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Original article
Protein kinase C isozymes regulate matrix metalloproteinase-1 expression and cell invasion in Helicobacter pylori infection
  1. Olga Sokolova1,
  2. Michael Vieth2,
  3. Michael Naumann1
  1. 1Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany
  2. 2Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
  1. Correspondence to Dr Olga Sokolova, Medical Faculty, Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany; olga.sokolova{at}med.ovgu.de

Abstract

Background Protein kinase C (PKC) signalling is often dysregulated in gastric cancer and therefore represents a potential target in cancer therapy. The Gram-negative bacterium Helicobacter pylori, which colonises the human stomach, plays a major role in the development of gastritis, peptic ulcer and gastric adenocarcinoma.

Objective To analyse the role of PKC isozymes as mediators of H pylori-induced pathogenesis.

Methods PKC phosphorylation was evaluated by immunoblotting and immunohistochemistry. Gene reporter assays, RT-PCR and invasion assays were performed to assess the role of PKC in the regulation of activator protein-1 (AP-1), matrix metalloproteinase-1 (MMP-1) and the invasion of H pylori-infected epithelial cells.

Results H pylori induced phosphorylation of PKC isozymes α, δ, θ in AGS cells, which was accompanied by the phosphorylation of PKC substrates, including PKCμ and myristoylated alanine-rich C kinase substrate (MARCKS), in a CagA-independent manner. Phospholipase C, phosphatidylinositol 3-kinase and Ca2+ were crucial for PKC activation on infection; inhibition of PKC diminished AP-1 induction and, subsequently, MMP-1 expression. Invasion assays confirmed PKC involvement in H pylori-induced MMP-1 secretion. In addition, analysis of biopsies from human gastric mucosa showed increased phosphorylation of PKC in active H pylori gastritis and gastric adenocarcinoma.

Conclusion The targeting of certain PKC isozymes might represent a suitable strategy to interfere with the MMP-1-dependent remodelling of infected tissue and to overcome the invasive behaviour of gastric cancer cells.

  • AP-1
  • CagA
  • c-Fos
  • MARCKS
  • PLC
  • cell signalling
  • adenocarcinoma
  • helicobacter pylori
  • bacterial infection
  • matrix metalloproteinase
  • helicobacter pylori—pathogenesis
  • inflammation
  • nuclear factor kappa b
  • signal transduction
  • molecular oncology
  • gastro-oesophageal reflux disease
  • barretts metaplasia
  • barretts carcinoma
  • gastro-oesphageal junction
  • mucosal pathology
  • gastritis
  • gastric inflammation
  • inflammatory bowel disease
  • gastrointestinal cancer
  • gastric neoplasia
  • gastric pre-cancer

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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Footnotes

  • Funding The work was funded in part by the Deutsche Forschungsgemeinschaft (SFB 854) and the Bundesministerium für Bildung und Forschung (FORSYS, BMBF-0313922) by grants to MN.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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