Balance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression

Jeng Yih Wu, Hong Lu, Yubo Sun, David Y. Graham, Herman S Cheung, Yoshio Yamaoka

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5111-5120
Number of pages10
JournalCancer Research
Volume66
Issue number10
DOIs
StatePublished - May 15 2006

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Matrix Metalloproteinase 1
Transcription Factor AP-1
Helicobacter pylori
Helicobacter Infections
Genomic Islands
Staphylococcal Protein A
Stomach Neoplasms
Messenger RNA
Chromatin Immunoprecipitation
Virulence Factors
Gastric Mucosa
Occupations
Reverse Transcription
Epithelial Cells
Polymerase Chain Reaction
Infection

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Balance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression. / Wu, Jeng Yih; Lu, Hong; Sun, Yubo; Graham, David Y.; Cheung, Herman S; Yamaoka, Yoshio.

In: Cancer Research, Vol. 66, No. 10, 15.05.2006, p. 5111-5120.

Research output: Contribution to journalArticle

Wu, Jeng Yih ; Lu, Hong ; Sun, Yubo ; Graham, David Y. ; Cheung, Herman S ; Yamaoka, Yoshio. / Balance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression. In: Cancer Research. 2006 ; Vol. 66, No. 10. pp. 5111-5120.
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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.",
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AB - 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.

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