title: Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis.
abstract: Glioblastoma (GBM) is the most common brain tumor in adults and the mesenchymal GBM subtype was reported to be the most malignant, presenting severe hypoxia and necrosis. Here, we investigated the possible role of a hypoxic microenvironment for inducing a mesenchymal and invasive phenotype. The exposure of non-mesenchymal SNB75 and U87 cells to hypoxia induced a strong change in cell morphology that was accompanied by enhanced invasive capacity and the acquisition of mesenchymal marker expression. Further analyses showed the induction of HIF1α and HIF2α by hypoxia and exposure to digoxin, a cardiac glycoside known to inhibit HIF1/2 expression, was able to prevent hypoxia-induced mesenchymal transition. ShRNA-mediated knockdown of HIF1α, and not HIF2α, prevented this transition, as well as the knockdown of the EMT transcription factor ZEB1. We provide further evidence for a hypoxia-induced mesenchymal shift in GBM primary material by showing co-localization of GLUT1, ZEB1 and the mesenchymal marker YKL40 in hypoxic regions of the tumor. Collectively, our results identify a HIF1α-ZEB1 signaling axis that promotes hypoxia induced mesenchymal shift and invasion in GBM in a cell line dependent fashion.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Justin V
authors.initials: JV
authors.lastname: Joseph
authors.affiliation: Department of Pathology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Conroy
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Kirill
authors.initials: K
authors.lastname: Pavlov
authors.affiliation: Department of Experimental Hematology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Sontakke
authors.affiliation: Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Tushar
authors.initials: T
authors.lastname: Tomar
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Ellie
authors.initials: E
authors.lastname: Eggens-Meijer
authors.affiliation: Department of Neuroscience, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Veerakumar
authors.initials: V
authors.lastname: Balasubramaniyan
authors.affiliation: Department of Neuro-surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Wagemakers
authors.affiliation: Department of Pathology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Wilfred F A
authors.initials: WF
authors.lastname: den Dunnen
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Electronic address: f.a.e.kruyt@umcg.nl.
authors.forename: Frank A E
authors.initials: FA
authors.lastname: Kruyt
mesh_terms: D054392:Adipokines / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape; D000071451:Chitinase-3-Like Protein 1; D004077:Digoxin / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D009336:Necrosis; D009361:Neoplasm Invasiveness; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D054392:Adipokines; D051792:Basic Helix-Loop-Helix Proteins; D000071451:Chitinase-3-Like Protein 1; D004077:Digoxin; D051272:Glucose Transporter Type 1; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D037102:Lectins; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C084533:CHI3L1 protein, human; C497442:HIF1A protein, human; C495677:SLC2A1 protein, human; C486307:ZEB1 protein, human
keywords: GBM; Invasion; Mesenchymal phenotype; hypoxia