Abstract
Chronic infection with the gastric pathogen
Helicobacter pylori
significantly increases the risk of developing atrophic gastritis, peptic ulcer disease, and gastric adenocarcinoma.
H. pylori
strains that possess the
cag
pathogenicity island, which translocates CagA into the host cells, augment these risks. The aim of this study was to determine the molecular mechanisms through which
H. pylori
upregulates the expression of plasminogen activator inhibitor 1 (PAI-1), a member of the urokinase activator system that is involved in tumor metastasis and angiogenesis. Levels of PAI-1 mRNA and protein were examined in tissues from
H. pylori
-infected patients and in vitro using AGS gastric epithelial cells. In vitro, cells were infected with toxigenic
cag
-positive or nontoxigenic
cag
-negative strains of
H. pylori
or isogenic mutants. The amount of PAI-1 secretion was measured by enzyme-linked immunosorbent assay, and mRNA levels were determined using real-time PCR. The regulation of PAI-1 was examined using the extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor and small interfering RNA. Analysis of human biopsy samples revealed an increase in both PAI-1 mRNA and protein levels in patients with
H. pylori
gastritis compared to those of uninfected controls. Infection of AGS cells with
H. pylori
significantly increased PAI-1 mRNA expression and the secretion of PAI-1 protein. Moreover, PAI-1 mRNA and protein production was more pronounced when AGS cells were infected by
H. pylori
strains carrying a functional
cag
secretion system than when cells were infected by strains lacking this system. PAI-1 secretion was also reduced when cells were infected with either
cagE
-negative or
cagA
-negative mutants. The ectopic overexpression of CagA significantly increased the levels of PAI-1 mRNA and protein, whereas blockade of the ERK1/2 pathway inhibited
H. pylori
-mediated PAI-1 upregulation. These findings suggest that the upregulation of PAI-1 in
H. pylori
-infected gastric epithelial cells may contribute to the carcinogenic process.
