Helicobacter pylori (H. pylori) Induces Snail Expression via GSK-3β Signaling in Human Gastric Cancer Cells

Abstract

Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related mortality worldwide. Infection with a gastric-specific pathogen Helicobacter pylori (H. pylori) is the principal factor implicated in the etiology of gastric cancer. Snail has been reported to provoke changes in the cell shape or morphogenetic movement. In the present study, we found that H. pylori infection resulted in morphological changes as well as disruption of interaction between human gastric cancer AGS cells. Moreover, H. pylori treatment induced up-regulation of Snail expression through inactivation of glycogen synthase kinase-3β (GSK-3β), an endogenous inhibitor of Snail. The induction of Snail by H. pylori was regulated at multiple levels. These include increased transcription, inhibition of protein degradation, and enhancement of nuclear accumulation of Snail. Pre-treatment of AGS cells with N-acetylcysteine, a reactive oxygen species (ROS) scavenger, reversed the inactivation of GSK-3β signaling and attenuated the up-regulation of Snail by H. pylori. Intriguingly, when Snail was targeted by small interfering RNA (siRNA), the cell-cell interaction of AGS was intact regardless of the presence of H. pylori. These findings suggest that Snail expression induced by H. pylori and hummingbird phenotype as a consequence in human gastric cancer cells were mediated by GSK-3β signaling.