMed  Google Scholar 

  5. Ushijima T, Nakajima T, Maekita T (2006) DNA methylation as a marker for the past and future. J Gastroenterol 41:401–407

    Article  CAS  PubMed  Google Scholar 

  6. Chan AO, Chu KM, Huang C et al (2007) Association between Helicobacter pylori infection and interleukin 1beta polymorphism predispose to CpG island methylation in gastric cancer. Gut 56:595–597

    Article  PubMed  Google Scholar 

  7. Chan AO, Peng JZ, Lam SK et al (2006) Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut 55:463–468

    Article  CAS  PubMed  Google Scholar 

  8. Leung WK, Man EP, Yu J et al (2006) Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach. Clin Cancer Res 12:3216–3221

    Article  CAS  PubMed  Google Scholar 

  9. Perri F, Cotugno R, Piepoli A et al (2007) Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication. Am J Gastroenterol 102:1361–1371

    Article  CAS  PubMed  Google Scholar 

  10. El-Omar EM, Carrington M, Chow WH et al (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402

    Article  CAS  PubMed  Google Scholar 

  11. Hwang IR, Kodama T, Kikuchi S et al (2002) Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology 123:1793–1803

    Article  CAS  PubMed  Google Scholar 

  12. Wang M, Furuta T, Takashima M et al (1999) Relation between interleukin-1beta messenger RNA in gastric fundic mucosa and gastric juice pH in patients infected with Helicobacter pylori. J Gastroenterol 34 Suppl:10–17

    Google Scholar 

  13. Wallace JL, Cucala M, Mugridge K, Parente L (1991) Secretagogue-specific effects of interleukin-1 on gastric acid secretion. Am J Physiol 261:559–564

    Google Scholar 

  14. Hodge DR, Xiao W, Clausen PA, Heidecker G, Szyf M, Farrar WL (2001) Interleukin-6 regulation of the human DNA methyltransferase (hDNMT) gene in human erythroleukemia cells. J Biol Chem 276:39508–39511

    Article  CAS  PubMed  Google Scholar 

  15. Hodge DR, Peng B, Cherry JC et al (2005) Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 65:4673–4682

    Article  CAS  PubMed  Google Scholar 

  16. Hmadcha A, Bedoya FJ, Sobrino F, Pintado E (1999) Methylation-dependent gene silencing induced by interleukin 1beta via nitric oxide production. J Exp Med 190:1595–1604

    Article  CAS  PubMed  Google Scholar 

  17. Wehbe H, Henson R, Meng F, Mize-Berge J, Patel T (2006) Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res 66:10517–10524

    Article  CAS  PubMed  Google Scholar 

  18. Li C, Xia HH, Xie W et al (2007) Association between interleukin-1 gene polymorphisms and Helicobacter pylori infection in gastric carcinogenesis in a Chinese population. J Gastroenterol Hepatol 22:234–239

    Article  CAS  PubMed  Google Scholar 

  19. Fishman D, Faulds G, Jeffery R et al (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369–1376

    Article  CAS  PubMed  Google Scholar 

  20. Chang YW, Jang JY, Kim NH et al (2005) Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer. Int J Cancer 114:465–471

    Article  CAS  PubMed  Google Scholar 

  21. Taguchi A, Ohmiya N, Shirai K et al (2005) Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan. Cancer Epidemiol Biomark Prev 14:2487–2493

    Article  CAS  Google Scholar 

  22. Olomolaiye O, Wood NA, Bidwell JL (1998) A novel NlaIII polymorphism in the human IL-6 promoter. Eur J Immunogenet 25:267

    CAS  PubMed  Google Scholar 

  23. Terry CF, Loukaci V, Green FR (2000) Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275:18138–18144

    Article  CAS  PubMed  Google Scholar 

  24. Yoo EJ, Park SY, Cho NY, Kim N, Lee HS, Kang GH (2008) Helicobacter pylori-infection-associated CpG island hypermethylation in the stomach and its possible association with Polycomb repressive marks. Virchows Arch 452:515–524

    Article  CAS  PubMed  Google Scholar 

  25. Mihara M, Yoshida Y, Tsukamoto T et al (2006) Methylation of multiple genes in gastric glands with intestinal metaplasia: a disorder with polyclonal origins. Am J Pathol 169:1643–1651

    Article  CAS  PubMed  Google Scholar 

  26. Kang GH, Lee S, Cho NY et al (2008) DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest 88:161–170

    Article  CAS  PubMed  Google Scholar 

  27. Eads CA, Danenberg KD, Kawakami K et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32

    Article  CAS  PubMed  Google Scholar 

  28. Ogino S, Kawasaki T, Brahmandam M et al (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 8:209–217

    Article  CAS  PubMed  Google Scholar 

  29. Trinh BN, Long TI, Laird PW (2001) DNA methylation analysis by MethyLight technology. Methods 25:456–462

    Article  CAS  PubMed  Google Scholar 

  30. Ohm JE, McGarvey KM, Yu X et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237–242

    Article  CAS  PubMed  Google Scholar 

  31. Schlesinger Y, Straussman R, Keshet I et al (2007) Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39:232–236

    Article  CAS  PubMed  Google Scholar 

  32. Widschwendter M, Fiegl H, Egle D et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39:157–158

    Article  CAS  PubMed  Google Scholar 

  33. Lee TI, Jenner RG, Boyer LA et al (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301–313

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST, no. M10750030001-08N5003-00110), a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720540), and Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0093820)

Conflict of interest

There are no financial or other interests with regard to the submitted manuscript that might be construed as a conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Eun Joo Yoo, Nam-Yun Cho & Gyeong Hoon Kang

  2. Department of Pathology, National Cancer Center, Goyang, Gyeonggi-do, South Korea

    Seog-Yun Park

  3. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Nayoung Kim

  4. Department of Pathology, the Second Stage Brain Korea 21 Project and Seoul National, University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, South Korea

    Hye Seung Lee & Gyeong Hoon Kang

  5. Department of Statistics, Sungkyunkwan University, Seoul, South Korea

    Donguk Kim

Authors
  1. Eun Joo Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seog-Yun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nam-Yun Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nayoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hye Seung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donguk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gyeong Hoon Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gyeong Hoon Kang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoo, E.J., Park, SY., Cho, NY. et al. Influence of IL1B polymorphism on CpG island hypermethylation in Helicobacter pylori-infected gastric cancer. Virchows Arch 456, 647–652 (2010). https://doi.org/10.1007/s00428-010-0918-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-010-0918-4

Keywords

Search

Navigation