Analysis of the 3' Variable Region of Cytotoxin-Associated Gene A (cagA) in Helicobacter pylori Isolates in China

DOI: 10.4236/pp.2013.45A003   PDF   HTML     2,771 Downloads   4,311 Views   Citations


Infection by the bacterium Helicobacter pylori is a putative cause of various gastric disorders, including gastric adenocarcinoma. Incident rates are associated with variants of the H. pylori virulence factor cytotoxin-associated gene A protein (CagA), encoded by the gene cagA. However, these variants have not been characterized in China, where gastric cancer is common. We investigated the diversity of CagA variants in H. pylori strains isolated from a Chinese population. The 3' variable region of cagA genes from 66 clinical isolates in China were amplified by polymerase chain reaction, sequenced, aligned, and analyzed. All 66 H. pylori strains were CagA-positive, of which 93.9% were East Asian type and the tyrosine phosphorylation motifs (TPMs) were EPIYA-ABD. The remainder was Western type, in which TPMs were EPIYA-ABC. Interestingly, two of sixty-two strains (3.2%) of the East Asian type were mutated into ESIYA-B, whereas all four Western type (100%) strains were mutated into EPIYT-B. Both of the two strains with Western-type CagA obtained from gastric cancer patients contained a distinguished mutation on the first residue following the EPIYA site in the EPIYA-A motif. The predominant CagA type in these H. pylori strains isolated from Chinese patients in China was East Asian, with TPMs EPIYA-ABD, and there existed mutations in both the East Asian and Western type CagA.

Share and Cite:

B. Li, D. Du, W. Sun, Q. Cao, Z. Zhang and Z. Du, "Analysis of the 3' Variable Region of Cytotoxin-Associated Gene A (cagA) in Helicobacter pylori Isolates in China," Pharmacology & Pharmacy, Vol. 4 No. 5A, 2013, pp. 13-18. doi: 10.4236/pp.2013.45A003.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Covacci, J. L. Telford, G. Del Giudice, J. Parsonnet and R. Rappuoli, “Helicobacter pylori Virulence and Genetic Geography,” Science, Vol. 284, No. 5418, 1999, pp. 1328-1333. doi:10.1126/science.284.5418.1328
[2] J. C. Atherton, “The Pathogenesis of Helicobacter pylori-Induced Gastro-Duodenal Diseases,” Annual Review of Pathology, Vol. 1, 2006, pp. 63-96. doi:10.1146/annurev.pathol.1.110304.100125
[3] M. J. Blaser, “Helicobacter pylori and Gastric Diseases,” British Medical Journal, Vol. 316, No. 7143, 1998, pp. 1507-1510. doi:10.1136/bmj.316.7143.1507
[4] E. Ogorodnik and R. D. Raffaniello, “Analysis of the 3′-Variable Region of the cagA Gene from Helicobacter pylori Strains Infecting Patients at New York City Hospitals,” Microbial Pathogenesis, Vol. 56, 2012, pp. 29-34. doi:10.1016/j.micpath.2012.10.003
[5] C. Chomvarin, K. Phusri, K. Sawadpanich, P. Mairiang, W. Namwat, C. Wongkham and C. Hahnvajanawong, “Prevalence of CagA EPIYA Motifs in Helicobacter pylori among Dyspeptic Patients in Northeast Thailand,” The Southeast Asian Journal of Tropical Medicine and Public Health, Vol. 43, No. 1, 2012, pp. 105-115.
