H. pylori-induced inflammation and gastric cancer

Summary

Principal Investigator: Richard M Peek
Abstract: DESCRIPTION (provided by applicant): Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and Helicobacter pylori is the strongest identified risk factor for this malignancy, yet only a fraction of colonized persons ever develop neoplasia. One H. pylori determinant associated with gastric cancer is the cag pathogenicity island, and several cag genes encode components of a type IV secretion system which exports bacterial proteins such as CagA into host epithelial cells. Our group has now demonstrated that H. pylori cag+ strains selectively activate ?-catenin and the EGF receptor (EGFR), host effectors that influence carcinogenesis, in gastric epithelial cells. We have also demonstrated that an environmental factor associated with gastric cancer, salt, augments the ability of H. pylori cag+ strains to induce aberrant epithelial responses. Therefore, the overarching objective of this Application is delineation of the molecular signaling events initiated by H. pylori:epithelial cell contact that regulate phenotypes related to gastric carcinogenesis. This PPG will integrate studies of host-pathogen interactions initiated by biomedical researchers who have made a strong and clear commitment to research within the fields of gastroenterology, cancer biology, carcinogenesis, and microbiology, and will generate results that would not be attainable through independent investigation. The component Projects are driven by discrete hypotheses, yet are cohesive in that each focuses on H. pylori:epithelial interactions that induce cellular responses with carcinogenic potential. The individual projects include: Project 1. Mechanisms that regulate Helicobacter pylori-induced ?-catenin activation (PI-Richard Peek). Project 2. EGFR activation in H. pylori-induced gastric cancer (PI-Brent Polk). Project 3. Helicobacter pylori cag pathogenicity island and gastric carcinogenesis (PI-Timothy Cover). The efforts of each Project will be further unified by dynamic interactions with Specific Core facilities, which include the Gastric Histopathology Core (Core A), the Proteomics Core (Core B), and an Administrative Core (Core C). By maintaining a grounded focus on fundamental interactions that occur at the H. pylori:epithelial interface, results from this proposal will not only improve our understanding of gastric cancer, but will also facilitate identification of potential therapeutic targets for prevention and more effective treatment of this disease.
Funding Period: 2009-01-01 - 2013-12-31
more information: NIH RePORT

Top Publications

  1. pmc L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis
    Lori A Coburn
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 7:e33546. 2012
  2. pmc Structural analysis of the oligomeric states of Helicobacter pylori VacA toxin
    Melissa G Chambers
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    J Mol Biol 425:524-35. 2013
  3. pmc When guests simply will not leave
    Lydia E Wroblewski
    Department of Medicine, Vanderbilt University, Nashville, TN 37232 2279, USA
    Cell Host Microbe 12:733-4. 2012
  4. pmc Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans
    Jennifer M Noto
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Clin Invest 123:479-92. 2013
  5. pmc Helicobacter pylori promotes the expression of Krüppel-like factor 5, a mediator of carcinogenesis, in vitro and in vivo
    Jennifer M Noto
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 8:e54344. 2013
  6. pmc Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes
    Stacy S Duncan
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    PLoS ONE 8:e55120. 2013
  7. pmc Functional plasticity in the type IV secretion system of Helicobacter pylori
    Roberto M Barrozo
    Center for Comparative Medicine, University of California Davis, Davis, California, United States of America
    PLoS Pathog 9:e1003189. 2013
  8. pmc Gastric cancer prevention by demethylation
    Barbara G Schneider
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Cancer Prev Res (Phila) 6:253-6. 2013
  9. pmc Haem oxygenase-1 inhibits phosphorylation of the Helicobacter pylori oncoprotein CagA in gastric epithelial cells
    Alain P Gobert
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    Cell Microbiol 15:145-56. 2013
  10. pmc Genetic manipulation of a naturally competent bacterium, Helicobacter pylori
    Jennifer M Noto
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, MRB IV 1030C MRB IV, Nashville, TN, USA
    Methods Mol Biol 921:51-9. 2012

Detail Information

Publications87

  1. pmc L-arginine supplementation improves responses to injury and inflammation in dextran sulfate sodium colitis
    Lori A Coburn
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 7:e33546. 2012
    ..These preclinical studies indicate that L-Arg supplementation could be a potential therapy for IBD, and that one mechanism of action may be functional enhancement of iNOS activity...
