Balance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression.
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.
Wu
Jeng Yih
JY
Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030, USA.
Lu
Hong
H
Sun
Yubo
Y
Graham
David Y
DY
Cheung
Herman S
HS
Yamaoka
Yoshio
Y
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
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