Variación en el número de repeticiones EPIYA-C en la proteína CagA de aislamientos colombianos de Helicobacter pylori y su capacidad para inducir fenotipo colibrí en células epiteliales gástricas
Palabras clave:
Helicobacter pylori, proteína CagA, polimorfismo, gastritis, neoplasias del estómago, úlcera duodenal
Resumen
Introducción. En los aislamientos de Helicobacter pylori del hemisferio occidental, se ha observado que el número de repeticiones EPIYA-C en la proteína CagA es un factor de riesgo para cáncer gástrico. La proteína CagA es introducida en la célula epitelial y, posteriormente, es fosforilada en las tirosinas presentes en los motivos EPIYA e induce rearreglos en el citoesqueleto.Objetivos. Nuestro propósito fue evaluar el número de repeticiones EPIYA-C y la habilidad para inducir rearreglos en el citoesqueleto en los aislamientos de H. pylori positivos para cagA, provenientes de pacientes colombianos con enfermedad gastroduodenal.
Materiales y métodos. Mediante PCR, se analizó la región 3´ que contiene las repeticiones EPIYA-C, en 93 aislamientos de H. pylori positivos para cagA provenientes de 49 pacientes con gastritis, 17 con cáncer gástrico y 24 con úlcera duodenal. Los rearreglos del citoesqueleto se evaluaron mediante cultivos simultáneos de células AGS con las cepas de H. pylori.
Resultados. En gastritis y úlcera duodenal se observó la mayor frecuencia de aislamientos con EPIYA C; los aislamientos con tres repeticiones EPIYA-C se encontraron con mayor frecuencia en cáncer gástrico. Encontramos un riesgo de cáncer gástrico significativamente mayor para individuos infectados con cepas con tres repeticiones EPIYA-C (OR=12,4; IC95% 2,32-66,3). Los aislamientos provenientes de cáncer gástrico mostraron mayores porcentajes de inducción de rearreglos en el citoesqueleto que los observados con aislamientos provenientes de gastritis (prueba de Mann-Whitney menor de 0,005).
Conclusiones. La infección con cepas de H. pylori con tres repeticiones EPIYA-C puede conferir un mayor riesgo de desarrollar cáncer gástrico.
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Referencias bibliográficas
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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.
Cómo citar
1.
Quiroga AJ, Huertas A, Cómbita AL, Bravo MM. Variación en el número de repeticiones EPIYA-C en la proteína CagA de aislamientos colombianos de Helicobacter pylori y su capacidad para inducir fenotipo colibrí en células epiteliales gástricas. Biomed. [Internet]. 4 de agosto de 2010 [citado 7 de abril de 2025];30(2):251-8. Disponible en: https://revistabiomedicaorg.biteca.online/index.php/biomedica/article/view/188
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