scholarly journals Increased expression of the urokinase plasminogen activator system by Helicobacter pylori in gastric epithelial cells

2008 ◽  
Vol 295 (3) ◽  
pp. G431-G441 ◽  
Author(s):  
Susan Kenny ◽  
Cedric Duval ◽  
Stephen J. Sammut ◽  
Islay Steele ◽  
D. Mark Pritchard ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Plasminogen Activator ◽  
Egf Receptor ◽  
Gastric Epithelial Cells ◽  
Epithelial Cell Proliferation ◽  
H Pylori ◽  
Pai 1

The gastric pathogen Helicobacter pylori ( H. pylori) is linked to peptic ulcer and gastric cancer, but the relevant pathophysiological mechanisms are unclear. We now report that H. pylori stimulates the expression of plasminogen activator inhibitor (PAI)-1, urokinase plasminogen activator (uPA), and its receptor (uPAR) in gastric epithelial cells and the consequences for epithelial cell proliferation. Real-time PCR of biopsies from gastric corpus, but not antrum, showed significantly increased PAI-1, uPA, and uPAR in H. pylori-positive patients. Transfection of primary human gastric epithelial cells with uPA, PAI-1, or uPAR promoters in luciferase reporter constructs revealed expression of all three in H+/K+ATPase- and vesicular monoamine transporter 2-expressing cells; uPA was also expressed in pepsinogen- and uPAR-containing trefoil peptide-1-expressing cells. In each case expression was increased in response to H. pylori and for uPA, but not PAI-1 or uPAR, required the virulence factor CagE. H. pylori also stimulated soluble and cell surface-bound uPA activity, and both were further increased by PAI-1 knockdown, consistent with PAI-1 inhibition of endogenous uPA. H. pylori stimulated epithelial cell proliferation, which was inhibited by uPA immunoneutralization and uPAR knockdown; exogenous uPA also stimulated proliferation that was further increased after PAI-1 knockdown. The proliferative effects of uPA were inhibited by immunoneutralization of the EGF receptor and of heparin-binding EGF (HB-EGF) by the mutant diphtheria toxin CRM197 and an EGF receptor tyrosine kinase inhibitor. H. pylori induction of uPA therefore leads to epithelial proliferation through activation of HB-EGF and is normally inhibited by concomitant induction of PAI-1; treatments directed at inhibition of uPA may slow the progression to gastric cancer.

scholarly journals Inhibitory Effect of β-Carotene on Helicobacter pylori-Induced TRAF Expression and Hyper-Proliferation in Gastric Epithelial Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 637 ◽  
Author(s):  
Yongchae Park ◽  
Hanbit Lee ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Nadph Oxidase ◽  
Gastric Epithelial Cells ◽  
Gastric Cancer Cells ◽  
Ags Cells ◽  
H Pylori ◽  
Β Carotene

Helicobacter pylori infection causes the hyper-proliferation of gastric epithelial cells that leads to the development of gastric cancer. Overexpression of tumor necrosis factor receptor associated factor (TRAF) is shown in gastric cancer cells. The dietary antioxidant β-carotene has been shown to counter hyper-proliferation in H. pylori-infected gastric epithelial cells. The present study was carried out to examine the β-carotene mechanism of action. We first showed that H. pylori infection decreases cellular IκBα levels while increasing cell viability, NADPH oxidase activity, reactive oxygen species production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and TRAF1 and TRAF2 gene expression, as well as protein–protein interaction in gastric epithelial AGS cells. We then demonstrated that pretreatment of cells with β-carotene significantly attenuates these effects. Our findings support the proposal that β-carotene has anti-cancer activity by reducing NADPH oxidase-mediated production of ROS, NF-κB activation and NF-κB-regulated TRAF1 and TRAF2 gene expression, and hyper-proliferation in AGS cells. We suggest that the consumption of β-carotene-enriched foods could decrease the incidence of H. pylori-associated gastric disorders.

scholarly journals Phylogeographic Origin of Helicobacter pylori Determines Host-Adaptive Responses upon Coculture with Gastric Epithelial Cells

2013 ◽  
Vol 81 (7) ◽  
pp. 2468-2477 ◽  
Author(s):  
Alexander Sheh ◽  
Rupesh Chaturvedi ◽  
D. Scott Merrell ◽  
Pelayo Correa ◽  
Keith T. Wilson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Gastric Disease ◽  
Gastric Epithelial Cells ◽  
Gastric Cancer Risk ◽  
Content Type ◽  
H Pylori ◽  
Induced Apoptosis

