Outer membrane vesicles enhance the carcinogenic potential of Helicobacter pylori.
Chronic Helicobacter pylori infection is associated with an increased risk of gastric carcinogenesis. These non-invasive bacteria colonize the gastric mucosa and constitutively shed small outer membrane vesicles (OMV). In this study, we investigated the direct effect of H.pylori OMV on cellular events associated with carcinogenesis. We observed increased micronuclei formation in AGS human gastric epithelial cells treated with OMV isolated from a toxigenic H.pylori strain (60190). This effect was absent in OMV from strain 60190v:1 that has a mutant vacA, indicating VacA-dependent micronuclei formation. VacA induces intracellular vacuolation, and reduced acridine orange staining indicated disruption in the integrity of these vacuoles. This was accompanied by an alteration in iron metabolism and glutathione (GSH) loss, suggesting a role for oxidative stress in genomic damage. Increasing intracellular GSH levels with a GSH ester abrogated the VacA-mediated increase in micronuclei formation. In conclusion, OMV-mediated delivery of VacA to the gastric epithelium may constitute a new mechanism for H.pylori-induced gastric carcinogenesis.
Chitcholtan
Kenny
K
Department of Surgery, University of Otago Christchurch, Christchurch, New Zealand.
Hampton
Mark B
MB
Keenan
Jacqueline I
JI
D001426:Bacterial Proteins; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D002471:Cell Transformation, Neoplastic; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000378:metabolism; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D007501:Iron / Q000378:metabolism; D048629:Micronuclei, Chromosome-Defective; D018384:Oxidative Stress / Q000502:physiology; D050050:Protein Carbonylation / Q000502:physiology; D013274:Stomach Neoplasms / Q000473:pathology / Q000821:virology*; D022161:Transport Vesicles / Q000378:metabolism / Q000821:virology*
D001426:Bacterial Proteins; C074689:VacA protein, Helicobacter pylori; D007501:Iron; D005978:Glutathione