Skip to main content
Log in

Role of vacuolating cytotoxin VacA and cytotoxin-associated antigen CagA of Helicobacter pylori in the progression of gastric cancer

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Helicobacter (H.) pylori strains that express the cagA and s1a vacA genes are associated with an increased risk for gastric cancer. Here, we examined the association between the products of these virulence genes with the development of gastric cancer by immunohistochemical staining of gastric biopsy specimens taken from 208 routine gastroscopies and 43 gastric cancer patients. The correlation was analyzed by multivariate logistic regression. CagA and VacA expressions in gastric mucosa were significantly associated with chronic gastritis (CG) and intestinal metaplasia (IM), respectively, accompanying CG independent of age. The association of CagA expression with IM accompanying CG was increased in patients over 50-year old (p < 0.01) and that of VacA with CG was significant in patients younger than 50 year (p < 0.05). VacA and CagA were associated with mild IM incidence (p = 0.025 and p = 0.076, respectively) but not advanced IM. In the 43 gastric cancer patients, positivity for VacA was significantly higher in cases of CG and IM than carcinoma (p = 0.042), while that for CagA was slightly higher for individuals with carcinoma than those with CG and IM. These results indicate that CagA and VacA are critical factors for inducing CG and the subsequent progression of IM from CG with an increasing age.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Blaser MJ, Perez-Perez GI, Kleanthous H et al (1995) Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55(10):2111–2115

    PubMed  CAS  Google Scholar 

  2. Marshall BJ, Warren JR (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1(8390):1311–1315

    Article  PubMed  CAS  Google Scholar 

  3. Helicobacter pylori in peptic ulcer disease (1994) NIH Consens Statement 12(1):1–23

  4. Kodama M, Murakami K, Okimoto T et al (2012) Helicobacter pylori eradication improves gastric atrophy and intestinal metaplasia in long-term observation. Digestion 85(2):126–130

    Article  PubMed  Google Scholar 

  5. Pimanov SI, Makarenko EV, Voropaeva AV et al (2008) Helicobacter pylori eradication improves gastric histology and decreases serum gastrin, pepsinogen I and pepsinogen II levels in patients with duodenal ulcer. J Gastroenterol Hepatol 23(11):1666–1671

    Article  PubMed  Google Scholar 

  6. Correa P (1992) Human gastric carcinogenesis: multistep and multifactorial process. Cancer Res 52(24):6735–6740

    PubMed  CAS  Google Scholar 

  7. Leung WK, Ng EK, Chan WY, Auyeung AC et al (2005) Risk factors associated with the development of intestinal metaplasia in first-degree relatives of gastric cancer patients. Cancer Epidemiol Biomark Prev 14(12):2982–2986

    Article  CAS  Google Scholar 

  8. Lamb A, Chen LF (2013) Role of the Helicobacter pylori-induced inflammatory response in the development of gastric cancer. J Cell Biochem 114(3):491–497

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Houghton J, Wang TC (2005) Helicobacter pylori and gastric cancer: a new paradigm for inflammation-associated epithelial cancers. Gastroenterology 128(6):1567–1578

    Article  PubMed  CAS  Google Scholar 

  10. Uemura N, Okamoto S, Yamamoto S et al (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345(11):784–789

    Article  PubMed  CAS  Google Scholar 

  11. Sepulveda AR (2013) Helicobacter, inflammation, and gastric cancer. Curr Pathobiol Rep 1(1):9–18

    Article  PubMed  PubMed Central  Google Scholar 

  12. González CA, Figueiredo C, Lic CB et al (2011) Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: a long-term follow-up in a high-risk area in Spain. Am J Gastroenterol 106(5):867–874

    Article  PubMed  Google Scholar 

  13. Atherton JC, Cao P, Peek RM Jr et al (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori: association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 270(30):17771–17777

    Article  PubMed  CAS  Google Scholar 

  14. Greenfield LK, Jones NL (2013) Modulation of autophagy by Helicobacter pylori and its role in gastric carcinogenesis. Trends Microbiol 21(11):602–612

    Article  PubMed  CAS  Google Scholar 

  15. Zambon CF, Navaglia F, Basso D et al (2003) Helicobacter pylori babA, cagA, and s1 vacA genes work synergistically in causing intestinal metaplasia. J Clin Pathol 56(4):287–291

    Article  PubMed  PubMed Central  Google Scholar 

  16. Basso D, Zambon CF, Letley DP et al (2008) Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 135(1):91–99

    Article  PubMed  CAS  Google Scholar 

  17. The eurohepygast study group (2002) Risk factors for atrophic chronic gastritis in a European population: results of the Eurohepygast study. Gut 50(6):779–785

