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Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA.
Chaturvedi R, Asim M, Romero-Gallo J, Barry DP, Hoge S, de Sablet T, Delgado AG, Wroblewski LE, Piazuelo MB, Yan F, Israel DA, Casero RA, Correa P, Gobert AP, Polk DB, Peek RM, Wilson KT
(2011) Gastroenterology 141: 1696-708.e1-2
MeSH Terms: Animals, Antigens, Bacterial, Apoptosis, Bacterial Proteins, Cell Line, Cell Transformation, Neoplastic, Cells, Cultured, DNA Damage, Disease Models, Animal, Epithelial Cells, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Mice, Mice, Inbred C57BL, Oxidative Stress, Oxidoreductases Acting on CH-NH Group Donors, Risk Factors, Stomach, Stomach Neoplasms
Show Abstract · Added March 5, 2014
BACKGROUND & AIMS - Helicobacter pylori-induced gastric carcinogenesis has been linked to the microbial oncoprotein cytotoxin-associated gene A (CagA). 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.
METHODS - Levels of SMO, apoptosis, and DNA damage (8-oxoguanosine) were measured in gastric epithelial cell lines infected with cagA(+) or cagA(-)H pylori strains, or transfected with a CagA expression plasmid, in the absence or presence of SMO small interfering RNA, or an SMO inhibitor. The role of CagA in induction of SMO and DNA damage was assessed in H pylori-infected gastritis tissues from humans, gerbils, and both wild-type and hypergastrinemic insulin-gastrin mice, using immunohistochemistry and flow cytometry.
RESULTS - cagA(+) strains or ectopic expression of CagA, but not cagA(-) strains, led to increased levels of SMO, apoptosis, and DNA damage in gastric epithelial cells, and knockdown or inhibition of SMO blocked apoptosis and DNA damage. There was increased SMO expression, apoptosis, and DNA damage in gastric tissues from humans infected with cagA(+), but not cagA(-) strains. In gerbils and mice, DNA damage was CagA-dependent and present in cells that expressed SMO. Gastric epithelial cells with DNA damage that were negative for markers of apoptosis accounted for 42%-69% of cells in gerbils and insulin-gastrin mice with dysplasia and carcinoma.
CONCLUSIONS - By inducing SMO, H pylori CagA generates cells with oxidative DNA damage, and a subpopulation of these cells are resistant to apoptosis and thus at high risk for malignant transformation.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
0 Communities
7 Members
0 Resources
22 MeSH Terms
β-Catenin and p120 mediate PPARδ-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia.
Nagy TA, Wroblewski LE, Wang D, Piazuelo MB, Delgado A, Romero-Gallo J, Noto J, Israel DA, Ogden SR, Correa P, Cover TL, Peek RM
(2011) Gastroenterology 141: 553-64
MeSH Terms: Adenocarcinoma, Animals, Antigens, Bacterial, Bacterial Proteins, Catenins, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Cyclin E, Epithelial Cells, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Ki-67 Antigen, Oncogene Proteins, PPAR delta, Signal Transduction, Stomach Neoplasms, beta Catenin
Show Abstract · Added July 26, 2012
BACKGROUND & AIMS - Colonization of gastric mucosa by Helicobacter pylori leads to epithelial hyperproliferation, which increases the risk for gastric adenocarcinoma. One H pylori virulence locus associated with cancer risk, cag, encodes a secretion system that transports effectors into host cells and leads to aberrant activation of β-catenin and p120-catenin (p120). Peroxisome proliferator-activated receptor (PPAR)δ is a ligand-activated transcription factor that affects oncogenesis in conjunction with β-catenin. 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.
METHODS - Gastric epithelial cells or colonies were co-cultured with the H pylori cag(+) strain 7.13 or cagE(-), cagA(-), soluble lytic transglycosylase(-), or cagA(-)/soluble lytic transglycosylase(-) mutants. Levels of PPARδ and cyclin E1 were determined by real-time, reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy; proliferation was measured in 3-dimensional culture. PPARδ and Ki67 expression were determined by immunohistochemical analysis of human biopsies and rodent gastric mucosa.
RESULTS - H pylori induced β-catenin- and p120-dependent expression and activation of PPARδ in gastric epithelial cells, which were mediated by the cag secretion system substrates CagA and peptidoglycan. H pylori stimulated proliferation in vitro, which required PPARδ-mediated activation of cyclin E1; H pylori did not induce expression of cyclin E1 in a genetic model of PPARδ deficiency. PPARδ expression and proliferation in rodent and human gastric tissue was selectively induced by cag(+) strains and PPARδ levels normalized after eradication of H pylori.
