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Balance between Polyoma Enhancing Activator 3 and Activator Protein 1 Regulates Helicobacter pylori–Stimulated Matrix Metalloproteinase 1 Expression

¹ Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; ² Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; ³ Shanghai Institute of Digestive Diseases and Shanghai Renji Hospital, Shanghai, China; and ⁴ Department of Medicine, University of Miami School of Medicine, Miami, Florida

Requests for reprints: Yoshio Yamaoka, Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center (111D), Room 3A-320, 2002 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-7597; Fax: 713-795-4471; E-mail: yyamaoka{at}bcm.tmc.edu.

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. (Cancer Res 2006; 66(10): 5111-20)

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