ABSTRACTWhileHelicobacter pyloriinfects over 50% of the world's population, the mechanisms involved in the development of gastric disease are not fully understood. Bacterial, host, and environmental factors play a role in disease outcome. To investigate the role of bacterial factors inH. pyloripathogenesis, global gene expression of sixH. pyloriisolates was analyzed during coculture with gastric epithelial cells. Clustering analysis of six Colombian clinical isolates from a region with low gastric cancer risk and a region with high gastric cancer risk segregated strains based on their phylogeographic origin. One hundred forty-six genes had increased expression in European strains, while 350 genes had increased expression in African strains. Differential expression was observed in genes associated with motility, pathogenicity, and other adaptations to the host environment. European strains had greater expression of the virulence factorscagA,vacA, andbabBand were associated with increased gastric histologic lesions in patients. In AGS cells, European strains promoted significantly higher interleukin-8 (IL-8) expression than did African strains. African strains significantly induced apoptosis, whereas only one European strain significantly induced apoptosis. Our data suggest that gene expression profiles of clinical isolates can discriminate strains by phylogeographic origin and that these profiles are associated with changes in expression of the proinflammatory and protumorigenic cytokine IL-8 and levels of apoptosis in host epithelial cells. These findings support the hypothesis that bacterial factors determined by the phylogeographic origin ofH. pyloristrains may promote increased gastric disease.

Intrafamilial Infection of Helicobacter Pylori: Abnormal Gastric Epithelial Cells, Pedestal-Rich H. Pylori Adherence, and a Gene Mutation in a Child with Protein-Losing Gastroenteropathy

2019 ◽  
Vol 2 (3) ◽  
pp. 83-99
Author(s):  
T.W. Wan ◽  
O. Khokhlova ◽  
W. Higuchi ◽  
I. Protasova ◽  
Olga V. Peryanova ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Epithelial Cells ◽  
Gene Mutation ◽  
Virulence Factor ◽  
East Asian ◽  
Gastric Epithelium ◽  
Gastric Epithelial Cells ◽  
H Pylori

Abstract Helicobacter pylori, one of the most prevalent human pathogens, colonizes the gastric mucosa and is associated with gastric diseases, such as gastritis and peptic ulcers, and is also a bacterial risk factor for gastric cancer. Cytotoxin-associated gene A (CagA) protein, a major virulence factor of H. pylori, is phosphorylated in cells at its Glu-Pro-IIe-Tyr-Ala (EPIYA) motif and is considered to trigger gastric cancer. CagA is classified into two forms, Western CagA with EPIYA-ABC and East Asian CagA with EPIYA-ABD, with the latter associated with a high risk of developing gastric cancer. CagA causes morphological transformation of cells, yielding the “hummingbird” phenotype in AGS cells and possibly membranous pedestals in the gastric epithelium, albeit rarely. H. pylori adherence to the gastric mucosa is not yet fully understood. Here, we describe an intrafamilial infection case of H. pylori, focusing on the gastric epithelium, H. pylori adherence, and a gene mutation in a child with protein-losing gastroenteropathy (characterized by excessive loss of plasma proteins into the gastrointestinal tract). H. pylori, which also infected family members (mother and father), was genetically a single clone with the virulence genes of an East Asian type. The patient’ gastric mucosa exhibited some unique features. Endoscopy revealed the presence of protein plugs on the mucosal surface, which were immunoelectrophoretically similar to serum proteins. Electron microscopy revealed abnormal gastric epithelial cells, totally covered with the secretions or possessing small swollen structures and irregular microvilli. The patient’s H. pylori infection was characterized by frequently occurring thick pedestals, formed along adherent H. pylori. The serum protein level returned to normal and the protein plugs disappeared after the successful eradication of H. pylori, albeit with lag periods for healing. He had a mutation in the OCRL1 gene, associated with Dent disease (asymptomatic proteinuria). Thus, in the patient’s gastric mucosa, we found the abnormal gastric epithelial cells, which may be caused by an OCRL1 mutation or H. pylori, and pedestal-rich H. pylori infection, possibly caused by a higher level of action of CagA in the abnormal epithelial cells. The data suggests a novel H. pylori virulence factor associated with “excessive plasma protein release”.