CONCLUSIONS - The H pylori cag secretion system activates β-catenin, p120, and PPARδ, which promote gastric epithelial cell proliferation via activation of cyclin E1. PPARδ might contribute to gastric adenocarcinoma development in humans.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
1 Communities
5 Members
0 Resources
21 MeSH Terms
Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface.
Tan S, Noto JM, Romero-Gallo J, Peek RM, Amieva MR
(2011) PLoS Pathog 7: e1002050
MeSH Terms: Adaptation, Physiological, Animals, Antigens, Bacterial, Bacterial Adhesion, Bacterial Proteins, Caco-2 Cells, Cell Line, Cell Membrane, Cell Polarity, Dogs, Down-Regulation, Epithelium, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Intercellular Junctions, Iron, Receptors, Transferrin, Sequence Deletion, Signal Transduction, Transcytosis, Transferrin
Show Abstract · Added March 5, 2014
Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche.
0 Communities
2 Members
0 Resources
24 MeSH Terms
Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells.
Wei J, Nagy TA, Vilgelm A, Zaika E, Ogden SR, Romero-Gallo J, Piazuelo MB, Correa P, Washington MK, El-Rifai W, Peek RM, Zaika A
(2010) Gastroenterology 139: 1333-43
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Cell Line, Tumor, Gastric Mucosa, Gerbillinae, Helicobacter pylori, Humans, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-mdm2, Stomach Neoplasms, Tumor Suppressor Protein p53, Virulence
Show Abstract · Added June 14, 2013
BACKGROUND & AIMS - Infection with the gastric mucosal pathogen Helicobacter pylori is the strongest identified risk factor for distal gastric cancer. These bacteria colonize a significant part of the world's population. We investigated the molecular mechanisms of p53 regulation in H pylori-infected cells.
METHODS - Mongolian gerbils were challenged with H pylori and their gastric tissues were analyzed by immunohistochemistry and immunoblotting with p53 antibodies. Gastric epithelial cells were co-cultured with H pylori and the regulation of p53 was assessed by real-time polymerase chain reaction, immunoblotting, immunofluorescence, and cell survival assays. Short hairpin RNA and dominant-negative mutants were used to inhibit activities of Human Double Minute 2 (HDM2) and AKT1 proteins.
RESULTS - We found that in addition to previously reported up-regulation of p53, H pylori can also negatively regulate p53 by increasing ubiquitination and proteasomal degradation via activation of the serine/threonine kinase AKT1, which phosphorylates and activates the ubiquitin ligase HDM2. These effects were mediated by the bacterial virulence factor CagA; ectopic expression of CagA in gastric epithelial cells increased phosphorylation of HDM2 along with the ubiquitination and proteasomal degradation of p53. The decrease in p53 levels increased survival of gastric epithelial cells that had sustained DNA damage.
CONCLUSIONS - H pylori is able to inhibit the tumor suppressor p53. H pylori activates AKT1, resulting in phosphorylation and activation of HDM2 and subsequent degradation of p53 in gastric epithelial cells. H pylori-induced dysregulation of p53 is a potential mechanism by which the microorganism increases the risk of gastric cancer in infected individuals.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
0 Communities
5 Members
0 Resources
13 MeSH Terms
Detailed in vivo analysis of the role of Helicobacter pylori Fur in colonization and disease.
Miles S, Piazuelo MB, Semino-Mora C, Washington MK, Dubois A, Peek RM, Correa P, Merrell DS
(2010) Infect Immun 78: 3073-82
MeSH Terms: Animals, Bacterial Proteins, Disease Progression, Gastric Mucosa, Gastritis, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Male, Pyloric Antrum, Stomach
Show Abstract · Added March 5, 2014
Helicobacter pylori persistently colonizes the harsh and dynamic environment of the stomach in over one-half of the world's population and has been identified as a causal agent in a spectrum of pathologies that range from gastritis to invasive adenocarcinoma. The ferric uptake regulator (Fur) is one of the few regulatory proteins that has been identified in H. pylori. Fur regulates genes important for acid acclimation and oxidative stress and has been shown to be important for colonization of H. pylori in both murine and Mongolian gerbil models of infection. To more thoroughly define the role of Fur in vivo, we conducted an extensive temporal analysis of the location of, competitive ability of, and resultant pathology induced by a Deltafur strain in the Mongolian gerbil model of infection and compared the results to results for its wild-type parent. We found that at the earliest time points postinfection, significantly more Deltafur bacteria than wild-type bacteria were recovered. However, this trend was reversed by day 3, when there was significantly increased recovery of the wild-type strain. The increased recovery of the Deltafur strain at 1 day postinfection reflected increased recovery from both the corpus and the antrum of the stomach. When the wild-type strain was allowed to colonize first, the Deltafur strain was unable to compete for colonization at any time postinfection. However, when the Deltafur strain was allowed to colonize first, the wild type efficiently outcompeted the Deltafur strain only at early times postinfection. Finally, we demonstrated that there was a delay in the development and severity of inflammation and pathology of the Deltafur strain in the gastric mucosa even after comparable levels of colonization occurred. Together, these data indicate that H. 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.