  2. pmc Structural analysis of the oligomeric states of Helicobacter pylori VacA toxin
    Melissa G Chambers
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    J Mol Biol 425:524-35. 2013
    ..By providing the most detailed view of the VacA structure to date, these data offer new insights into the toxin's channel-forming component and the intermolecular interactions that underlie oligomeric assembly...
  3. pmc When guests simply will not leave
    Lydia E Wroblewski
    Department of Medicine, Vanderbilt University, Nashville, TN 37232 2279, USA
    Cell Host Microbe 12:733-4. 2012
    ..Tsugawa et al. (2012) now report a mechanism of checks and balances used by Helicobacter pylori that is undermined by gastric stem cells, which may lower the threshold for gastric cancer...
  4. pmc Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans
    Jennifer M Noto
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Clin Invest 123:479-92. 2013
    ..These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer...
  5. pmc Helicobacter pylori promotes the expression of Krüppel-like factor 5, a mediator of carcinogenesis, in vitro and in vivo
    Jennifer M Noto
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 8:e54344. 2013
    ..These results indicate that H. pylori induces expression of KLF5 in gastric epithelial cells in vitro and in vivo, and that the degree of KLF5 expression parallels the severity of premalignant lesions in human gastric carcinogenesis...
  6. pmc Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes
    Stacy S Duncan
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    PLoS ONE 8:e55120. 2013
    ..pylori strains. Moreover, these divergent genes represent robust biomarkers that can be used to differentiate East Asian and non-Asian H. pylori strains...
  7. pmc Functional plasticity in the type IV secretion system of Helicobacter pylori
    Roberto M Barrozo
    Center for Comparative Medicine, University of California Davis, Davis, California, United States of America
    PLoS Pathog 9:e1003189. 2013
    ..pylori T4SS. We propose that CagY functions as a sort of molecular switch or perhaps a rheostat that alters the function of the T4SS and "tunes" the host inflammatory response so as to maximize persistent infection...
  8. pmc Gastric cancer prevention by demethylation
    Barbara G Schneider
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Cancer Prev Res (Phila) 6:253-6. 2013
    ..The findings also raise the exciting possibility of cancer prevention by altering DNA methylation events early during tumorigenesis...
  9. pmc Haem oxygenase-1 inhibits phosphorylation of the Helicobacter pylori oncoprotein CagA in gastric epithelial cells
    Alain P Gobert
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    Cell Microbiol 15:145-56. 2013
    ..These data highlight a mechanism by which the innate immune response of the host can restrict the pathogenicity of H. pylori by attenuating CagA phosphorylation in gastric epithelial cells...
  10. pmc Genetic manipulation of a naturally competent bacterium, Helicobacter pylori
    Jennifer M Noto
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, MRB IV 1030C MRB IV, Nashville, TN, USA
    Methods Mol Biol 921:51-9. 2012
    ..pylori genes. This chapter discusses the methods involved in H. pylori chromosomal DNA isolation, mutagenesis of individual genes, and natural transformation...
  11. pmc Spermine oxidase, a polyamine catabolic enzyme that links Helicobacter pylori CagA and gastric cancer risk
    Rupesh Chaturvedi
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center Nashville, TN, USA
    Gut Microbes 3:48-56. 2012
    ..Inhibition of polyamine synthesis or SMO could abrogate the development of this cell population that may represent precursors for neoplastic transformation...
  12. pmc Analysis of Helicobacter pylori cagA promoter elements required for salt-induced upregulation of CagA expression
    John T Loh
    Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 80:3094-106. 2012
    ..In summary, there is considerable heterogeneity among H. pylori strains in salt-regulated CagA expression, and these differences are attributable to variation in a specific DNA motif upstream of the cagA transcriptional start site...
  13. pmc Alterations in Helicobacter pylori triggered by contact with gastric epithelial cells
    Elizabeth M Johnson
    Department of Medicine, Vanderbilt University School of Medicine Nashville, TN, USA
    Front Cell Infect Microbiol 2:17. 2012
    ..pylori, and upon entry into this niche, the bacteria alter their behavior in a manner that optimizes bacterial proliferation and persistent colonization of the host...
  14. pmc An RGD helper sequence in CagL of Helicobacter pylori assists in interactions with integrins and injection of CagA
    Jens Conradi
    Department of Chemistry, Bielefeld University Bielefeld, Germany
    Front Cell Infect Microbiol 2:70. 2012
    ..pylori pathogenesis...
