Polymorphism in the CagA EPIYA Motif Impacts Development of Gastric Cancer

ABSTRACT Helicobacter pylori causes diseases ranging from gastritis to peptic ulcer disease to gastric cancer. Geographically, areas with high incidences of H. pylori infection often overlap with areas with high incidences of gastric cancer, which remains one of the leading causes of cancer-related deaths worldwide. Strains of H. pylori that carry the virulence factor cytotoxin-associated gene A (cagA) are much more likely to be associated with the development of gastric cancer. Moreover, particular C-terminal polymorphisms in CagA vary by geography and have been suggested to influence disease development. We conducted a large-scale molecular epidemiologic analysis of South Korean strains and herein report a statistical link between the East Asian CagA EPIYA-ABD genotype and the development of gastric cancer. Characterization of a subset of the Korean isolates showed that all strains from cancer patients expressed and delivered phosphorylatable CagA to host cells, whereas the presence of the cagA gene did not strictly correlate to expression and delivery of CagA in all noncancer strains.

[1]  K. Yoo,et al.  Incidence estimation of stomach cancer among Koreans. , 1991, Journal of Korean medical science.

[2]  Nayoung Kim,et al.  Analysis of the 3′ Variable Region of the cagA Gene of Helicobacter pylori Isolated in Koreans , 2007, Digestive Diseases and Sciences.

[3]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[4]  F. Bäckhed,et al.  Helicobacter pylori Infection Induces Interleukin-8 Receptor Expression in the Human Gastric Epithelium , 2003, Infection and Immunity.

[5]  E. El-Omar,et al.  Differences in Helicobacter pylori CagA tyrosine phosphorylation motif patterns between western and East Asian strains, and influences on interleukin-8 secretion. , 2008, Journal of medical microbiology.

[6]  M. Kidd,et al.  Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. , 2004, Gastroenterology.

[7]  Wilson W. Wong,et al.  Materials and Methods , 1999 .

[8]  G. Stevenson,et al.  Infection with Helicobacter pylori. , 1996, AJR. American journal of roentgenology.

[9]  S. Falkow,et al.  Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells , 2002, Cellular microbiology.

[10]  Takeshi Azuma,et al.  SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein , 2001, Science.

[11]  D. Graham,et al.  Relationship between the cagA 3' repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. , 1999, Gastroenterology.

[12]  Reza Ghadimi,et al.  Are there any real Helicobacter pylori infection-negative gastric cancers in Asia? , 2007, Asian Pacific journal of cancer prevention : APJCP.

[13]  T. Azuma,et al.  Correlation between variation of the 3' region of the cagA gene in Helicobacter pylori and disease outcome in Japan. , 2002, The Journal of infectious diseases.

[14]  Megumi Higuchi,et al.  Attenuation of Helicobacter pylori CagA·SHP-2 Signaling by Interaction between CagA and C-terminal Src Kinase* , 2003, The Journal of Biological Chemistry.

[15]  B. Neel,et al.  The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. , 2003, Trends in biochemical sciences.

[16]  R. Rappuoli,et al.  c‐Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs , 2002, Molecular microbiology.

[17]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[18]  R. Warnke,et al.  Helicobacter pylori infection and gastric lymphoma. , 1994, The New England journal of medicine.

[19]  T. Azuma,et al.  Focal Adhesion Kinase Is a Substrate and Downstream Effector of SHP-2 Complexed with Helicobacter pylori CagA , 2006, Molecular and Cellular Biology.

[20]  S. Falkow,et al.  Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Blaser,et al.  Gastric adenocarcinoma and Helicobacter pylori infection. , 1991, Journal of the National Cancer Institute.

[22]  里見 聡子.  Relationship between the diversity of the cagA gene of Helicobacter pylori and gastric cancer in Okinawa, Japan , 2006 .

[23]  A. Zuckerman,et al.  IARC Monographs on the Evaluation of Carcinogenic Risks to Humans , 1995, IARC monographs on the evaluation of carcinogenic risks to humans.

[24]  B. Gold,et al.  The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer. , 2000, Annual review of microbiology.

