RRC ID 1948
Author Wu JY, Lu H, Sun Y, Graham DY, Cheung HS, Yamaoka Y.
Title Balance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression.
Journal Cancer Res
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.
Volume 66(10)
Pages 5111-20
Published 2006-5-15
DOI 10.1158/0008-5472.CAN-06-0383
PII 66/10/5111
PMID 16707434
PMC PMC3130055
MeSH Bacterial Outer Membrane Proteins / physiology Gastric Mucosa / enzymology Gastric Mucosa / microbiology Gene Expression Regulation, Enzymologic Helicobacter Infections / enzymology* Helicobacter Infections / genetics Helicobacter Infections / metabolism Helicobacter pylori / metabolism Helicobacter pylori / pathogenicity Helicobacter pylori / physiology* Humans MAP Kinase Signaling System Matrix Metalloproteinase 1 / biosynthesis* Matrix Metalloproteinase 1 / genetics Promoter Regions, Genetic Proto-Oncogene Proteins c-fos / biosynthesis Proto-Oncogene Proteins c-fos / genetics Proto-Oncogene Proteins c-fos / metabolism Proto-Oncogene Proteins c-jun / biosynthesis Proto-Oncogene Proteins c-jun / genetics Proto-Oncogene Proteins c-jun / metabolism RNA, Messenger / biosynthesis RNA, Messenger / genetics Stomach Neoplasms / enzymology* Stomach Neoplasms / microbiology* Transcription Factor AP-1 / metabolism* Transcription Factors / metabolism* Virulence Factors / physiology* raf Kinases / biosynthesis raf Kinases / genetics raf Kinases / metabolism ras Proteins / biosynthesis ras Proteins / genetics ras Proteins / metabolism rhoA GTP-Binding Protein / biosynthesis rhoA GTP-Binding Protein / genetics rhoA GTP-Binding Protein / metabolism
IF 8.378
Times Cited 33
Human and Animal Cells MKN45