Helicobacter pylori interferes with an embryonic stem cell micro RNA cluster to block cell cycle progression.
Résumé
UNLABELLED: ABSTRACT: BACKGROUND: MicroRNAs, post-transcriptional regulators of eukaryotic gene expression, are implicated in host defense against pathogens. Viruses and bacteria have evolved strategies that suppress microRNA functions, resulting in a sustainable infection. In this work we report that Helicobacter pylori, a human stomach-colonizing bacterium responsible for severe gastric inflammatory diseases and gastric cancers, downregulates an embryonic stem cell microRNA cluster in proliferating gastric epithelial cells to achieve cell cycle arrest. RESULTS: Using a deep sequencing approach in the AGS cell line, a widely used cell culture model to recapitulate early events of H. pylori infection of gastric mucosa, we reveal that hsa-miR-372 is the most abundant microRNA expressed in this cell line, where, together with hsa-miR-373, it promotes cell proliferation by silencing large tumor suppressor homolog 2 (LATS2) gene expression. Shortly after H. pylori infection, miR-372 and miR-373 synthesis is highly inhibited, leading to the post-transcriptional release of LATS2 expression and thus, to a cell cycle arrest at the G1/S transition. This downregulation of a specific cell-cycle-regulating microRNA is dependent on the translocation of the bacterial effector CagA into the host cells, a mechanism highly associated with the development of severe atrophic gastritis and intestinal-type gastric carcinoma. CONCLUSIONS: These data constitute a novel example of host-pathogen interplay involving microRNAs, and unveil the couple LATS2/miR-372 and miR-373 as an unexpected mechanism in infection-induced cell cycle arrest in proliferating gastric cells, which may be relevant in inhibition of gastric epithelium renewal, a major host defense mechanism against bacterial infections.
Fichier principal
1758-907X-2-7.pdf (1.36 Mo)
Télécharger le fichier
1758-907X-2-7-S1.PDF (423.32 Ko)
Télécharger le fichier
1758-907X-2-7-S2.PDF (2.4 Mo)
Télécharger le fichier
1758-907X-2-7-S3.PDF (1.18 Mo)
Télécharger le fichier
1758-907X-2-7-S4.PDF (4.69 Mo)
Télécharger le fichier
1758-907X-2-7-S5.PDF (1.12 Mo)
Télécharger le fichier
1758-907X-2-7-S6.PDF (4.22 Mo)
Télécharger le fichier
1758-907X-2-7-S7.PDF (2.69 Mo)
Télécharger le fichier
1758-907X-2-7.xml (113.15 Ko)
Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre
Format : Autre