[6] L. Shokrzadeh, K. Baghaei, Y. Yamaoka, H. Dabiri, F. Jafari, N. Sahebekhtiari, A. Tahami, M. Sugimoto, H. Zojaji and M. R. Zali, “Analysis of 3′-End Variable Region of the CagA Gene in Helicobacter pylori Isolated from Iranian Population,” Journal of Gastroenterology and Hepatology, Vol. 25, No. 1, 2010, pp. 172-177. doi:10.1111/j.1440-1746.2009.05979.x
[7] S. Jang, K. R. Jones, C. H. Olsen, Y. M. Joo, Y. J. Yoo, I. S. Chung, J. H. Cha and D. S. Merrell, “Epidemiological Link between Gastric Disease and Polymorphisms in Vac A and CagA,” Journal of Clinical Microbiology, Vol. 48, No. 2, 2010, pp. 559-567. doi:10.1128/JCM.01501-09
[8] S. Kumar, A. Kumar and V. K. Dixit, “Diversity in the Cag Pathogenicity Island of Helicobacter pylori Isolates in populations from North and South India,” Journal of Medical Microbiology, Vol. 59, No. 1, 2010, pp. 32-40. doi:10.1099/jmm.0.013763-0
[9] S. Satomi, A. Yamakawa, S. Matsunaga, R. Masaki, T. Inagaki, T. Okuda, H. Suto, Y. Ito, Y. Yamazaki, M. Kuriyama, Y. Keida, H. Kutsumi and T. Azuma, “Relationship between the Diversity of the cagA Gene of Helicobacter pylori and Gastric Cancer in Okinawa, Japan,” Journal of Gastroenterology, Vol. 41, No. 7, 2006, pp. 668-673. doi:10.1007/s00535-006-1838-6
[10] S. Odenbreit, J. Püls, B. Sedlmaier, E. Gerland, W. Fischer and R. Haas, “Translocation of Helicobacter pylori CagA into Gastric Epithelial Cells by Type IV Secretion,” Science, Vol. 287, No. 5457, 2000, pp. 1497-1500. doi:10.1126/science.287.5457.1497
[11] R. H. Argent, Y. Zhang and J. C.Atherton, “Simple Method for Determination of the Number of Helicobacter pylori CagA Variable-Region EPIYA Tyrosine Phosphorylation Motifs by PCR,” Journal of Clinical Microbiology, Vol. 43, No. 2, 2005, pp. 791-795. doi:10.1128/JCM.43.2.791-795.2005
[12] H. Higashi, R. Tsutsumi, A. Fujita, S. Yamazaki, M. Asaka, T. Azuma and M. Hatakeyama, “Biological Activity of the Helicobacter pylori Virulence Factor CagA Is Determined by Variation in the Tyrosine Phosphorylation Sites,” Proceedings of the National Academy of Sciences of the USA, Vol. 99, No. 22, 2002, pp. 14428-14433. doi:10.1073/pnas.222375399
[13] M. Hatakeyama, “Oncogenic Mechanisms of the Helicobacter pylori CagA Protein,” Nature Reviews Cancer, Vol. 4, No. 9, 2004, pp. 688-694. doi:10.1038/nrc1433
[14] R. M. Ferreira, J. C. Machado, M. Leite, F. Carneiro and C. Figueiredo, “The Number of Helicobacter pylori CagA EPIYA C Tyrosine Phosphorylation Motifs Influences the Pattern of Gastritis and the Development of Gastric Carcinoma,” Histopathology, Vol. 60, No. 6, 2012, pp. 992-998. doi:10.1111/j.1365-2559.2012.04190.x
[15] D. De Souza, L. J. Fabri, A. Nash, D. J. Hilton, N. A. Nicola and M. Baca, “SH2 Domains from Suppressor of Cytokine Signaling-3 and Protein Tyrosine Phosphatase SHP-2 Have Similar Binding Specificities,” Biochemistry, Vol. 41, No. 29, 2002, pp. 9229-9236. doi:10.1021/bi0259507
[16] Z. J. Pan, R. W. van der Hulst, M. Feller, S. D. Xiao, G. N. Tytgat, J. Dankert and A. van der Ende, “Equally High Prevalences of Infection with CagA-Positive Helicobacter pylori in Chinese Patients with Peptic Ulcer Disease and Those with Chronic Gastritis-Associated Dyspepsia,” Journal of Clinical Microbiology, Vol. 35, No. 6, 1997, pp. 1344-1347.