  15. pmc Polymorphisms of the acid sensing histidine kinase gene arsS in Helicobacter pylori populations from anatomically distinct gastric sites
    Daniel R Hallinger
    Department of Biology, The College of William and Mary, Integrated Science Center 3051, Williamsburg, VA 23185, USA
    Microb Pathog 53:227-33. 2012
    ..These findings suggest that four C-terminal variations of ArsS adds to the complexity of the ArsRS acid adaptation mechanism as a whole and may influence the ability of H. pylori to persist in the gastric niche for decades...
  16. pmc Perspectives on methodology for in vitro culture of Helicobacter pylori
    Timothy L Cover
    Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
    Methods Mol Biol 921:11-5. 2012
    ..Analysis of H. pylori growth in chemically defined media has provided insight into the nutritional requirements, physiology, and metabolic capacities of this organism...
  17. pmc The Helicobacter pylori cag Pathogenicity Island
    Jennifer M Noto
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, MRB IV 1030C MRB IV, Nashville, TN, USA
    Methods Mol Biol 921:41-50. 2012
    ..The following chapters will explore the manipulation of bacterial factors in order to understand their role in gastric mucosal disease...
  18. pmc High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis
    Jennifer A Gaddy
    Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 81:2258-67. 2013
    ..Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA(+) H. pylori strains...
  19. pmc Flagellar localization of a Helicobacter pylori autotransporter protein
    Jana N Radin
    Department of Medicine, Vanderbilt University, School of Medicine, Nashville, Tennessee, USA
    MBio 4:e00613-12. 2013
    ..The flagellar localization of FaaA differs markedly from the localization of other known autotransporters, and the current results reveal an important role of FaaA in flagellar localization and motility...
  20. pmc Phylogeographic origin of Helicobacter pylori determines host-adaptive responses upon coculture with gastric epithelial cells
    Alexander Sheh
    Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
    Infect Immun 81:2468-77. 2013
    ..These findings support the hypothesis that bacterial factors determined by the phylogeographic origin of H. pylori strains may promote increased gastric disease...
  21. pmc Role of connexin 43 in Helicobacter pylori VacA-induced cell death
    Jana N Radin
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Infect Immun 82:423-32. 2014
    ....
  22. pmc Activation of the epidermal growth factor receptor in macrophages regulates cytokine production and experimental colitis
    Ning Lu
    Department of Breast Cancer Medical Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, P R China
    J Immunol 192:1013-23. 2014
    ..These results reveal an integrated response of macrophages regulated by EGFR in intestinal inflammatory disorders. ..
  23. pmc Gastrointestinal malignancy and the microbiome
    Maria T Abreu
    Division of Gastroenterology, Departments of Medicine and Microbiology and Immunology, University of Miami, Miami, Florida
    Gastroenterology 146:1534-1546.e3. 2014
    ..Strategies to manipulate the microbiome, or the immune response to such bacteria, could be developed to prevent or treat certain gastrointestinal cancers...
  24. pmc Helicobacter pylori: expect the unexpected
    Giovanni Suarez
    Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA
    Mol Microbiol 91:858-61. 2014
    ..The versatility of the newly discovered enzyme LpxJ may allow H. pylori to quickly adapt to dynamic and hostile conditions present within its cognate gastric niche...
  25. pmc Human and Helicobacter pylori coevolution shapes the risk of gastric disease
    Nuri Kodaman
    Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Divisions of Gastroenterology and Infectious Diseases, Department of Medicine, and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
    Proc Natl Acad Sci U S A 111:1455-60. 2014
    ..Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population. ..
  26. pmc Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage
    Rupesh Chaturvedi
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
    Gastroenterology 146:1739-51.e14. 2014
    ..A subpopulation of SMOX(high) cells are resistant to apoptosis, despite their high levels of DNA damage. Because epidermal growth factor receptor (EGFR) activation can regulate apoptosis, we determined its role in SMOX-mediated effects...
  27. pmc Diet, Helicobacter pylori strain-specific infection, and gastric cancer risk among Chinese men
    Meira Epplein
    a Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Nutr Cancer 66:550-7. 2014
    ..01, respectively). In this population with over 90% prevalence of CagA-positive H. pylori infection, categorizing individuals using H. pylori multiplex serology may identify individuals for whom a diet intervention may be effective. ..
