title: Balance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression.
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.
authors.affiliation: Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jeng Yih
authors.initials: JY
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Yubo
authors.initials: Y
authors.lastname: Sun
authors.forename: David Y
authors.initials: DY
authors.lastname: Graham
authors.forename: Herman S
authors.initials: HS
authors.lastname: Cheung
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamaoka
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000502:physiology; D005753:Gastric Mucosa / Q000201:enzymology / Q000382:microbiology; D015971:Gene Expression Regulation, Enzymologic; D016481:Helicobacter Infections / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000382:microbiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D037521:Virulence Factors / Q000502:physiology*; D048490:raf Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D037521:Virulence Factors; C065788:transcription factor PEA3; C066737:RHOA protein, human; D048490:raf Kinases; D020781:Matrix Metalloproteinase 1; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein