Variation in the number of EPIYA-C repeats in CagA protein from Colombian Helicobacter pylori strains and its ability to induce hummingbird phenotype in gastric epithelial cells
Keywords:
Helicobacter pylori, polymorphism, genetic, gastritis, stomach neoplasm, duodenal ulcer
Abstract
Introduction. Studies using Western Helicobacter pylori strains have shown that a risk factor for gastric cancer is the number of EPIYA-C motifs in the cytotoxin-associated A protein. CagA is delivered into epithelial cells, where it becomes tyrosine phosphorylated in their EPIYA repeats and induces cytoskeleton rearrangements.Objectives. The objective of this study was to evaluate H. pylori cagA positive strains isolated from Colombian patients with gastroduodenal diseases for the number of EPIYA-C repeats in cagA and their ability to induce cytoskeleton rearrangements in epithelial cells.
Materials and methods. We analyzed the 3' EPIYA repeats region of cagA by PCR in 93 H. pylori cagA positive strains from 49 patients with gastritis, 17 with gastric cancer, and 24 with duodenal ulcer. AGS cells exposed to the various H. pylori isolates were evaluated for rearrangements in their cytoskeleton.
Results. Strains with one EPIYA-C were the most frequent in gastritis and duodenal ulcer patients. Strains with three EPIYA-C were mainly found in gastric cancer. We found a significantly higher risk of gastric cancer for individuals infected with strains harboring three EPIYA-C motifs (OR=12.4, CI95%: 2.32-66.3). Strains from gastric cancer showed significantly higher percentages of induction of cytoskeleton rearrangements in comparison with those from gastritis (p Mann-Whitney<0.005).
Conclusions. H. pylori strains with three EPIYA-C repeats can confer an increased risk of cancer to infected individuals.
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References
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23. Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y, et al. Correlation between variation of the 3' region of the cagA gene in Helicobacter pylori and disease outcome in Japan. J Infect Dis. 2002;186:1621-30.
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25. Basso D, Zambon CF, Letley DP, Stranges A, Marchet A, Rhead JL, et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology. 2008;135:91-9.
26. Reyes-Leon A, Atherton JC, Argent RH, Puente JL, Torres J. Heterogeneity in the activity of Mexican Helicobacter pylori strains on gastric epithelial cells and it's association with diversity in the cagA gene. Infect Immun. 2007;75:3445-54
27. Bravo LE, van Doom LJ, Realpe JL, Correa P. Virulence-associated genotypes of Helicobacter pylori: do they explain the African enigma? Am J Gastroenterol. 2002;97:2839-42.
28. Pineros M, Ferlay J, Murillo R. Cancer incidence estimates at the national and district levels in Colombia. Salud Publica Mex. 2006;48:455-65.
29. Naito M, Yamazaki T, Tsutsumi R, Higashi H, Onoe K, Yamazaki S, et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology. 2006;130: 1181-90.
30. Yamaoka Y, Osato MS, Sepulveda AR, Gutierrez O, Figura N, Kim JG, et al. Molecular epidemiology of Helicobacter pylori: separation of H. pylori from East Asian and non-Asian countries. Epidemiol Infect. 2000;124:91-6.
31. Panayotopoulou EG, Sgouras DN, Papadakos K, Kalliaropoulos A, Papatheodoridis G, Mentis AF, et al. Strategy to characterize the number and type of repeating EPIYA phosphorylation motifs in the carboxyl terminus of CagA protein in Helicobacter pylori clinical isolates. J Clin Microbiol. 2007;45:488-95.
32. Snaith A, El-Omar EM. Helicobacter pylori: host genetics and disease outcomes. Expert Rev Gastroenterol Hepatol. 2008;2:577-85.
33. Argent RH, Thomas RJ, viles-Jimenez F, Letley DP, Limb MC, El-Omar EM, et al. Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. Clin Cancer Res. 2008;14:2227-35.
34. Aras RA, Lee Y, Kim SK, Israel D, Peek RM Jr, Blaser MJ. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype. J Infect Dis. 2003;188:486-96.
35. Covacci A, Falkow S, Berg DE, Rappuoli R. Did the inheritance of a pathogenicity island modify the virulence of Helicobacter pylori? Trends Microbiol. 1997;5:205-8.
36. Yamaoka Y, Kodama T, Kashima K, Graham DY, Sepulveda AR. Variants of the 3' region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. J Clin Microbiol. 1998;36: 2258-63.
2. Blaser MJ, Berg DE. Helicobacter pylori genetic diversity and risk of human disease. J Clin Invest. 2001;107:767-73.
3. Israel DA, Peek RM. Pathogenesis of Helicobacter pylori-induced gastric inflammation. Aliment Pharmacol Ther. 2001;15:1271-90.
4. Parsonnet J. Helicobacter pylori: the size of the problem. Gut. 1998;43 (Suppl. 1):S6-9.
5. Peek RM, Jr., Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2:28-37.
6. Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology. 2004;127:514-23.
7. Tummuru MK, Cover TL, Blaser MJ. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun. 1993;61:1799-809.
8. Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 1995;55:2111-5.
9. Camargo MC, Mera R, Correa P, Peek RM, Jr., Fontham ET, Goodman KJ, et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:1674-87.
10. Gorouhi F, Islami F, Bahrami H, Kamangar F. Tumour-necrosis factor-A polymorphisms and gastric cancer risk: a meta-analysis. Br J Cancer. 2008;98:1443-51.
11. Bae JM, Lee EJ, Guyatt G. Citrus fruit intake and stomach cancer risk: a quantitative systematic review. Gastric Cancer. 2008;11:23-32.
12. Cittelly DM, Huertas MG, Martinez JD, Oliveros R, Posso H, Bravo MM, et al. Helicobacter pylori genotypes in non atrophic gastritis are different of the found in peptic ulcer, premalignant lesions and gastric cancer in Colombia. Rev Med Chil. 2002;130:143-51.
13. Kidd M, Lastovica AJ, Atherton JC, Louw JA. Conservation of the cag pathogenicity island is associated with vacA alleles and gastroduodenal disease in South African Helicobacter pylori isolates. Gut. 2001;49:11-7.
14. Nilsson C, Sillen A, Eriksson L, Strand ML, Enroth H, Normark S, et al. Correlation between cag pathogenicity island composition and Helicobacter pylori-associated gastroduodenal disease. Infect Immun. 2003;71:6573-81.
15. Quiroga AJ, Cittelly DM, Bravo MM. BabA2, oipA and cagE Helicobacter pylori genotypes in Colombian patients with gastroduodenal diseases. Biomédica. 2005;25:325-34.
16. Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA. 1996;93:14648-53.
17. Akopyants NS, Clifton SW, Kersulyte D, Crabtree JE, Youree BE, Reece CA, et al. Analyses of the cag pathogenicity island of Helicobacter pylori. Mol Microbiol. 1998;28:37-53.
18. Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287:1497-500.
19. Stein M, Rappuoli R, Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci USA. 2000;97:1263-8.
20. Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol. 2002;43:971-80.
21. Segal ED, Cha J, Lo J, Falkow S, Tompkins LS. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci USA. 1999;96:14559-64.
22. Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci USA. 2002;99:14428-33.
23. Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y, et al. Correlation between variation of the 3' region of the cagA gene in Helicobacter pylori and disease outcome in Japan. J Infect Dis. 2002;186:1621-30.
24. Yamaoka Y, el Zimaity HM, Gutierrez O, Figura N, Kim JG, Kodama T, et al. Relationship between the cagA 3' repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. Gastroenterology. 1999;117:342-9.
25. Basso D, Zambon CF, Letley DP, Stranges A, Marchet A, Rhead JL, et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology. 2008;135:91-9.
26. Reyes-Leon A, Atherton JC, Argent RH, Puente JL, Torres J. Heterogeneity in the activity of Mexican Helicobacter pylori strains on gastric epithelial cells and it's association with diversity in the cagA gene. Infect Immun. 2007;75:3445-54
27. Bravo LE, van Doom LJ, Realpe JL, Correa P. Virulence-associated genotypes of Helicobacter pylori: do they explain the African enigma? Am J Gastroenterol. 2002;97:2839-42.
28. Pineros M, Ferlay J, Murillo R. Cancer incidence estimates at the national and district levels in Colombia. Salud Publica Mex. 2006;48:455-65.
29. Naito M, Yamazaki T, Tsutsumi R, Higashi H, Onoe K, Yamazaki S, et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology. 2006;130: 1181-90.
30. Yamaoka Y, Osato MS, Sepulveda AR, Gutierrez O, Figura N, Kim JG, et al. Molecular epidemiology of Helicobacter pylori: separation of H. pylori from East Asian and non-Asian countries. Epidemiol Infect. 2000;124:91-6.
31. Panayotopoulou EG, Sgouras DN, Papadakos K, Kalliaropoulos A, Papatheodoridis G, Mentis AF, et al. Strategy to characterize the number and type of repeating EPIYA phosphorylation motifs in the carboxyl terminus of CagA protein in Helicobacter pylori clinical isolates. J Clin Microbiol. 2007;45:488-95.
32. Snaith A, El-Omar EM. Helicobacter pylori: host genetics and disease outcomes. Expert Rev Gastroenterol Hepatol. 2008;2:577-85.
33. Argent RH, Thomas RJ, viles-Jimenez F, Letley DP, Limb MC, El-Omar EM, et al. Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. Clin Cancer Res. 2008;14:2227-35.
34. Aras RA, Lee Y, Kim SK, Israel D, Peek RM Jr, Blaser MJ. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype. J Infect Dis. 2003;188:486-96.
35. Covacci A, Falkow S, Berg DE, Rappuoli R. Did the inheritance of a pathogenicity island modify the virulence of Helicobacter pylori? Trends Microbiol. 1997;5:205-8.
36. Yamaoka Y, Kodama T, Kashima K, Graham DY, Sepulveda AR. Variants of the 3' region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. J Clin Microbiol. 1998;36: 2258-63.
How to Cite
1.
Quiroga AJ, Huertas A, Cómbita AL, Bravo MM. Variation in the number of EPIYA-C repeats in CagA protein from Colombian Helicobacter pylori strains and its ability to induce hummingbird phenotype in gastric epithelial cells. biomedica [Internet]. 2010 Aug. 4 [cited 2024 May 19];30(2):251-8. Available from: https://revistabiomedica.org/index.php/biomedica/article/view/188
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