title: Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma.
abstract: BACKGROUND
  Ionizing irradiation is an effective treatment for malignant glioma (MG); however, a higher rate of recurrence with more aggressive phenotypes is a vital issue. Although epithelial-mesenchymal transition (EMT) is involved in irradiation-induced cancer progression, the role for such phenotypic transition in MG remains unknown.
  
  
  METHODS
  To investigate the mechanism of irradiation-dependent tumor progression in MG, we performed immunohistochemistry (IHC) and qRT-PCR using primary and recurrent MG specimens, MG cell lines, and primary culture cells of MG. siRNA technique was used for MG cell lines.
  
  
  RESULTS
  In 22 cases of clinically recurrent MG, the expression of the mesenchymal markers vimentin and CD44 was found to be increased by IHC. In paired identical MG of 7 patients, the expression of collagen, MMPs, and YKL-40 were also elevated in the recurrent MGs, suggesting the The Cancer Genome Atlas-based mesenchymal subtype. Among EMT regulators, sustained elevation of Snail was observed in MG cells at 21 days after irradiation. Cells exhibited an upregulation of migration, invasion, numbers of focal adhesion, and MMP-2 production, and all of these mesenchymal features were abrogated by Snail knockdown. Intriguingly, phosphorylation of ERK1/2 and GSK-3β were increased after irradiation in a Snail-dependent manner, and TGF-β was elevated in both fibroblasts and macrophages but not in MG cells after irradiation. It was noteworthy that irradiated cells also expressed stemness features such as SOX2 expression and tumor-forming potential in vivo.
  
  
  CONCLUSIONS
  We here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (R.M., M.T., A.E., T.K., M.T., S.T.); Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (L.W., H.N., S.T.); Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Y.O.); Department of Radiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (H.S.); Department of Neurosurgery, Nakamura Memorial Hospital, Sapporo, Japan (T.I).
authors.forename: Roshan
authors.initials: R
authors.lastname: Mahabir
authors.forename: Mishie
authors.initials: M
authors.lastname: Tanino
authors.forename: Aiman
authors.initials: A
authors.lastname: Elmansuri
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Taichi
authors.initials: T
authors.lastname: Kimura
authors.forename: Tamio
authors.initials: T
authors.lastname: Itoh
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shirato
authors.forename: Masumi
authors.initials: M
authors.lastname: Tsuda
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000528:radiation effects*; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000528:radiation effects*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000071250:Snail Family Transcription Factors; D014157:Transcription Factors
keywords: Snail; The Cancer Genome Atlas (TCGA); epithelial-mesenchymal transition (EMT); irradiation; malignant glioma