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-kappaB 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-kappaB activation. ZEB1 expression and NF-kappaB 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-kappaB binding site, recruiting NF-kappaB upon infection and trans-activating the microRNA cluster transcription. In conclusion, in gastric epithelial cells, cagPAI+ H. pylori activates NF-kappaB, which transactivates ZEB1, subsequently promoting mesenchymal transition. The unexpected N-FkappaB-dependent increase of miR-200 levels likely thwarts the irreversible loss of epithelial identity in that critical situation.
Baud, J., Varon, C., Chabas, S., Chambonnier, L., Darfeuille, F., & Staedel, C. (2013). Helicobacter pylori Initiates a Mesenchymal Transition through ZEB1 in Gastric Epithelial Cells. PLoS ONE, 8(4). https://doi.org/10.1371/journal.pone.0060315