scholarly journals Identification of Functional Interactome of Gastric Cancer Cells with Helicobacter pylori Outer Membrane Protein HpaA by HPLC-MS/MS

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ruyue Fan ◽  
Xiurui Han ◽  
Di Xiao ◽  
Lihua He ◽  
Yanan Gong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Cell Lines ◽  
Outer Membrane Protein ◽  
Regulation Of Transcription ◽  
Gastric Epithelial Cells ◽  
H Pylori

HpaA as an outer membrane protein of Helicobacter pylori (H. pylori) plays a significant role in the adhesion to the human stomach, but the functional relation between HpaA and gastric epithelial cells is still not clear. To screen the interaction between HpaA and cellular proteins in gastric epithelial cells, the HpaA protein from H. pylori 26695 fused with a tag (6× His) was expressed and purified successfully, the secondary structure was estimated by the Circular Dichroism (CD) spectrum, and the purified recombinant protein was used to perform the pull-down assays with gastric cancer cell lines (AGS and SGC-7901) lysates, respectively. The pull-down proteins were identified by high-performance liquid chromatography tandem mass spectrometry system (HPLC-MS/MS). A total of 9 and 13 proteins related were analyzed from AGS and SGC-7901 cell lysates, respectively. ANXA2 was considered as putative HpaA functional partner discovered from lysates of both cell lines with high score and coverage. It is hypothesized that HpaA may be involved in the biological process of regulation of transcription and nucleic acid metabolism during the adhesion of H. pylori to human gastric epithelial cells, and HpaA-binding proteins also be used as targets for the development of antiadhesion drugs against H. pylori.

scholarly journals Engagement of CEACAM1 by Helicobacter pylori HopQ Is Important for the Activation of Non-Canonical NF-κB in Gastric Epithelial Cells

2021 ◽  
Vol 9 (8) ◽  
pp. 1748
Author(s):  
Karin Taxauer ◽  
Youssef Hamway ◽  
Anna Ralser ◽  
Alisa Dietl ◽  
Karin Mink ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Surface Protein ◽  
Host Cells ◽  
Gastric Epithelial Cells ◽  
Gastric Cancer Cells ◽  
Tissue Samples ◽  
Mutant Strains ◽  
H Pylori

The gastric pathogen Helicobacter pylori infects half of the world’s population and is a major risk factor for gastric cancer development. In order to attach to human gastric epithelial cells and inject the oncoprotein CagA into host cells, H. pylori utilizes the outer membrane protein HopQ that binds to the cell surface protein CEACAM, which can be expressed on the gastric mucosa. Once bound, H. pylori activates a number of signaling pathways, including canonical and non-canonical NF-κB. We investigated whether HopQ–CEACAM interaction is involved in activating the non-canonical NF-κB signaling pathway. Different gastric cancer cells were infected with the H. pylori wild type, or HopQ mutant strains, and the activation of non-canonical NF-κB was related to CEACAM expression levels. The correlation between CEACAM levels and the activation of non-canonical NF-κB was confirmed in human gastric tissue samples. Taken together, our findings show that the HopQ–CEACAM interaction is important for activation of the non-canonical NF-κB pathway in gastric epithelial cells.

scholarly journals Helicobacter pylori and Epstein-Barr Virus Coinfection Stimulates Aggressiveness in Gastric Cancer through the Regulation of Gankyrin

mSphere ◽  
2021 ◽  
Author(s):  
Dharmendra Kashyap ◽  
Budhadev Baral ◽  
Shweta Jakhmola ◽  
Anil Kumar Singh ◽  
Hem Chandra Jha
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Synergistic Effects ◽  
Gastric Epithelial Cells ◽  
Content Type ◽  
Barr Virus ◽  
Epstein Barr ◽  
H Pylori

In the present study, we evaluated the synergistic effects of EBV and H. pylori infection on gastric epithelial cells in various coinfection models. These coinfection models were among the first to depict the exposures of gastric epithelial cells to EBV followed by H. pylori ; however, coinfection models exist that narrated the scenario upon exposure to H. pylori followed by that to EBV.

scholarly journals Helicobacter pylori and Epstein-Barr virus coinfection stimulates the aggressiveness in gastric cancer through the regulation of gankyrin

