title: Imaging the impact of Nox4 in cycling hypoxia-mediated U87 glioblastoma invasion and infiltration.
abstract: OBJECTIVE
  We determined the impact of the cycling hypoxia tumor microenvironment on tumor cell invasion and infiltration in U87 human glioblastoma cells and investigated the underlying mechanisms using molecular bio-techniques and imaging.
  
  
  METHODS
  The invasive phenotype of U87 cells and xenografts exposed to experimentally imposed cycling hypoxic stress in vitro and in vivo was determined by the matrigel invasion assay in vitro and dual optical reporter gene imaging in vivo. RNAi-knockdown technology was utilized to study the role of the NADPH oxidase subunit 4 (Nox4) on cycling hypoxia-mediated tumor invasion.
  
  
  RESULTS
  Cycling hypoxic stress significantly promoted tumor invasion in vitro and in vivo. However, Nox4 knockdown inhibited this effect. Nox4-generated reactive oxygen species (ROS) are required for cycling hypoxia-induced invasive potential in U87 cells through the activation of NF-κB- and ERK-mediated stimulation of MMP-9.
  
  
  CONCLUSIONS
  Cycling hypoxia-induced ROS via Nox4 should be considered for therapeutic targeting of tumor cell invasion and infiltration in glioblastoma.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University and Hospital, Taichung, Taiwan. chhsiehcmu@mail.cmu.edu.tw
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.forename: Hao-Teng
authors.initials: HT
authors.lastname: Chang
authors.forename: Wu-Chung
authors.initials: WC
authors.lastname: Shen
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D057054:Molecular Imaging / Q000379:methods*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9