  28. pmc Analysis of surface-exposed outer membrane proteins in Helicobacter pylori
    Bradley J Voss
    Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    J Bacteriol 196:2455-71. 2014
    ..Collectively, these results provide new insights into the repertoire of surface-exposed H. pylori proteins that may mediate bacterium-host interactions, as well as the cell surface topology of these proteins. ..
  29. pmc Strain-specific suppression of microRNA-320 by carcinogenic Helicobacter pylori promotes expression of the antiapoptotic protein Mcl-1
    Jennifer M Noto
    Jr, 2215 Garland Ave, Medical Research Bldg IV 1030C, Nashville, TN 37232
    Am J Physiol Gastrointest Liver Physiol 305:G786-96. 2013
    ..Collectively, these results indicate that H. pylori suppresses miR-320, upregulates Mcl-1, and decreases apoptosis in a cagA-dependent manner, which likely confers an increased risk for gastric carcinogenesis...
  30. pmc Virulence of infecting Helicobacter pylori strains and intensity of mononuclear cell infiltration are associated with levels of DNA hypermethylation in gastric mucosae
    Barbara G Schneider
    Division of Gastroenterology Department of Medicine Vanderbilt University Medical Center Nashville, TN USA
    Epigenetics 8:1153-61. 2013
    ..pylori virulence, geographic region and measures of chronic inflammation. These genes seem predisposed to sustain significant quantitative changes in DNA methylation at early stages of the gastric precancerous process. ..
  31. pmc Control of gene expression in Helicobacter pylori using the Tet repressor
    Mark S McClain
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA Electronic address
    J Microbiol Methods 95:336-41. 2013
    ..These studies demonstrate the effectiveness of the tetR-tetO system to control gene expression in H. pylori and provide an improved system for studying H. pylori physiology and pathogenesis. ..
  32. pmc Helicobacter pylori in gastric carcinogenesis: mechanisms
    Lydia E Wroblewski
    Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    Gastroenterol Clin North Am 42:285-98. 2013
    ..This review focuses on the specific mechanisms used by H pylori to drive gastric carcinogenesis...
  33. pmc Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells
    Johanna C Sierra
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    Am J Physiol Gastrointest Liver Physiol 305:G196-203. 2013
    ..Collectively, these findings indicate that aberrant activation of the EGFR-COX-2 axis may lower the threshold for carcinogenesis associated with chronic H. pylori infection...
  34. pmc Deletion of cationic amino acid transporter 2 exacerbates dextran sulfate sodium colitis and leads to an IL-17-predominant T cell response
    Kshipra Singh
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    Am J Physiol Gastrointest Liver Physiol 305:G225-40. 2013
    ..Thus CAT2 plays an important role in controlling inflammation and IL-17 activation in an injury model of colitis, and impaired L-Arg availability may contribute to UC pathogenesis...
  35. pmc Spermine oxidase is a regulator of macrophage host response to Helicobacter pylori: enhancement of antimicrobial nitric oxide generation by depletion of spermine
    Rupesh Chaturvedi
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, 1030C MRBIV, 2215 Garland Avenue, Nashville, TN, 37232, USA
    Amino Acids 46:531-42. 2014
    ..pylori stimulation. By depleting spermine, SMO can abrogate the inhibitory effect of polyamines on innate immune responses to H. pylori by enhancing antimicrobial NO production...
  36. pmc Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis
    Caitlyn W Barrett
    Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
    PLoS ONE 8:e67845. 2013
    ..Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis. ..
  37. pmc Use of the noninvasive entero-test in the detection of Helicobacter pylori in children in an endemic area in Colombia
    Richard N Arboleda
    Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    J Pediatr Gastroenterol Nutr 57:192-6. 2013
    ..We aimed to validate the use of the Entero-test to culture and genotype H pylori strains from asymptomatic Colombian children...
  38. pmc Helicobacter pylori protein-specific antibodies and risk of colorectal cancer
    Meira Epplein
    Authors Affiliations Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt Ingram Cancer Center, and Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee International Epidemiology Institute, Rockville, Maryland and Division of Genome Modifications and Carcinogenesis, Infection and Cancer Program, German Cancer Research Center DFKZ, Heidelberg, Germany
    Cancer Epidemiol Biomarkers Prev 22:1964-74. 2013
    ..We assessed the association of H. pylori protein-specific infection and colorectal cancer risk in the prospective cohort, the Southern Community Cohort Study...
  39. pmc Circulating cytokines and gastric cancer risk
    Meira Epplein
    Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 6th Floor, Nashville, TN, 37203 1738, USA
    Cancer Causes Control 24:2245-50. 2013
    ....
