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. 2023 Aug;28(4):e12987.
doi: 10.1111/hel.12987. Epub 2023 May 4.

Induction of MMP-3 and MMP-9 expression during Helicobacter pylori infection via MAPK signaling pathways

Ioannis Karayiannis  1   2 , Beatriz Martinez-Gonzalez  1 , Eleftherios Kontizas  1 , Androniki Voulgari Kokkota  1 , Kalliopi Petraki  3 , Andreas Mentis  1 , Panagoula Kollia  2 , Dionyssios Nicholas Sgouras  1
Affiliations

Induction of MMP-3 and MMP-9 expression during Helicobacter pylori infection via MAPK signaling pathways

Ioannis Karayiannis et al. Helicobacter. 2023 Aug.

Abstract

Background and aims: Helicobacter pylori (H. pylori)-induced gastric pathology involves remodeling of extracellular matrix mediated by aberrant activity of matrix metalloproteinases (MMPs). We have previously shown that in vitro H. pylori infection leads to MMP-3 and MMP-9 overexpression, associated with phosphorylation of bacterial oncoprotein CagA. We extended these findings in an in vivo model of H. pylori infection and further assessed the involvement of MAPK pathways in MMP expression.

Materials and methods: C57BL/6 mice were infected with H. pylori strains HPARE, HPARE ΔCagA, and SS1, for 6 and 9 months. Transcriptional expression of Mmp-3 and Mmp-9 was evaluated via qPCR while respective protein levels in the gastric mucosa were determined immunohistochemically. Epithelial cell lines AGS and GES-1 were infected with H. pylori strain P12 in the presence of chemical inhibitors of JNK, ERK1/2, and p38 pathways, for 24 h. mRNA and protein expression of MMP-3 and MMP-9 were determined via qPCR and Western blot, respectively.

Results: We observed transcriptional activation of Mmp-3 and Mmp-9 as well as aberrant MMP-3 and MMP-9 protein expression in murine gastric tissue following H. pylori infection. CagA expression was associated with MMP upregulation, particularly during the early time points of infection. We found that inhibition of ERK1/2 resulted in reduced mRNA and protein expression of MMP-3 and MMP-9 during H. pylori infection, in both cell lines. Expressed protein levels of both MMPs were also found reduced in the presence of JNK pathway inhibitors in both cell lines. However, p38 inhibition resulted in a more complex effect, probably attributed to the accumulation of phospho-p38 and increased phospho-ERK1/2 activity due to crosstalk between MAPK pathways.

Conclusions: H. pylori colonization leads to the upregulation of MMP-3 and MMP-9 in vivo, which primarily involves ERK1/2 and JNK pathways. Therefore, their inhibition may potentially offer a protective effect against gastric carcinogenesis and metastasis.

Keywords: Helicobacter pylori; CagA; MAPKs; MMP-3/Stromelysin-1; MMP-9/gelatinase B; matrix metalloproteinases.

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References

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