[17] P. Bertuccio, L. Chatenoud, F. Levi, D. Praud, J. Ferlay, E. Negri, M. Malvezzi and C. La Vecchia, “Recent Patterns in Gastric Cancer: A Global Overview,” International Journal of Cancer, Vol. 125, No. 3, 2009, pp. 666-673. doi:10.1002/ijc.24290
[18] R. M. Peek Jr., S. F. Moss, K. T. Tham, G. I. Pérez-Pérez, S. Wang, G. G. Miller, J. C. Atherton, P. R. Holt and M. J. Blaser, “Helicobacter pylori CagA+ Strains and Dissociation of Gastric Epithelial Cell Proliferation from Apopto-sis,” Journal of the National Cancer Institute, Vol. 89, No. 12, 1997, pp. 863-868. doi:10.1093/jnci/89.12.863
[19] H. Higashi, K. Yokoyama, Y. Fujii, S. Ren, H. Yuasa, I. Saadat, N. Murata-Kamiya, T. Azuma and M. Hatakeyama, “EPIYA Motif Is a Membrane-Targeting Signal of Helicobacter pylori Virulence Factor CagA in Mammalian Cells,” Journal of Biological Chemistry, Vol. 280, No. 24, 2005, pp. 23130-23137. doi:10.1074/jbc.M503583200
[20] M. Naito, T. Yamazaki, R. Tsutsumi, H. Higashi, K. Onoe, S. Yamazaki, T. Azuma and M. Hatakeyama, “Influence of EPIYA-Repeat Polymorphism on the Phosphorylation-Dependent Biological Activity of Helicobacter pylori CagA,” Gastroenterology, Vol. 130, No. 4, 2006, pp. 1181-1190. doi:10.1053/j.gastro.2005.12.038
[21] M. Suzuki, H. Mimuro, K. Kiga, M. Fukumatsu, N. Ishijima, H. Morikawa, S. Nagai, S. Koyasu, R. H. Gilman, D. Kersulyte, D. E. Berg and C. Sasakawa, “Helicobacter pylori CagA Phosphorylation-Independent Function in Epithelial Proliferation and Inflammation,” Cell Host & Microbe, Vol. 5, No. 1, 2009, pp. 23-34. doi:10.1016/j.chom.2008.11.010
[22] M. Asahi, T. Azuma, S. Ito, Y. Ito, H. Suto, Y. Nagai, M. Tsubokawa, Y. Tohyama, S. Maeda, M. Omata, T. Suzuki and C. Sasakawa, “Helicobacter pylori CagA Protein Can Be Tyrosine Phosphorylated in Gastric Epithelial Cells,” The Journal of Experimental Medicine, Vol. 191, No. 4, 2000, pp. 593-602. doi:10.1084/jem.191.4.593
[23] T. Azuma, S. Yamazaki, A. Yamakawa, M. Ohtani, A. Muramatsu, H. Suto, Y. Ito, M. Dojo, Y. Yamazaki, M. Kuriyama, Y. Keida, H. Higashi and M. Hatakeyama, “Association between Diversity in the Src Homology 2 Domain-Containing Tyrosine Phosphatase Binding Site of Helicobacter pylori CagA Protein and Gastric Atroph and Cancer,” The Journal of Infectious Diseases, Vol. 189, No. 5, 2004, pp. 820-827. doi:10.1086/381782
[24] H. Higashi, R. Tsutsumi, S. Muto, T. Sugiyama, T. Azuma, M. Asaka and M. Hatakeyama, “SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein,” Science, Vol. 295, No. 5555, 2002, pp. 683-686. doi:10.1126/science.1067147
[25] S. Yamazaki, A. Yamakawa, T. Okuda, M. Ohtani, H. Suto, Y. Ito, Y. Yamazaki, Y. Keida, H. Higashi, M. Hatakeyama and T. Azuma, “Distinct Diversity of vacA, cagA, and cagE Genes of Helicobacter pylori Associated with Peptic Ulcer in Japan,” Journal of Clinical Microbiology, Vol. 43, No. 8, 2005, pp. 3906-3916. doi:10.1128/JCM.43.8.3906-3916.2005
[26] X. Shunfu, Z. Guoxin, S. Ruihua, H. Bo and M. Yi, “Polymorphism of Variable Regions of CagA Protein,” Chinese Journal of Gastroenterology, Vol. 12, No. 6, 2007, pp. 357-361.