    Article  PubMed Central  Google Scholar 

  18. Lee HS, Choe G, Kim WH et al (2006) Expression of Lewis antigens and their precursors in gastric mucosa: relationship with Helicobacter pylori infection and gastric carcinogenesis. J Pathol 209(1):88–94

    Article  PubMed  CAS  Google Scholar 

  19. Dixon MF, Genta RM, Yardley JH et al (1996) The updated Sydney system. International workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol 20(10):1161–1181

    Article  PubMed  CAS  Google Scholar 

  20. Lee HS, Lee HK, Kim HS et al (2001) MUC1, MUC2, MUC5AC, and MUC6 expression in gastric carcinomas: their roles as prognostic indicators. Cancer 92(6):1427–1434

    Article  PubMed  CAS  Google Scholar 

  21. Ki MR, Lee HR, Goo MJ et al (2008) Differential regulation of ERK1/2 and p38 MAP kinases in VacA-induced apoptosis of gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol 294(3):G635–G647

    Article  PubMed  CAS  Google Scholar 

  22. Ki MR, Hong IH, Park JK et al (2009) Potent neutralization of vacuolating cytotoxin (VacA) of Helicobacter pylori by immunoglobulins against the soluble recombinant VacA. Anticancer Res 29(6):2393–2402

    PubMed  CAS  Google Scholar 

  23. Kimmel B, Bosserhoff A, Frank R et al (2000) Identification of immunodominant antigens from Helicobacter pylori and evaluation of their reactivities with sera from patients with different gastroduodenal pathologies. Infect Immun 68(2):915–920

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Asaka M, Kato M, Graham DY (2010) Prevention of gastric cancer by Helicobacter pylori eradication. Intern Med 49(7):633–636

    Article  PubMed  Google Scholar 

  25. Maehata Y, Nakamura S, Fujisawa K et al (2012) Long-term effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer. Gastrointest Endosc 75(1):39–46

    Article  PubMed  Google Scholar 

  26. Raider G, Fischer W, Haas R (2005) Interaction of Helicobacter pylori with host cells: function of secreted and translocated molecules. Curr Opin Microbiol 8(1):67–73

    Article  Google Scholar 

  27. Leunk RD, Johnson PT, David BC et al (1988) Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J Med Microbiol 26(2):93–99

    Article  PubMed  CAS  Google Scholar 

  28. Galmiche A, Rassow J, Doye A et al (2000) The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J 19(23):6361–6370

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Cover TL, Krishna US, Israel DA (2003) Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res 63(5):951–957

    PubMed  CAS  Google Scholar 

  30. Boncristiano M, Paccani SR, Barone S et al (2003) The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med 198(12):1887–1897

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Gebert B, Fischer W, Weiss E et al (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301(5636):1099–1102

    Article  PubMed  CAS  Google Scholar 

  32. Supajatura V, Ushio H, Wada A et al (2002) Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines. J Immunol 168(6):2603–2607

    Article  PubMed  CAS  Google Scholar 

  33. Yang I, Nell S, Suerbaum S (2013) Survival in hostile territory: the microbiota of the stomach. FEMS Microbiol Rev 37(5):736–761

    Article  PubMed  CAS  Google Scholar 

  34. Stein M, Bagnoli F, Halenbeck R et al (2002) c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 43(4):971–980

    Article  PubMed  CAS  Google Scholar 

  35. Segal ED, Cha J, Lo J et al (1999) Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci USA 96(25):14559–14564

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. De Luca A, Baldi A, Russo P et al (2003) Coexpression of Helicobacter pylori’s proteins CagA and HspB induces cell proliferation in AGS gastric epithelial cells, independently from the bacterial infection. Cancer Res 63(19):6350–6356

    PubMed  Google Scholar 

  37. von Herbay A, Rudi J (2000) Role of apoptosis in gastric epithelial turnover. Microsc Res Tech 48(5):303–311

    Article  Google Scholar 

  38. Anagnostopoulos GK, Stefanou D, Arkoumani E et al (2005) Bax and Bcl-2 protein expression in gastric precancerous lesions: immunohistochemical study. J Gastroenterol Hepatol 20(11):1674–1678

    Article  PubMed  CAS  Google Scholar 

  39. Andl CD, Mizushima T, Nakagawa H et al (2003) Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo. J Biol Chem 278(3):1824–1830

    Article  PubMed  CAS  Google Scholar 

  40. Wang LJ, Chen SJ, Chen Z et al (2006) Morphological and pathologic changes of experimental chronic atrophic gastritis (CAG) and the regulating mechanism of protein expression in rats. J Zhejiang Univ 7(8):634–640

