title: Helicobacter pylori initiates a mesenchymal transition through ZEB1 in gastric epithelial cells.
abstract: Chronic Helicobacter pylori infection provokes an inflammation of the gastric mucosa, at high risk for ulcer and cancer development. The most virulent strains harbor the cag pathogenicity island (cagPAI) encoding a type 4 secretion system, which allows delivery of bacterial effectors into gastric epithelial cells, inducing pro-inflammatory responses and phenotypic alterations reminiscent of an epithelial-to-mesenchymal transition (EMT). This study characterizes EMT features in H. pylori-infected gastric epithelial cells, and investigates their relationship with NF-κB activation. Cultured human gastric epithelial cell lines were challenged with a cagPAI+ H. pylori strain or cag isogenic mutants. Morphological changes, epithelial and mesenchymal gene expression and EMT-related microRNAs were studied. H. pylori up-regulates mesenchymal markers, including ZEB1. This transcription factor is prominently involved in the mesenchymal transition of infected cells and its up-regulation depends on cagPAI and NF-κB activation. ZEB1 expression and NF-κB activation were confirmed by immunohistochemistry in gastric mucosa from cagPAI+ H. pylori-infected patients. Gastric epithelial cell lines express high miR-200 levels, which are linked to ZEB1 in a reciprocal negative feedback loop and maintain their epithelial phenotype in non-infected conditions. However, miR-200b/c were increased upon infection, despite ZEB1 up-regulation and mesenchymal morphology. In the miR-200b-200a-429 cluster promoter, we identified a functional NF-κB binding site, recruiting NF-κB upon infection and trans-activating the microRNA cluster transcription. In conclusion, in gastric epithelial cells, cagPAI+ H. pylori activates NF-κB, which transactivates ZEB1, subsequently promoting mesenchymal transition. The unexpected N-FκB-dependent increase of miR-200 levels likely thwarts the irreversible loss of epithelial identity in that critical situation.
authors.affiliation: University Bordeaux, ARNA Laboratory, Bordeaux, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Baud
authors.forename: Christine
authors.initials: C
authors.lastname: Varon
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chabas
authors.forename: Lucie
authors.initials: L
authors.lastname: Chambonnier
authors.forename: Fabien
authors.initials: F
authors.lastname: Darfeuille
authors.forename: Cathy
authors.initials: C
authors.lastname: Staedel
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology*; D005756:Gastritis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015870:Gene Expression; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000235:genetics*; D016480:Helicobacter pylori / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
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