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 À72 and À181 and, surprisingly, vacancy of the À88 PEA-3 site. Electrophoretic mobility shift, supershift, and chromatin immunoprecipitation assays showed increased binding of c-Fos and c-Jun to the À72 and À181 AP-1 sites during H. pylori infection. Importantly, during wild-type H. pylori infection, we detected increased PEA-3 binding to the À72AP-1 site and decreased PEA-3 binding to the À88 PEA-3 site. However, during infection with the cag PAI and oipA mutants, PEA-3 binding to the À88 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.

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

“…Furthermore, it was shown that Wnt5a signaling recruits JunD to the AP-1 site of the MMP-1 promoter region. These results were consistent with the previous observations Wnt5a and aggressiveness of prostate cancer H Yamamoto et al that the AP-1 site in the promoter region of the MMP-1 gene is critical for its transcriptional regulation (Angel et al, 1987) and that c-Jun and JunD bind to the AP-1 site (Doyle et al, 1997;Wu et al, 2006). In addition, knockdown of Fz2 and Ror2 reduced Wnt5a-dependent invasion and increment in MMP-1 mRNA.…”

“…In addition, Go¨6976 suppressed Wnt5a-dependent JNK activation (Figure 5c), suggesting Wnt5a activates JNK through PKD. c-Jun or JunD has been shown to bind to the AP-1 site in the promoter region of MMP-1 in MKN45 and U937 cells (Doyle et al, 1997;Wu et al, 2006). In a chromatin immunoprecipitation assay, MMP-1 promoter occupancy of JunD was decreased in DU145/Wnt5a knockdown cells compared with DU145/control cells (Figure 5d).…”

Role ofCD14Promoter Polymorphisms inHelicobacter pyloriInfection–Related Gastric Carcinoma

“…A 227-bp region upstream of the major transcriptional start site was found to drive higher reporter activity compared with the 128-bp, 449-bp, 2.3-kb, and 4.2-kb ones in monocytes (47). Stimulatory protein 1 and CCAAT/enhancer-binding protein binding sites, located at nucleotides À110 and À135, were shown to be critical for the CD14 expression (50,51).…”

Functional and Intracellular Signaling Differences Associated with the Helicobacter pylori AlpAB Adhesin from Western and East Asian Strains

“…The levels of c-fos and c-jun mRNAs were measured by SYBR green I-based quantitative real time RT-PCR and, following normalization to glyceraldehyde-3-phosphate dehydrogenase mRNA, were expressed as -fold induction relative to the uninfected control, as previously described (23,24).…”