2020 ◽  
Author(s):  
Dharmendra Kashyap ◽  
Budhadev Baral ◽  
Nidhi Varshney ◽  
Anil Kumar Singh ◽  
Hem Chandra Jha
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Molecular Mechanism ◽  
Epstein Barr Virus ◽  
Gastric Epithelial Cells ◽  
Carcinogenic Activity ◽  
Barr Virus ◽  
Epstein Barr ◽  
H Pylori

AbstractPersistent coinfection of Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV) promotes aggressive gastric carcinoma. The molecular mechanisms underlying the aggressiveness in H. pylori and EBV coinfected gastric cancer is not well characterized. In the current study, we investigated the molecular mechanism involved in the cooperation of H. pylori and EBV-driven proliferation of gastric epithelial cells. Results showed that the coinfections are significantly more advantageous to the pathogens to create a microenvironment that favors the higher pathogen-associated gene expression. The EBV latent genes EBNA1 and EBNA3C are highly overexpressed in the coinfections compared to individual EBV infection at different time points (12 and 24 hrs). The H. pylori-associated genes 16s rRNA, CagA, and BabA has also been highly overexpressed in coinfections compared to H. pylori alone. Gankyrin is a small protein of 25 KDa involved in multiple biological and physiological processes. The upregulation of gankyrin modulates the various cell signaling pathways, leading to oncogenesis. The gankyrin shows a similar expression pattern as EBNA3C at both transcript and protein levels, suggesting a possible correlation. Further EBV and H. pylori create microenvironments that induce cell transformation and oncogenesis by dysregulation of the cell-cycle regulator, GC marker, cell migration, DNA response, and antiapoptotic genes in infected gastric epithelial cells by enhancing the expression of gankyrin. Our study provides new insights into the molecular mechanism where the interplay between two oncogenic agents (H. pylori and EBV) leads to the enhanced carcinogenic activity of gastric epithelial cells through overexpression of oncoprotein gankyrin.ImportanceIn the present study, we have evaluated the synergistic effect of EBV and H. pylori infection on gastric epithelial cells in various coinfection models. These coinfection models depict the first exposures of gastric epithelial cells with EBV and then the H. pylori. While other coinfection models narrated the first exposures of H. pylori followed by the infection of EBV. This led to an enhanced oncogenic phenotype in gastric epithelial cells. We determined the coinfection of EBV and H. pylori enhanced the expression of oncogenic protein gankyrin. The interplay between EBV and H. pylori promotes the oncogenic properties of AGS cells through the newly discovered oncoprotein gankyrin. EBV and H. pylori mediated upregulation of gankyrin further dysregulates various cancer-associated hallmarks of genes such as cell-migratory, gastric cancer marker, tumor suppressor, DNA damage response, and proapoptotic genes.

scholarly journals Helicobacter pylori VacA Induces Programmed Necrosis in Gastric Epithelial Cells

2011 ◽  
Vol 79 (7) ◽  
pp. 2535-2543 ◽  
Author(s):  
Jana N. Radin ◽  
Christian González-Rivera ◽  
Susan E. Ivie ◽  
Mark S. McClain ◽  
Timothy L. Cover
Keyword(s):  
Gastric Cancer ◽  
Cell Death ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Human Stomach ◽  
Gastric Epithelial Cells ◽  
Wild Type ◽  
Programmed Necrosis ◽  
Content Type ◽  
H Pylori

ABSTRACTHelicobacter pyloriis a Gram-negative bacterium that colonizes the human stomach and contributes to the development of peptic ulcer disease and gastric cancer. The secreted pore-forming toxin VacA is one of the major virulence factors ofH. pylori. In the current study, we show that AZ-521 human gastric epithelial cells are highly susceptible to VacA-induced cell death. Wild-type VacA causes death of these cells, whereas mutant VacA proteins defective in membrane channel formation do not. Incubation of AZ-521 cells with wild-type VacA results in cell swelling, poly(ADP-ribose) polymerase (PARP) activation, decreased intracellular ATP concentration, and lactate dehydrogenase (LDH) release. VacA-induced death of these cells is a caspase-independent process that results in cellular release of histone-binding protein high mobility group box 1 (HMGB1), a proinflammatory protein. These features are consistent with the occurrence of cell death through a programmed necrosis pathway and suggest that VacA can be included among the growing number of bacterial pore-forming toxins that induce cell death through programmed necrosis. We propose that VacA augmentsH. pylori-induced mucosal inflammation in the human stomach by causing programmed necrosis of gastric epithelial cells and subsequent release of proinflammatory proteins and may thereby contribute to the pathogenesis of gastric cancer and peptic ulceration.