[25]  M. Borodovsky,et al.  cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Coleman,et al.  Epidemiology of, and risk factors for, Helicobacter pylori infection among 3194 asymptomatic subjects in 17 populations. The EUROGAST Study Group. , 1993, Gut.

[27]  F. Mégraud,et al.  Epidemiology of Helicobacter pylori infection with special reference to professional risk. , 1997, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[28]  G. Friedman,et al.  Helicobacter pylori infection and the risk of gastric carcinoma. , 1991, The New England journal of medicine.

[29]  M. Blaser,et al.  Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. , 1995, Cancer research.

[30]  D. Roder,et al.  The epidemiology of gastric cancer , 2002, Gastric Cancer.

[31]  R. Rappuoli,et al.  Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. Bartsch,et al.  International Agency for Research on Cancer. , 1969, WHO chronicle.

[33]  T. McDaniel,et al.  Expanding the Helicobacter pylori Genetic Toolbox: Modification of an Endogenous Plasmid for Use as a Transcriptional Reporter and Complementation Vector , 2007, Applied and Environmental Microbiology.

[34]  Takeshi Azuma,et al.  Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Galle,et al.  Diversity of Helicobacter pylori vacA andcagA Genes and Relationship to VacA and CagA Protein Expression, Cytotoxin Production, and Associated Diseases , 1998, Journal of Clinical Microbiology.

[36]  K. Guillemin,et al.  The Helicobacter pylori cag Pathogenicity Island Protein CagN Is a Bacterial Membrane-Associated Protein That Is Processed at Its C Terminus , 2006, Infection and Immunity.

[37]  J. Atherton,et al.  Simple Method for Determination of the Number of Helicobacter pylori CagA Variable-Region EPIYA Tyrosine Phosphorylation Motifs by PCR , 2005, Journal of Clinical Microbiology.

[38]  S. Yamamoto.  Stomach cancer incidence in the world. , 2001, Japanese journal of clinical oncology.

[39]  Nizamettin Bayyurt,et al.  H pylori infection and other risk factors associated with peptic ulcers in Turkish patients: a retrospective study. , 2007, World journal of gastroenterology.

[40]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[41]  E. El-Omar,et al.  Toxigenic Helicobacter pylori Infection Precedes Gastric Hypochlorhydria in Cancer Relatives, and H. pylori Virulence Evolves in These Families , 2008, Clinical Cancer Research.

[42]  Takeshi Azuma,et al.  Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation* , 2004, Journal of Biological Chemistry.

[43]  A. Neugut,et al.  Epidemiology of gastric cancer. , 2006, World journal of gastroenterology.

[44]  H. Goto.  Helicobacter pylori and gastric diseases. , 2003, Nagoya journal of medical science.

[45]  T. Azuma,et al.  Association between diversity in the Src homology 2 domain--containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer. , 2004, The Journal of infectious diseases.

[46]  D. Kang,et al.  CagA-producing Helicobacter pylori and increased risk of gastric cancer: a nested case–control study in Korea , 2006, British Journal of Cancer.

[47]  S. Falkow,et al.  Disruption of the Epithelial Apical-Junctional Complex by Helicobacter pylori CagA , 2003, Science.

[48]  K. Murakami,et al.  Helicobacter pylori virulence and the diversity of gastric cancer in Asia. , 2008, Journal of medical microbiology.

[49]  L. Racioppi,et al.  Helicobacter pylori Induces Apoptosis of Human Monocytes but Not Monocyte-Derived Dendritic Cells: Role of the cag Pathogenicity Island , 2004, Infection and Immunity.

[50]  R. Assoian,et al.  Integrating the MAP kinase signal into the G1 phase cell cycle machinery. , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[51]  Jung Mogg Kim,et al.  Virulence factors of Helicobacter pylori in Korean isolates do not influence proinflammatory cytokine gene expression and apoptosis in human gastric epithelial cells, nor do these factors influence the clinical outcome , 2000, Journal of Gastroenterology.

[52]  T. Azuma,et al.  Relationship between the diversity of the cagA gene of Helicobacter pylori and gastric cancer in Okinawa, Japan , 2006, Journal of Gastroenterology.