The Expression of Epidermal Growth Factor Receptor in H. pylori Infected Intestinal Metaplasia and Gastric Cancer

Abstract

Purpose: The model of gastric cancer (GC) is proposed in which superficial gastritis is followed by chronic gastritis (CG), intestinal metaplasia (IM) and GC. Infection with H. pylori is one of the causalities for GC. Epidermal growth factor receptor (EGFR) is a receptor as a transmembrane glycoprotein with tyrosine kinase activity. It is thought to play a central role in cancer growth and progression. Overexpression of EGFR has been reported in many adenocarcinomas. The inhibitors of EGFR have recently shown antitumor activity and an overall survival benefit in many patients. IL-16, a pleiotrophic cytokine, is involved in the pathophysiological process of chronic inflammatory diseases. The aim of this study is to determine the changes in the expression of EGFR on IM and GC as well as the effect of H. pylori infection and IL-16 on epithelial cell proliferation and EGFR expression in gastric cells in vitro. Methods: Gastric biopsies, were classified by histological findings as CG without H. pylori infection (CG-), CG with H. pylori infection (CG+), IM without H. pylori infection (IM-), IM with H. pylori infection (IM+) and GC with H. pylori infection (GC+). For in vitro studies, AGS cells were incubated with combinations of IL-16 and H. pylori. Gastric epithelial cell proliferation was studied by BrdU uptake. The expression of EGFR was studied by ABC, ELISA and RT-PCR. Results: IL-16 expression was detected in all H. pylori infected gastric mucosa. In CG, EGFR was significantly increased by H. pylori infection (CG−: 7.30 ± 1.38% vs. CG+: 19.22 ± 2.79%, P < 0.01). In H. pylori infected mucosa, there was no significant difference on the EGFR protein levels between CG+ and IM+ (CG+: 19.22 ± 2.79% vs. IM+: 13.53 ± 4.11%), but in H. pylori infected gastric mucosa, EGFR expression increased in GC+ (29.43 ± 3.53%, P < 0.01) than CG+ and IM+. In vitro studies: H. pylori infection alone significantly decreased BrdU uptake and EGFR protein levels. Administration of IL-16 increased BrdU uptake and EGFR protein on AGS cells which was decreased by H. pylori infection. Co-incubation with IL-16 increased the expression of EGFR mRNA on H. pylori infected AGS cells. Pre-incubation with tyrosine kinase inhibitor, AG1478 reduced the expression of EGFR mRNA on H. pylori infected AGS cells which was increased by IL-16 administration. Conclusion: The expression of EGFR in long-term H. pylori infected gastric mucosa may indicate an early stage in carcinogenesis, because it appears before the histologically evident tumor. The expression of IL-16 by H. pylori infection can be a trigger for expression of EGFR, and it may also a factor for gastric carcinogenesis. The combination of chemotherapy drugs with the inhibitors of EGFR may be one of the potential treatments for gastric cancers.Table