Background: Gastric cancers are usually associated with and preceded by Helicobacter pylori (HP) infection, gastric atrophy, intestinal metaplasia, and dysplasia. HP infection alters cell kinetics of the gastric mucosa. Both proliferation and apoptosis are increased. Proinflammatory cytokines are responsible for some of these alterations. The mitogen-activated protein kinase (MAPK) signaling pathway has been implicated as a causative factor in these alterations based on in vitro studies. In this study, we investigated the effects of HP infection on gastric mucosal proliferation, apoptotic mechanisms, and the activation status of the MAPK signaling pathway at various stages of gastric carcinogenesis, especially intestinal metaplasia and dysplasia caused by HP infection.
Design: Stomach biopsies representing normal (n=20), HP+ (n=25), HP+ with intestinal metaplasia (n=25), HP+ with dysplasia (n=15) and gastric adenocarcinoma (n=30; 20 HP+ and 10 HP-) cases were selected. Cell proliferation was assessed by proliferating cell nuclear antigen immunostaining. Apoptosis and survival-related markers; cleaved caspase-3, and phospho-MAPK extracellular signal-regulated kinase (ERK) were detected by immunohistochemical methods.
Results: Proliferation index (proliferating cell nuclear antigen) and cleaved caspase-3 expression were higher in the HP+, HP+ with intestinal metaplasia, and HP+ with dysplasia groups than in normal controls (P<0.05). Cleaved caspase-3 activity was also high in the adenocarcinomas. Phospho-MAPK(ERK) expression was increased in the HP+, HP+ with intestinal metaplasia, HP+ with dysplasia and adenocarcinomas compared with the normal control group. Whereas HP- gastric carcinomas had a lower expression of phospho-MAPK.
Conclusions: HP infection increases the proliferative rate of gastric foveolar cells in conjunction with an increased apoptotic rate and activation of MAPK(ERK). MAPK activation seems to be a significant and persistent event in the HP-induced neoplastic transformation.