Helicobacter pylori (H. pylori) is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of H. pylori-associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether H. pylori infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in H. pylori-infected Mongolian gerbil gastric tissues and cells co-cultured with H. pylori by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with H. pylori infection. Furthermore, H. pylori infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with H. pylori. Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without H. pylori. The levels of p-AKT and p-GSK3β were increased in H. pylori-infected Mongolian gerbils. In conclusion, the present study demonstrated that H. pylori infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.

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), were evaluated in gastric tissue samples from Mongolian gerbils and in the human gastric epithelial mucosa cell line GES-1 using immunohistochemistry, western blotting and Transwell assays. The in vivo and in vitro results of the present study demonstrated that H. pylori infection induced the phosphorylation and inactivation of PTEN at Ser380/Thr382/383, and the subsequent phosphorylation and activation of FAK at Tyr397. Gastric epithelial cell invasion was also increased. Furthermore, stable expression of a dominant-negative PTEN mutant inhibited the enhanced FAK activation and cell invasion induced by H. pylori infection. These results suggest that the mechanism underlying H. pylori-induced carcinogenesis may involve promoting cell invasion through the phosphorylation of PTEN and the activation of FAK.