0 Communities
2 Members
0 Resources
11 MeSH Terms
Expression of the BabA adhesin during experimental infection with Helicobacter pylori.
Styer CM, Hansen LM, Cooke CL, Gundersen AM, Choi SS, Berg DE, Benghezal M, Marshall BJ, Peek RM, Borén T, Solnick JV
(2010) Infect Immun 78: 1593-600
MeSH Terms: Adaptation, Biological, Adhesins, Bacterial, Animals, Bacterial Adhesion, DNA, Bacterial, Female, Gastric Mucosa, Gene Knockout Techniques, Genetic Complementation Test, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Macaca mulatta, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Sequence Analysis, DNA
Show Abstract · Added March 5, 2014
The Helicobacter pylori babA gene encodes an outer membrane protein that mediates binding to fucosylated ABH antigens of the ABO blood group. We recently demonstrated that BabA expression is lost during experimental infection of rhesus macaques with H. pylori J166. We sought to test the generality of this observation by comparison of different H. pylori strains and different animal hosts. Challenge of macaques with H. pylori J99 yielded output strains that lost BabA expression, either by selection and then expansion of a subpopulation of J99 that had a single-base-pair mutation that encoded a stop codon or by gene conversion of babA with a duplicate copy of babB, a paralog of unknown function. Challenge of mice with H. pylori J166, which unlike J99, has 5' CT repeats in babA, resulted in loss of BabA expression due to phase variation. In the gerbil, Leb binding was lost by replacement of the babA gene that encoded Leb binding with a nonbinding allele that differed at six amino acid residues. Complementation experiments confirmed that change in these six amino acids of BabA was sufficient to eliminate binding to Leb and to gastric tissue. These results demonstrate that BabA expression in vivo is highly dynamic, and the findings implicate specific amino acid residues as critical for binding to fucosylated ABH antigens. 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.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13.
Stanton PK, Potter PE, Aguilar J, Decandia M, Moskal JR
(2009) Neuroreport 20: 1193-7
MeSH Terms: Animals, Brain Ischemia, Carotid Artery Diseases, Cell Death, Cell Hypoxia, Female, Gerbillinae, Glucose, Hippocampus, In Vitro Techniques, Male, Neurons, Neuroprotective Agents, Oligopeptides, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Serine, Stroke, Time Factors
Show Abstract · Added January 19, 2016
GLYX-13 (threonine-proline-proline-threonine-amide) is an amidated di-pyrrolidine that acts as a functional partial agonist at the glycine site on N-methyl-D-aspartate glutamate receptors (NMDARs). GLYX-13 can both increase NMDAR conductance at NR2B-containing receptors, and reduce conductance of non-NR2B-containing receptors. Here, we report that GLYX-13 potently reduces delayed (24 h) death of CA1 pyramidal neurons produced by bilateral carotid occlusion in Mongolian gerbils, when administered up to 5 h post-ischemia. GLYX-13 also reduced delayed (24 h) neuronal death of CA1, CA3, and dentate gyrus principal neurons elicited by oxygen/glucose deprivation in in-vitro hippocampal organotypic slice cultures, when applied up to 2 h post-oxygen/glucose deprivation. The glycine site full agonist D-serine completely occluded neuroprotection, indicating that GLYX-13 acts by modulating activation of this site.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Delineation of a carcinogenic Helicobacter pylori proteome.
Franco AT, Friedman DB, Nagy TA, Romero-Gallo J, Krishna U, Kendall A, Israel DA, Tegtmeyer N, Washington MK, Peek RM
(2009) Mol Cell Proteomics 8: 1947-58
MeSH Terms: Animals, Bacterial Proteins, Blotting, Western, Cell Line, Electrophoresis, Gel, Two-Dimensional, Flagellin, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Male, Microscopy, Electron, Transmission, Mutation, Missense, Proteome, Proteomics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Stomach Neoplasms
Show Abstract · Added March 13, 2012
Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, yet only a fraction of infected persons ever develop cancer. The extensive genetic diversity inherent to this pathogen has precluded comprehensive analyses of constituents that mediate carcinogenesis. We previously reported that in vivo adaptation of a non-carcinogenic H. pylori strain endowed the output derivative with the ability to induce adenocarcinoma, providing a unique opportunity to identify proteins selectively expressed by an oncogenic H. pylori strain. Using a global proteomics DIGE/MS approach, a novel missense mutation of the flagellar protein FlaA was identified that affects structure and function of this virulence-related organelle. Among 25 additional differentially abundant proteins, this approach also identified new proteins previously unassociated with gastric cancer, generating a profile of H. pylori proteins to use in vaccine development and for screening persons infected with strains most likely to induce severe disease.
