Protein kinase C isozymes regulate matrix metalloproteinase-1 expression and cell invasion in Helicobacter pylori infection
- 1Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany
- 2Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
- Correspondence to Dr Olga Sokolova, Medical Faculty, Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany;
Contributors OS: experiments, analysis, interpretation of data and manuscript preparation; MV: biopsy collection, immunohistochemistry; MN: interpretation of data, manuscript preparation, and study supervision.
- Accepted 20 January 2012
- Published Online First 22 March 2012
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.
- cell signalling
- helicobacter pylori
- bacterial infection
- matrix metalloproteinase
- helicobacter pylori—pathogenesis
- nuclear factor kappa b
- signal transduction
- molecular oncology
- gastro-oesophageal reflux disease
- barretts metaplasia
- barretts carcinoma
- gastro-oesphageal junction
- mucosal pathology
- gastric inflammation
- inflammatory bowel disease
- gastrointestinal cancer
- gastric neoplasia
- gastric pre-cancer
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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