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Helicobacter pylori induces Snail expression through ROS‐mediated activation of Erk and inactivation of GSK‐3β in human gastric cancer cells
Author(s) -
Ngo HoangKieuChi,
Lee Hee Geum,
Piao JuanYu,
Zhong Xiancai,
Lee HaNa,
Han HyeongJun,
Kim Wonki,
Kim DoHee,
Cha YoungNam,
Na HyeKyung,
Surh YoungJoon
Publication year - 2016
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22464
Subject(s) - biology , snail , mapk/erk pathway , helicobacter pylori , cancer cell , cancer research , microbiology and biotechnology , small interfering rna , cancer , signal transduction , cell culture , transfection , ecology , genetics
Helicobacter pylori ( H. pylori ) infection has been known to be implicated in human gastric carcinogenesis. Snail, the zinc‐finger transcription factor known as a key inducer of changes in the cell shape and morphogenetic movement, is aberrantly overexpressed and correlates with lymph node metastasis in gastric cancer. In the present study, we investigated whether H. pylori could induce Snail activation to provoke these changes. Using a cell scatter assay, we noticed that human gastric cancer AGS cells infected with H. pylori underwent morphological changes as well as disruption of cell–cell interaction, which was then reversed by silencing of Snail by use of small interfering RNA (siRNA). In addition, infection with H. pylori resulted in an increased intracellular level of Snail in gastric cancer cells, which was abrogated in the presence of U0126 and LY294002, inhibitors of MEK/Erk and PI3K/Akt pathways, respectively. Cycloheximide pulse‐chase experiments coupled with immunocytochemical analysis revealed that the induction of Snail by H. pylori was regulated at multiple levels, including increased transcription of Snail mRNA, inhibition of protein degradation, and enhancement of nuclear translocation of Snail. Pre‐treatment of AGS cells with N ‐acetylcysteine, a well‐known reactive oxygen species (ROS) scavenger, attenuated the H. pylori ‐induced activation of Erk, its binding to Snail promoter, inactivation of GSK‐3β, and accumulation of Snail. Collectively, these findings suggest that the upregulation of Snail expression induced by H. pylori and transformation to a spindle‐like shape as a consequence in gastric cancer cells are attributable to ROS‐mediated activation of Erk and the inhibition of GSK‐3β signaling. © 2016 Wiley Periodicals, Inc.