Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

AbstractChronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and -independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a “hit-and-run” process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the “hit-and-run” process of gastric carcinogenesis.

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

Microorganisms ◽

10.3390/microorganisms9081748 ◽

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.

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Lactobacilli Reduce Helicobacter pylori Attachment to Host Gastric Epithelial Cells by Inhibiting Adhesion Gene Expression

Infection and Immunity ◽

10.1128/iai.00163-16 ◽

2016 ◽

Vol 84 (5) ◽

pp. 1526-1535 ◽

Cited By ~ 20

Author(s):

Nele de Klerk ◽

Lisa Maudsdotter ◽

Hanna Gebreegziabher ◽

Sunil D. Saroj ◽

Beatrice Eriksson ◽

...

Keyword(s):

Helicobacter Pylori ◽

Epithelial Cells ◽

Molecular Mechanisms ◽

Binding Capacity ◽

Host Cells ◽

Gastric Epithelial Cells ◽

Content Type ◽

Effector Molecule ◽

H Pylori

The human gastrointestinal tract, including the harsh environment of the stomach, harbors a large variety of bacteria, of whichLactobacillusspecies are prominent members. The molecular mechanisms by which species of lactobacilli interfere with pathogen colonization are not fully characterized. In this study, we aimed to study the effect of lactobacillus strains upon the initial attachment ofHelicobacter pylorito host cells. Here we report a novel mechanism by which lactobacilli inhibit adherence of the gastric pathogenH. pylori. In a screen withLactobacillusisolates, we found that only a few could reduce adherence ofH. pylorito gastric epithelial cells. Decreased attachment was not due to competition for space or to lactobacillus-mediated killing of the pathogen. Instead, we show that lactobacilli act onH. pyloridirectly by an effector molecule that is released into the medium. This effector molecule acts onH. pyloriby inhibiting expression of the adhesin-encoding genesabA. Finally, we verified that inhibitory lactobacilli reducedH. pyloricolonization in anin vivomodel. In conclusion, certainLactobacillusstrains affect pathogen adherence by inhibitingsabAexpression and thereby reducingH. pyloribinding capacity.

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M1959 Helicobacter pylori cagA Tyrosine Phosphorylation Triggers the Interleukin-11/STAT3 Pathway in Gastric Epithelial Cells

Gastroenterology ◽

10.1016/s0016-5085(10)62069-0 ◽

2010 ◽

Vol 138 (5) ◽

pp. S-448

Author(s):

Kai Syin Lee ◽

Anastasia Kalantzis ◽

Naoko Murata-Kamiya ◽

Masanori Hatakeyama ◽

Andrew S. Giraud ◽

...

Keyword(s):

Helicobacter Pylori ◽

Epithelial Cells ◽

Tyrosine Phosphorylation ◽

Gastric Epithelial Cells ◽

Stat3 Pathway ◽

Interleukin 11

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Sa1201 - Bone Marrow-Derived Mesenchymal Stem Cells Participate in Helicobacter Pylori-Induced Gastric Cancer via Differentiating Into Gastric Epithelial Cells and Carcinoma Associated Fribroblasts

Gastroenterology ◽

10.1016/s0016-5085(18)31282-4 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-275-S-276

Author(s):

Huiying Shi ◽

Chaoqun Han ◽

Rong Lin

Keyword(s):

Gastric Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Helicobacter Pylori ◽

Mesenchymal Stem Cells ◽

Epithelial Cells ◽

Gastric Epithelial Cells

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Helicobacter pylori impairs DNA mismacth repair in gastric epithelial cells: A link with gastric carcinogenesis

Gastroenterology ◽

10.1016/s0016-5085(00)85609-7 ◽

2000 ◽

Vol 118 (4) ◽

pp. A867 ◽

Cited By ~ 6

Author(s):

Jae J. Kim ◽

Wai K. Leung ◽

Ling Wu ◽

David Y. Graham ◽

Antonia R. Sepulveda

Keyword(s):

Helicobacter Pylori ◽

Epithelial Cells ◽

Gastric Carcinogenesis ◽

Gastric Epithelial Cells

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

Antioxidants ◽

10.3390/antiox8120637 ◽

2019 ◽

Vol 8 (12) ◽

pp. 637 ◽

Cited By ~ 2

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.

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

Infection and Immunity ◽

10.1128/iai.01182-12 ◽

2013 ◽

Vol 81 (7) ◽

pp. 2468-2477 ◽

Cited By ~ 16

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.

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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

Medical University ◽

10.2478/medu-2019-0013 ◽

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”.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90283.2008 ◽

2008 ◽

Vol 295 (3) ◽

pp. G431-G441 ◽

Cited By ~ 20

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.

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