title: Helicobacter pylori Activates IL-6-STAT3 Signaling in Human Gastric Cancer Cells: Potential Roles for Reactive Oxygen Species.
abstract: BACKGROUND
  Recent studies have shown that Helicobacter pylori (H. pylori) activates signal transducer and activator of transcription 3 (STAT3) that plays an important role in gastric carcinogenesis. However, the molecular mechanism underlying H. pylori-mediated STAT3 activation is still not fully understood. In this study, we investigated H. pylori-induced activation of STAT3 signaling in AGS human gastric cancer cells and the underlying mechanism.
  
  
  METHODS
  AGS cells were cocultured with H. pylori, and STAT3 activation was assessed by Western blot analysis, electrophoretic mobility shift assay and immunocytochemistry. To demonstrate the involvement of reactive oxygen species (ROS) in H. pylori-activated STAT3 signaling, the antioxidant N-acetylcysteine was utilized. The expression and production of interleukin-6 (IL-6) were measured by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. The interaction between IL-6 and IL-6 receptor (IL-6R) was determined by the immunoprecipitation assay.
  
  
  RESULTS
  H. pylori activates STAT3 as evidenced by increases in phosphorylation on Tyr(705) , nuclear localization, DNA binding and transcriptional activity of this transcription factor. The nuclear translocation of STAT3 was also observed in H. pylori-inoculated mouse stomach. In the subsequent study, we found that H. pylori-induced STAT3 phosphorylation was dependent on IL-6. Notably, the increased IL-6 expression and the IL-6 and IL-6R binding were mediated by ROS produced as a consequence of H. pylori infection.
  
  
  CONCLUSIONS
  H. pylori-induced STAT3 activation is mediated, at least in part, through ROS-induced upregulation of IL-6 expression. These findings provide a novel molecular mechanism responsible for H. pylori-induced gastritis and gastric carcinogenesis.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Juan-Yu
authors.initials: JY
authors.lastname: Piao
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hee Geum
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, 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.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Do-Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hyeong-Jun
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hoang-Kieu-Chi
authors.initials: HK
authors.lastname: Ngo
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Sin-Aye
authors.initials: SA
authors.lastname: Park
authors.affiliation: Department of Food and Nutrition, Sungshin Women's University, Seoul, South Korea.
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Woo
authors.affiliation: Department of Health and Functional Food, College of Medicine and Science, Jeonju University, Jeonju, South Korea.
authors.forename: Jeong-Sang
authors.initials: JS
authors.lastname: Lee
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: College of Medicine, Inha University, Incheon, South Korea.
authors.forename: Young-Nam
authors.initials: YN
authors.lastname: Cha
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea. surh@snu.ac.kr.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea. surh@snu.ac.kr.|Cancer Research Institute, Seoul National University, Seoul, South Korea. surh@snu.ac.kr.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D024202:Electrophoretic Mobility Shift Assay; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Helicobacter pylori; gastritis; interleukin-6; interleukin-6 receptor; reactive oxygen species; signal transducer and activator of transcription 3