title: Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma.
abstract: Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O(6)-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.
authors.affiliation: Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
authors.forename: Agnete
authors.initials: A
authors.lastname: Svendsen
authors.forename: Joost J C
authors.initials: JJ
authors.lastname: Verhoeff
authors.forename: Heike
authors.initials: H
authors.lastname: Immervoll
authors.forename: Jan C
authors.initials: JC
authors.lastname: Brøgger
authors.forename: Justyna
authors.initials: J
authors.lastname: Kmiecik
authors.forename: Aurelie
authors.initials: A
authors.lastname: Poli
authors.forename: Inger A
authors.initials: IA
authors.lastname: Netland
authors.forename: Lars
authors.initials: L
authors.lastname: Prestegarden
authors.forename: Jesús
authors.initials: J
authors.lastname: Planagumà
authors.forename: Anja
authors.initials: A
authors.lastname: Torsvik
authors.forename: Anneli Bohne
authors.initials: AB
authors.lastname: Kjersem
authors.forename: Per Ø
authors.initials: PØ
authors.lastname: Sakariassen
authors.forename: Jan I
authors.initials: JI
authors.lastname: Heggdal
authors.forename: Wouter R
authors.initials: WR
authors.lastname: Van Furth
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Morten
authors.initials: M
authors.lastname: Lund-Johansen
authors.forename: Per Ø
authors.initials: PØ
authors.lastname: Enger
authors.forename: Joerg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Nicolaas H C
authors.initials: NH
authors.lastname: Brons
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Tronstad
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
authors.forename: Martha
authors.initials: M
authors.lastname: Chekenya
mesh_terms: D000368:Aged; D000941:Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000528:radiation effects; D014408:Biomarkers, Tumor / Q000378:metabolism* / Q000528:radiation effects; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics / Q000528:radiation effects; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D015996:Survival Rate / Q000639:trends; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D014408:Biomarkers, Tumor; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4