Protein kinase C isozymes regulate matrix metalloproteinase-1 expression and cell invasion in Helicobacter pylori infection
نویسندگان
چکیده
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 Ca(2+) 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.
منابع مشابه
Helicobacter pylori infection promotes the invasion and metastasis of gastric cancer through increasing the expression of matrix metalloproteinase-1 and matrix metalloproteinase-10
The aim of this study was to investigate the effect and mechanism of Helicobacter pylori infection in the invasion and metastasis of gastric cancer. Specimens from 80 patients with gastric cancer (of which 20 patients had metastatic gastric cancer) and 40 patients with chronic gastritis were included in this study. H. pylori infection was determined by ELISA and the expression of matrix metallo...
متن کاملBalance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression.
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 ...
متن کاملLinkage between Large intergenic non-coding RNA regulator of reprogramming and Stemness State in Samples with Helicobacter pylori Infection of Gastric Cancer Cells
Background: Long noncoding RNAs (lncRNAs), as non-protein coding transcripts, play key roles in tumor progression and stemness state in many malignancies, as their aberrant expression has been found in gastric cancer (GC) as one of the most common cancer worldwide. LINC-ROR (large intergenic noncoding RNA regulator of reprogramming) identified as an involved lncRNA in human malignancies, howeve...
متن کاملPhosphorylation of phosphatase and tensin homolog induced by Helicobacter pylori promotes cell invasion by activation of focal adhesion kinase
Phosphorylation of the phosphatase and tensin homolog (PTEN) tumor suppressor at Ser380/Thr382/Thr383 residues is a novel mechanism underlying PTEN inactivation in gastric carcinogenesis, which may be triggered by Helicobacter pylori infection. To investigate this further, the effect of H. pylori infection on PTEN phosphorylation and the subsequent activation of focal adhesion kinase (FAK), wer...
متن کاملStudy of Antimetastatic Effect of Genistein Through Inhibition of Expression of Matrix Metalloproteinase in A-549 Cell Line
The lung cancer is one of the most dangerous cancers and is also the leading cause of cancer death worldwide, accounting for about 1.3 million deaths annually. However in clinical practice, lung cancer therapies commonly do with chemotherapy, although it is hard because the lung cancer may progress to metastasis stage. The metastasis of lung cancer is highly dependent of expression of matrix me...
متن کامل