scholarly journals Helicobacter pylori Infection Stimulates Plasminogen Activator Inhibitor 1 Production by Gastric Epithelial Cells

2008 ◽  
Vol 76 (9) ◽  
pp. 3992-3999 ◽  
Author(s):  
A. C. Keates ◽  
S. Tummala ◽  
R. M. Peek ◽  
E. Csizmadia ◽  
B. Kunzli ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Plasminogen Activator Inhibitor ◽  
Gastric Epithelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Ags Cells ◽  
H Pylori ◽  
Activator Inhibitor ◽  
Pai 1

ABSTRACT Chronic infection with the gastric pathogen Helicobacter pylori significantly increases the risk of developing atrophic gastritis, peptic ulcer disease, and gastric adenocarcinoma. H. pylori strains that possess the cag pathogenicity island, which translocates CagA into the host cells, augment these risks. The aim of this study was to determine the molecular mechanisms through which H. pylori upregulates the expression of plasminogen activator inhibitor 1 (PAI-1), a member of the urokinase activator system that is involved in tumor metastasis and angiogenesis. Levels of PAI-1 mRNA and protein were examined in tissues from H. pylori-infected patients and in vitro using AGS gastric epithelial cells. In vitro, cells were infected with toxigenic cag-positive or nontoxigenic cag-negative strains of H. pylori or isogenic mutants. The amount of PAI-1 secretion was measured by enzyme-linked immunosorbent assay, and mRNA levels were determined using real-time PCR. The regulation of PAI-1 was examined using the extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor and small interfering RNA. Analysis of human biopsy samples revealed an increase in both PAI-1 mRNA and protein levels in patients with H. pylori gastritis compared to those of uninfected controls. Infection of AGS cells with H. pylori significantly increased PAI-1 mRNA expression and the secretion of PAI-1 protein. Moreover, PAI-1 mRNA and protein production was more pronounced when AGS cells were infected by H. pylori strains carrying a functional cag secretion system than when cells were infected by strains lacking this system. PAI-1 secretion was also reduced when cells were infected with either cagE-negative or cagA-negative mutants. The ectopic overexpression of CagA significantly increased the levels of PAI-1 mRNA and protein, whereas blockade of the ERK1/2 pathway inhibited H. pylori-mediated PAI-1 upregulation. These findings suggest that the upregulation of PAI-1 in H. pylori-infected gastric epithelial cells may contribute to the carcinogenic process.

Hydrotalcite Can Prevent the Damaging Effects of Helicobacter Pylori on Gastric Epithelial Cells

2018 ◽  
Vol 24 (3) ◽  
pp. 277-283 ◽  
Author(s):  
Shi Yanyan ◽  
Guo Yanlei ◽  
Zhang Ting ◽  
Ding Shigang
Keyword(s):  
Electron Microscopy ◽  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Cell Line ◽  
Cell Apoptosis ◽  
Gastric Cancer Cell Line ◽  
Gastric Epithelial Cells ◽  
Gastric Cells ◽  
H Pylori

AbstractBackground: Helicobacter pylori is a major cause of gastric diseases including gastric cancer. This study was aimed to explore whether hydrotalcite can inhibit H. pylori infection of gastric epithelial cells. Methods: the gastric epithelial cell line GES-1 and the gastric cancer cell line BGC823 were infected with H. pylori at multiplicities of infections (MOIs) of 50:1 and 100:1. Hydrotalcite was added to cell cultures. Cell apoptosis and cell cycle analysis were performed to measure the situation of cell growth. The main changes of cell ultrastructure were observed by transmission electron microscopy. H. pylori cell adhesion was observed by scanning electron microscopy. Results: hydrotalcite could significantly inhibit cell apoptosis of GES-1 and cell proliferation of BGC823 induced by H. pylori infection at an MOI of 50:1. Hydrotalcite treatment protected gastric cells from H. pylori infection, and H. pylori adhesion to gastric cells was reduced. However, hydrotalcite could not reverse damage induced by H. pylori infection at an MOI of 100:1. Conclusion: hydrotalcite can protect gastric cells from H. pylori infection when cell damage is not serious. It can weaken the damage of cells induced by H. pylori and decrease H. pylori adhesion to gastric cells.

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