  40. pmc Helicobacter pylori genotyping and sequencing using paraffin-embedded biopsies from residents of colombian areas with contrasting gastric cancer risks
    Liviu A Sicinschi
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Helicobacter 13:135-45. 2008
    ....
  41. pmc Helicobacter pylori: gastric cancer and beyond
    D Brent Polk
    Department of Pediatrics, University of Southern California, Los Angeles, CA 10027, USA
    Nat Rev Cancer 10:403-14. 2010
    ..pylori-infected human populations at increased risk for stomach cancer but will also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche...
  42. pmc Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa
    Arindam Saha
    Medical University of South Carolina, 96 Jonathan Lucas St, Charleston, SC 29425, USA
    Gut 59:874-81. 2010
    ..This study sought to identify bacterial genes involved in HKalpha repression and to assess their impact on acid secretion...
  43. pmc Polyamines Impair Immunity to Helicobacter pylori by Inhibiting L-Arginine Uptake Required for Nitric Oxide Production
    Rupesh Chaturvedi
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    Gastroenterology 139:1686-98, 1698.e1-6. 2010
    ..We determined if spermine inhibits iNOS-mediated immunity by reducing L-Arg uptake into macrophages...
  44. pmc Role of innate immunity in Helicobacter pylori-induced gastric malignancy
    Richard M Peek
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37232 2279, USA
    Physiol Rev 90:831-58. 2010
    ..pylori-infected individuals who can then be targeted for therapeutic intervention...
  45. pmc Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation
    Y H Tsang
    Department of Biochemistry, College of Medicine, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA
    Oncogene 29:5643-50. 2010
    ..Our studies identify RUNX3 as a novel cellular target of H. pylori CagA and also reveal a mechanism by which CagA functions as an oncoprotein by blocking the activity of gastric tumor suppressor RUNX3...
  46. pmc Mature chief cells are cryptic progenitors for metaplasia in the stomach
    Ki Taek Nam
    Nashville VA Medical Center and the Department of Surgery, Epithelial Biology Center, Nashville, Tennessee, USA
    Gastroenterology 139:2028-2037.e9. 2010
    ..We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells...
  47. pmc Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA
    Kelly A Gangwer
    Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    J Bacteriol 192:6126-35. 2010
    ..Taken together, these results indicate that positive selection has shaped the phylogenetic structure of VacA and CagA, and each of these virulence determinants has evolved separately from the core genome...
  48. pmc Helicobacter pylori and gastric cancer: factors that modulate disease risk
    Lydia E Wroblewski
    Division of Gastroenterology, Vanderbilt University School of Medicine, 2215 Garland Ave, 1030C MRB IV, Nashville, TN 37232 2279, USA
    Clin Microbiol Rev 23:713-39. 2010
    ..Since H. pylori inhibits the gastric epithelium of half of the world, it is crucial that we continue to gain understanding of host and microbial factors that increase the risk of developing more severe clinical outcomes...
  49. pmc Detailed in vivo analysis of the role of Helicobacter pylori Fur in colonization and disease
    Shana Miles
    Department of Microbiology and Immunology, Uniformed Services University of the Heath Sciences, Bethesda, Maryland 20814, USA
    Infect Immun 78:3073-82. 2010
    ..pylori Fur is most important at early stages of infection and illustrate the importance of the ability of H. pylori to adapt to its constantly fluctuating environment when it is establishing infection, inflammation, and disease...
  50. pmc Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages
    Mohammad Asim
    Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    J Biol Chem 285:20343-57. 2010
    ..A unique AP-1 complex in gastric macrophages contributes to the immune escape of H. pylori...
  51. pmc Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer
    Barbara G Schneider
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 0252, USA
    Int J Cancer 127:2588-97. 2010
    ....
  52. pmc Helicobacter pylori infection upregulates interleukin-18 production from gastric epithelial cells
    Masaaki Shimada
    Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya Memorial Hospital, Showa Ku, Nagoya, Japan
    Eur J Gastroenterol Hepatol 20:1144-50. 2008
    ..Helicobacter pylori infection induces a biased T helper type 1 (Th1) response that produces IFN-gamma and Fas ligand (FasL). Th1 cytokines are associated with apoptosis in the gastric epithelial cells...