0 Communities
4 Members
0 Resources
17 MeSH Terms
Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo.
Bronte-Tinkew DM, Terebiznik M, Franco A, Ang M, Ahn D, Mimuro H, Sasakawa C, Ropeleski MJ, Peek RM, Jones NL
(2009) Cancer Res 69: 632-9
MeSH Terms: Adenocarcinoma, Animals, Antigens, Bacterial, Bacterial Proteins, Cell Line, Tumor, Cell Nucleus, Cytokine Receptor gp130, Gerbillinae, HeLa Cells, Helicobacter Infections, Helicobacter pylori, Humans, Male, Phosphorylation, Receptors, Interleukin-6, STAT3 Transcription Factor, Stomach Neoplasms, Transcription, Genetic, Tyrosine
Show Abstract · Added March 5, 2014
Persistent infection with Helicobacter pylori confers an increased risk for the development of gastric cancer. However, the exact mechanisms whereby this bacterium causes carcinogenesis have not been completely elucidated. Recent evidence indicates that aberrant activation of the signal transducers and activators of transcription 3 (STAT3) signaling pathway may play a role in gastric carcinogenesis. Therefore, we hypothesized that H. pylori infection modulates STAT3 signaling, favoring gastric cancer development. In epithelial cells infected with H. pylori, STAT3 was activated, as assessed by immunoblotting for phosphorylated STAT3, immunofluorescence of translocated STAT3, fluorescence recovery after photobleaching, and luciferase activation in transfected cells. Activation was dependent on translocation but not phosphorylation of cytotoxin-associated gene A (CagA) in host cells. Activation seemed to be receptor-mediated because preincubation of cells with the interleukin-6 (IL-6) receptor superantagonist sant7 or inhibition of gp130 by a monoclonal antibody prevented H. pylori-mediated STAT3 activation. However, activation was not related to autocrine activation by IL-6 or IL-11. CagA+ wild-type H. pylori, but not the noncarcinogenic cagA- mutant, activated STAT3 in gastric epithelial cells in vivo in the gerbil model of H. pylori-mediated gastric carcinogenesis. Collectively, these results indicate that H. pylori CagA activates the STAT3 signaling pathway in vitro and in vivo, providing a potential mechanism by which chronic H. pylori infection promotes the development of gastric cancer.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors.
Franco AT, Johnston E, Krishna U, Yamaoka Y, Israel DA, Nagy TA, Wroblewski LE, Piazuelo MB, Correa P, Peek RM
(2008) Cancer Res 68: 379-87
MeSH Terms: Adenocarcinoma, Adhesins, Bacterial, Adult, Animals, Antigens, Bacterial, Bacterial Adhesion, Bacterial Outer Membrane Proteins, Bacterial Proteins, Cell Transformation, Neoplastic, Cells, Cultured, Gastritis, Gene Expression Regulation, Bacterial, Gerbillinae, Helicobacter pylori, Humans, Male, Middle Aged, Mutant Proteins, Stomach Neoplasms, Virulence Factors, beta Catenin
Show Abstract · Added March 5, 2014
Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, and strains that possess the cag secretion system, which translocates the bacterial effector CagA into host cells, augment cancer risk. H. pylori strains that express the vacuolating cytotoxin or the outer membrane protein OipA are similarly associated with severe pathologic outcomes. We previously reported that an in vivo adapted H. pylori strain, 7.13, induces gastric adenocarcinoma in rodent models of gastritis. In the current study, we used carcinogenic strain 7.13 as a prototype to define the role of virulence constituents in H. pylori-mediated carcinogenesis. Mongolian gerbils were infected with wild-type strain 7.13 or cagA(-), vacA(-), or oipA(-) mutants for 12 to 52 weeks. All infected gerbils developed gastritis; however, inflammation was significantly attenuated in animals infected with the cagA(-) but not the vacA(-) or oipA(-) strains. Gastric dysplasia and cancer developed in >50% of gerbils infected with either the wild-type or vacA(-) strain but in none of the animals infected with the cagA(-) strain. Inactivation of oipA decreased beta-catenin nuclear localization in vitro and reduced the incidence of cancer in gerbils. OipA expression was detected significantly more frequently among H. pylori strains isolated from human subjects with gastric cancer precursor lesions versus persons with gastritis alone. These results indicate that loss of CagA prevents the development of cancer in this model. Inactivation of oipA attenuates beta-catenin nuclear translocation and also decreases the incidence of carcinoma. In addition to defining factors that mediate H. pylori-induced cancer, these results provide insight into mechanisms that may regulate the development of other malignancies arising within the context of inflammatory states.
0 Communities
2 Members
0 Resources
21 MeSH Terms