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: Jeng Yih Wu, Hong Lu, Yubo Sun, David Y Graham, Herman S Cheung, Yoshio Yamaoka
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 10 Pg. 5111-20 (May 15 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16707434 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bacterial Outer Membrane Proteins
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-jun
• RNA, Messenger
• Transcription Factor AP-1
• Transcription Factors
• Virulence Factors
• transcription factor PEA3
• RHOA protein, human
• raf Kinases
• Matrix Metalloproteinase 1
• ras Proteins
• rhoA GTP-Binding Protein

Topics

• Bacterial Outer Membrane Proteins (physiology)
• Gastric Mucosa (enzymology, microbiology)
• Gene Expression Regulation, Enzymologic
• Helicobacter Infections (enzymology, genetics, metabolism)
• Helicobacter pylori (metabolism, pathogenicity, physiology)
• Humans
• MAP Kinase Signaling System
• Matrix Metalloproteinase 1 (biosynthesis, genetics)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-fos (biosynthesis, genetics, metabolism)
• Proto-Oncogene Proteins c-jun (biosynthesis, genetics, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Stomach Neoplasms (enzymology, microbiology)
• Transcription Factor AP-1 (metabolism)
• Transcription Factors (metabolism)
• Virulence Factors (physiology)
• raf Kinases (biosynthesis, genetics, metabolism)
• ras Proteins (biosynthesis, genetics, metabolism)
• rhoA GTP-Binding Protein (biosynthesis, genetics, metabolism)