  53. pmc Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation
    Lydia E Wroblewski
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 2279, USA
    Gastroenterology 136:236-46. 2009
    ..We determined whether MLCK was activated by H pylori and defined the mechanisms through which such activation dysregulates gastric epithelial barrier function...
  54. pmc Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis
    Fang Yan
    Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0696, USA
    Gastroenterology 136:1297-1307, e1-3. 2009
    ..Because EGFR signaling regulates cell survival, we investigated whether activation of EGFR following H pylori infection promotes gastric epithelial survival...
  55. pmc Delineation of a carcinogenic Helicobacter pylori proteome
    Aime T Franco
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 2279, USA
    Mol Cell Proteomics 8:1947-58. 2009
    ..pylori proteins to use in vaccine development and for screening persons infected with strains most likely to induce severe disease...
  56. pmc Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination
    Acacia Lamb
    Department of Biochemistry, College of Medicine, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    EMBO Rep 10:1242-9. 2009
    ..These findings show that polyubiquitination of TAK1 regulates the activation of NF-kappaB, which in turn is used by H. pylori CagA for the H. pylori-induced inflammatory response...
  57. pmc Matrix metalloproteinase-7 and premalignant host responses in Helicobacter pylori-infected mice
    Seth R Ogden
    Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232 2279, USA
    Cancer Res 70:30-5. 2010
    ..Collectively, these studies indicate that H. pylori-mediated induction of MMP-7 may serve to protect the gastric mucosa from pathophysiologic processes that promote carcinogenesis...
  58. pmc Expression of the BabA adhesin during experimental infection with Helicobacter pylori
    Cathy M Styer
    Department of Medicine and Microbiology, Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California 95616, USA
    Infect Immun 78:1593-600. 2010
    ..We hypothesize that modification of BabA expression during H. pylori infection is a mechanism to adapt to changing conditions of inflammation and glycan expression at the epithelial surface...
  59. pmc Analysis of protein expression regulated by the Helicobacter pylori ArsRS two-component signal transduction system
    John T Loh
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    J Bacteriol 192:2034-43. 2010
    ..These results provide further definition of the ArsRS regulon and underscore the importance of the ArsRS system in regulating expression of H. pylori proteins during bacterial growth at both neutral pH and acidic pH...
  60. pmc Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II
    Nuruddeen D Lewis
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    J Immunol 186:3632-41. 2011
    ..These studies demonstrate that Arg2 contributes to the immune evasion of H. pylori by limiting macrophage iNOS protein expression and NO production, mediating macrophage apoptosis, and restraining proinflammatory cytokine responses...
  61. pmc Methods to evaluate alterations in polyamine metabolism caused by Helicobacter pylori infection
    Alain P Gobert
    UR454 Unite de Microbiologie, INRA, Saint Genes Champanelle, France
    Methods Mol Biol 720:409-25. 2011
    ..In this chapter, we present a survey of the methods used to analyze the induction and the role of the enzymes related to polyamine metabolism, i.e., arginase, ODC, and SMO in H. pylori-infected macrophages...
  62. pmc Disruption of nitric oxide signaling by Helicobacter pylori results in enhanced inflammation by inhibition of heme oxygenase-1
    Alain P Gobert
    Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA
    J Immunol 187:5370-9. 2011
    ..pylori-infected mice inhibits chemokine generation and reduces inflammation. These data define a mechanism by which H. pylori favors its own pathogenesis by inhibiting HO-1 induction through the action of CagA...
  63. pmc Cationic amino acid transporter 2 enhances innate immunity during Helicobacter pylori infection
    Daniel P Barry
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 6:e29046. 2011
    ..These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection...
  64. pmc Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa
    M Dinis-Ribeiro
    Department of Gastroenterology, Portuguese Oncology Institute of Coimbra, Portugal
    Endoscopy 44:74-94. 2012
    ....
  65. pmc Cell-associated hemolysis induced by Helicobacter pylori is mediated by phospholipases with mitogen-activated protein kinase-activating properties
    Ramakrishnan Sitaraman
    Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Clin Microbiol 50:1014-8. 2012
    ..Inactivation of PldD inhibited activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), indicating that H. pylori hemolytic phospholipases also harbor MAPK-activating properties...
  66. pmc J-Western forms of Helicobacter pylori cagA constitute a distinct phylogenetic group with a widespread geographic distribution
    Stacy S Duncan
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    J Bacteriol 194:1593-604. 2012
    ..pylori...
  67. pmc Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans
    Deepa Raju
    Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
    Gastroenterology 142:1160-71. 2012
    ..We previously found that limited exposure to VacA induces autophagy of gastric cells, which eliminates the toxin; we investigated whether autophagy serves as a defense mechanism against H pylori infection...
  68. pmc L-arginine uptake by cationic amino acid transporter 2 is essential for colonic epithelial cell restitution
    Kshipra Singh
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Am J Physiol Gastrointest Liver Physiol 302:G1061-73. 2012
    ..Uptake of L-Arg, and its metabolism by Arg1 to L-Orn and conversion to L-Pro by OAT is essential for colonic epithelial wound repair...
  69. pmc Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface
    Carrie L Shaffer
    Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
    PLoS Pathog 7:e1002237. 2011
    ..In summary, these results indicate that CagH, CagI, and CagL are components of a T4SS subassembly involved in pilus biogenesis, and highlight the important role played by unique constituents of the H. pylori cag T4SS...
  70. pmc Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis
    Rupesh Chaturvedi
    Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, 1030C MRBIV, 2215 Garland Avenue, Nashville, TN 37232, USA
    Amino Acids 42:627-40. 2012
    ..Our studies indicate novel targets for therapeutic intervention in H. pylori-associated diseases, including gastritis, ulcer disease, and gastric cancer...
  71. pmc Analysis of cagA in Helicobacter pylori strains from Colombian populations with contrasting gastric cancer risk reveals a biomarker for disease severity
    John T Loh
    Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    Cancer Epidemiol Biomarkers Prev 20:2237-49. 2011
    ..Helicobacter pylori infection is a risk factor for the development of gastric cancer, and the bacterial oncoprotein CagA contributes to gastric carcinogenesis...
  72. pmc Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk
    Thibaut de Sablet
    Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, MRBIV, Room 1030C, 2215 Garland Avenue, Nashville, TN 37232, USA
    Gut 60:1189-95. 2011
    ..Our aim was to investigate the ancestral origin of H pylori strains isolated from subjects in these high- and low-risk regions and to determine whether this is a predictive determinant of precancerous lesions...
  73. pmc Difluoromethylornithine is a novel inhibitor of Helicobacter pylori growth, CagA translocation, and interleukin-8 induction
    Daniel P Barry
    Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 6:e17510. 2011
    ..These findings suggest that DFMO has effects on H. pylori that may contribute to its effectiveness in reducing gastritis and colonization and may be a useful addition to anti-H. pylori therapies...
  74. pmc Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells
    Jana N Radin
    Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 2605, USA
    Infect Immun 79:2535-43. 2011
    ....
  75. pmc Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans
    Mohammed Soutto
    Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Clin Invest 121:1753-67. 2011
    ....
  76. pmc TNF-α converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival
    Valda C Hilliard
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Am J Physiol Gastrointest Liver Physiol 301:G338-46. 2011
    ..These findings have important implications for understanding how ErbB4 protects the colon from apoptosis-induced tissue injury in inflammatory conditions such as IBD...
  77. pmc Biomarkers in exploring the frontiers of diagnosis, prognosis, and therapy of Barrett's esophagus
    Patrick Yachimski
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    Cancer Prev Res (Phila) 4:783-6. 2011
    ..Identification of novel tissue biomarkers within BE may allow for more accurate endoscopic risk stratification and provide potential targets for chemoprevention...
  78. pmc β-Catenin and p120 mediate PPARδ-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia
    Toni A Nagy
    Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
    Gastroenterology 141:553-64. 2011
    ..We used a carcinogenic H pylori strain to define the role of microbial virulence constituents and PPARδ in regulating epithelial responses that mediate development of adenocarcinoma...
  79. pmc Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA
    Rupesh Chaturvedi
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232 0252, USA
    Gastroenterology 141:1696-708.e1-2. 2011
    ..Spermine oxidase (SMO) metabolizes the polyamine spermine into spermidine and generates H(2)O(2), which causes apoptosis and DNA damage. We determined if pathogenic effects of CagA are attributable to SMO...
  80. pmc Non-invasive genotyping of Helicobacter pylori cagA, vacA, and hopQ from asymptomatic children
    Liviu A Sicinschi
    Division of Gastroenterology, Dept of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    Helicobacter 17:96-106. 2012
    ..Our aim is to genotype cagA, hopQ, and vacA alleles in stool DNA samples of healthy Colombian children residing in an area with high incidence of gastric cancer, to avoid selection bias resulting from endoscopy...