title: Helicobacter pylori induces Snail expression through ROS-mediated activation of Erk and inactivation of GSK-3β in human gastric cancer cells.
abstract: 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.
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hoang-Kieu-Chi
authors.initials: HK
authors.lastname: Ngo
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hee Geum
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Juan-Yu
authors.initials: JY
authors.lastname: Piao
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Xiancai
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Lee
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hyeong-Jun
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Wonki
authors.initials: W
authors.lastname: Kim
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Do-Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Inha University, Incheon, South Korea.
authors.forename: Young-Nam
authors.initials: YN
authors.lastname: Cha
authors.affiliation: Department of Food and Nutrition, Sungshin Women's University, Seoul, South Korea.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Na
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.|Cancer Research Institute, Seoul National University, Seoul, South Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; D000071250:Snail Family Transcription Factors; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Helicobacter pylori; Snail; epithelial mesenchymal transition; gastric carcinogenesis