    Article  CAS  Google Scholar 

  41. Tabassam FH, Graham DY, Yamaoka Y (2009) Helicobacter pylori activate epidermal growth factor receptor and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3 beta phosphorylation. Cell Microbiol 11(1):70–82

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Ashktorab H, Daremipouran M, Wilson M et al (2007) Transactivation of the EGFR by AP-1 is induced by Helicobacter pylori in gastric cancer. Am J Gastroenterol 102(10):2135–2146

    Article  PubMed  CAS  Google Scholar 

  43. Keates S, Keates AS, Nath S et al (2005) Transactivation of the epidermal growth factor receptor by cag + Helicobacter pylori induces upregulation of the early growth response gene Egr-1 in gastric epithelial cells. Gut 54(10):1363–1369

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Osborn M, Mazzoleni G, Santini D et al (1988) Villin, intestinal brush border hydrolases and keratin polypeptides in intestinal metaplasia and gastric cancer; an immunohistologic study emphasizing the different degrees of intestinal and gastric differentiation in signet ring cell carcinomas. Virchows Arch A Pathol Anat Histopathol 413(4):303–312

    Article  PubMed  CAS  Google Scholar 

  45. Renehan AG, O’Dwyer ST, Haboubi NJ et al (2002) Early cellular events in colorectal carcinogenesis. Colorectal Dis 4(2):76–89

    Article  PubMed  Google Scholar 

  46. Yokoyama K, Higashi H, Ishikawa S et al (2005) Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc Natl Aca Sci USA 102(27):9661–9666

    Article  CAS  Google Scholar 

  47. Iijima K, Koike T, Sekine H et al (2009) Sustained epithelial proliferation in a functionally irreversible fundic mucosa after Helicobacter pylori eradication. J Gastroenterol 44(1):47–55

    Article  PubMed  Google Scholar 

  48. Karita M, Teramukai S, Matsumoto S et al (2005) Intracellular VacA is a valuable marker to predict whether Helicobacter pylori induces progressive atrophyic gastritis that is associated with the development of gastric cancer. Dig Dis Sci 50(1):56–64

    Article  PubMed  CAS  Google Scholar 

  49. Annibale B, Lahner E, Santucci A et al (2007) CagA and VacA are immunoblot markers of past Helicobacter pylori infection in atrophic body gastritis. Helicobacter 12(1):23–30

    Article  PubMed  CAS  Google Scholar 

  50. Negrini R, Savio A, Poiesi C et al (1996) Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology 111(3):655–665

    Article  PubMed  CAS  Google Scholar 

  51. Amedei A, Bergman MP, Appelmelk BJ et al (2003) Molecular mimicry between Helicobacter pylori antigens and H+, K+-adenosine triphosphatase in human gastric autoimmunity. J Exp Med 198(8):1147–1156

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Bergman MP, vandenbroucke-grauls CM, Appelmelk BJ et al (2005) The story so far: Helicobacter pylori and gastric autoimmunity. Int Rev Immunol 24(1–2):63–91

    Article  PubMed  CAS  Google Scholar 

  53. Dohmen K, Shigematsu H, Miyamoto Y et al (2002) Atrophic corpus gastritis and Helicobacter pylori infection in primary biliary cirrhosis. Dig Dis Sci 47(1):162–169

    Article  PubMed  Google Scholar 

  54. Goo MJ, Ki MR, Lee HR et al (2008) Primary biliary cirrhosis, similar to that in human beings, in a male C57BL/6 mouse infected with Helicobacter pylori. Eur J Ggastroenterol Hepatol 20(10):1045–1048

    Article  Google Scholar 

  55. De Bolos C, Garrido M, Real FX (1995) MUC6 apomucin shows a distinct normal tissue distribution that correlates with Lewis antigen expression in the human stomach. Gastroenterology 109(3):723–734

    Article  PubMed  Google Scholar 

  56. Gonzalez-Valencia G, Munoz-Perez L, Morales-Espinosa R et al (2008) Lewis antigen expression by Helicobacter pylori strains colonizing different resions of the stomach of individual patients. J Clin Microbiol 46(8):2783–2785

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by Bio-industry Technology Development Program (312062-5) of iPET (Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries), Ministry for Food, Agriculture, Forestry and Fisheries, and Kyungpook National University Research Fund, 2013, Republic of Korea.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kyu-Shik Jeong.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ki, MR., Hwang, M., Kim, AY. et al. Role of vacuolating cytotoxin VacA and cytotoxin-associated antigen CagA of Helicobacter pylori in the progression of gastric cancer. Mol Cell Biochem 396, 23–32 (2014). https://doi.org/10.1007/s11010-014-2138-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2138-8

Keywords

Navigation