[27] A. Reyes-Leon, J. C. Atherton, R. H. Argent, J. L. Puente and J. Torres, “Heterogeneity in the Activity of Mexican Helicobacter pylori Strains in Gastric Epithelial Cells and Its Association with Diversity in the cagA Gene,” Infection and Immunity, Vol. 75, No. 7, 2007, pp. 3445-3454. doi:10.1128/IAI.01951-06
[28] E. G. Panayotopoulou, D. N. Sgouras, K. Papadakos, A. Kalliaropoulos, G. Papatheodoridis, A. F. Mentis and A. J. Archimandritis, “Strategy to Characterize the Number and Type of Repeating EPIYA Phosphorylation Motifs in the Carboxyl Terminus of CagA Protein in Helicobacter pylori Clinical,” Journal of Clinical Microbiology, Vol. 45, No. 2, 2007, pp. 488-495. doi:10.1128/JCM.01616-06
[29] Y. Yamaoka, T. Kodama, K. Kashima and D. Y. Graham, “Antibody against Helicobacter pylori CagA and VacA and the Risk for Gastric Cancer,” Journal of Clinical Pathology, Vol. 52, No. 3, 1999, pp. 215-218. doi:10.1136/jcp.52.3.215
[30] S. Backert, T. Schwarz, S. Miehlke, C. Kirsch, C. Sommer, T. Kwok, M. Gerhard, U. B. Goebel, N. Lehn, W. Koenig and T. F. Meyer, “Functional Analysis of the Cag Pathogenicity Island in Helicobacter pylori Isolates from Patients with Gastritis, Peptic Ulcer, and Gastric Cancer,” Infection and Immunity, Vol. 72, No. 2, 2004, pp. 1043-1056. doi:10.1128/IAI.72.2.1043-1056.2004
[31] Y. Hirata, A. Yanai, W. Shibata, Y. Mitsuno, S. Maeda, K. Ogura, H. Yoshida, T. Kawabe, M. Omata, “Functional Variability of CagA Gene in Japanese Isolates of Helicobacter pylori,” Gene, Vol. 343, No. 1, 2004, pp. 165-172. doi:10.1016/j.gene.2004.08.026
[32] D. Nishiya, T. Shimoyama, T. Yoshimura, M. Tanaka, S. Fukuda and A. Munakata, “Genes Inside the cagPAI of Helicobacter pylori Are Not Associated with Gastric Cancer in Japan.” Hepatogastroenterology, Vol. 51, No. 57, 2004, pp. 891-894.
[33] S. Sahara, M. Sugimoto, R. K. Vilaichone, V. Mahachai, H. Miyajima, T. Furuta and Y. Yamaoka, “Role of Helicobacter pylori cagA EPIYA Motif and vacA Geno-Types for the Development of Gastrointestinal Diseases in Southeast Asian Countries: A Meta-Analysis,” BMC Infectious Diseases, Vol. 12, 2012, p. 223. doi:10.1186/1471-2334-12-223
[34] A. Karlsson, A. Ryberg, M. Nosouhi Dehnoei, K. Borch and H. J. Monstein, “Association between cagA and vacA Genotypes and Pathogenesis in a Helicobacter pylori Infected Population from South-Eastern Sweden,” BMC Microbiology, Vol. 12, 2012, p. 129. doi:10.1186/1471-2180/12-129
[35] H. M. Schmidt, K. L. Goh, K. M. Fock, I. Hilmi, S. Dhamodaran, D. Forman and H. Mitchell, “Distinct cagA EPIYA Motifs Are Associated with Ethnic Diversity in Malaysia and Singapore,” Helicobacter, Vol. 14, No. 4, 2009, pp. 256-263. doi:10.1111/j.1523-5378.2009.00684.x

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.