Helicobacter pylori CagA activates the Signal Transducer and Activator of Transcription 3 (STAT3) pathway in vitro and in vivo

摘要

Persistent infection with H. pylori confers an increased risk for the development of gastric cancer, however, the exact mechanism(s) whereby this bacterium causes carcinogenesis have not been completely elucidated. Recent evidence indicates that aberrant activation of the STAT3 signaling pathway may play a role in gastric carcinogenesis. Therefore, we hypothesized that H. pylori infection modulates STAT3 signalling, favouring gastric cancer development. In epithelial cells infected with H. pylori, STAT3 was activated as assessed by immunoblotting for phospho-STAT3, immunofluorescence of translocated STAT3, fluorescence recovery after photo-bleaching and luciferase activation in transfected cells. Activation was dependent on translocation, but not phosphorylation of CagA in host cells. Activation appeared to be receptor-mediated since pre-incubation of cells with the IL-6R superantagonist sant7 or inhibition of gp130 by a monoclonal antibody prevented H. pylori-mediated STAT3 activation. However, activation was not related to autocrine activation by IL-6 or IL-11. CagA+ wildtype H. pylori but not the non-carcinogenic cagA- mutant activated STAT3 in gastric epithelial cells in vivo in the gerbil model of H. pylori-mediated gastric carcinogenesis. Collectively, these results indicate that H. pylori CagA activates the STAT3 signaling pathway in vitro and in vivo, providing a potential mechanism by which chronic H. pylori infection promotes the development of gastric cancer.