Abstract
Helicobacter pylori
infection and elevated expression of tissue matrix metalloproteinase 1 (MMP-1) are both associated with gastric cancer. We investigated the regulation of MMP-1 expression during
H. pylori
infection. Real-time reverse transcription-PCR was used to examine mucosal MMP-1 mRNA levels in 55 patients with gastric cancers and 61 control patients. Increased MMP-1 mRNA levels in the gastric mucosa and epithelial cells were observed in
H. pylori
infections in which both the
cag
pathogenicity island (PAI) and outer inflammatory protein A (OipA) were expressed. The combined induction of
c-fos, c-jun,
and polyoma enhancing activator-3 (
pea-3
) by
H. pylori
caused maximal increase in MMP-1 expression. Activation of the MMP-1 promoter by
H. pylori
involved occupation of the activator protein 1 (AP-1) sites at −72 and −181 and, surprisingly, vacancy of the −88 PEA-3 site. Electrophoretic mobility shift, supershift, and chromatin immunoprecipitation assays showed increased binding of c-Fos and c-Jun to the −72 and −181 AP-1 sites during
H. pylori
infection. Importantly, during wild-type
H. pylori
infection, we detected increased PEA-3 binding to the −72AP-1 site and decreased PEA-3 binding to the −88 PEA-3 site. However, during infection with the
cag
PAI and
oipA
mutants, PEA-3 binding to the −88 site was detected. MMP-1 and
pea-3
activities are increased in gastric cancers. Maximal activation of MMP-1 transcription requires the
cag
PAI and OipA, which regulate AP-1 and PEA-3 binding. Thus,
cag
PAI and OipA provide a possible link between bacterial virulence factors and important host factors related to disease pathogenesis.
