title: Nox4-derived ROS signaling contributes to TGF-β-induced epithelial-mesenchymal transition in pancreatic cancer cells.
abstract: Transforming growth factor (TGF)-β induces epithelial-mesenchymal transition (EMT) in pancreatic adenocarcinoma. In this study, we investigated how NADPH oxidase (Nox) 4-generated reactive oxygen species (ROS) regulate TGF-β-induced EMT in pancreatic cancer cells.
  
  
  METHODS
  Pancreatic cancer cells were transfected with Nox4 siRNAs or PTP1B mutants and subjected to TGF-β-induced EMT assay. Expression of Nox4, TGF-β, and N-cadherin was immunohistochemically-examined with patient tumor samples.
  
  
  RESULTS
  Treatment of pancreatic cancer cells with TGF-β induced Nox4 expression, indicating that Nox4 represents a major source for ROS production. The Nox4 inhibitor diphenylene iodonium and Nox4 siRNAs blocked TGF-β-induced EMT phenotype including morphological changes, augmented migration, and altered expression of E-cadherin and Snail. Furthermore, PTP1B as a redox-sensor for Nox4-derived ROS participated in TGF-β-promoted EMT. Nox4, TGF-β, and N-cadherin were up-regulated in tumors from pancreatic cancer patients.
  
  
  CONCLUSIONS
  These findings suggest that Nox4-derived ROS, at least in part, transmit TGF-β-triggered EMT signals through PTP1B in pancreatic cancer.
authors.affiliation: Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. kamatat@shinshu-u.ac.jp.
authors.forename: Risako
authors.initials: R
authors.lastname: Hiraga
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kato
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Tohru
authors.initials: T
authors.lastname: Kamata
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D058750:Epithelial-Mesenchymal Transition; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D016166:Free Radical Scavengers; D009861:Onium Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C007517:diphenyleneiodonium; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D000111:Acetylcysteine
keywords: EMT; Nox4; TGF-β; pancreatic cancer