Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma

Roshan Mahabir, Mishie Tanino, Aiman Elmansuri, Lei Wang, Taichi Kimura, Tamio Itoh, Yusuke Ohba, Hiroshi Nishihara, Hiroki Shirato, Masumi Tsuda, Shinya Tanaka

Research output: Contribution to journalArticle

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Abstract

BackgroundIonizing 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.MethodsTo 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.ResultsIn 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.ConclusionsWe here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.

Original languageEnglish
Pages (from-to)671-685
Number of pages15
JournalNeuro-oncology
Volume16
Issue number5
DOIs
Publication statusPublished - 2014 Jan 1
Externally publishedYes

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Glioma
Neuroglia
Epithelial-Mesenchymal Transition
Snails
Matrix Metalloproteinases
Neoplasms
Immunohistochemistry
Glycogen Synthase Kinase 3
Cell Line
Focal Adhesions
Primary Cell Culture
Atlases
Vimentin
Small Interfering RNA
Up-Regulation
Collagen
Fibroblasts
Macrophages
Phosphorylation
Genome

Keywords

  • Epithelial-mesenchymal transition (EMT)
  • Irradiation
  • Malignant glioma
  • Snail
  • The Cancer Genome Atlas (TCGA)

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Mahabir, R., Tanino, M., Elmansuri, A., Wang, L., Kimura, T., Itoh, T., ... Tanaka, S. (2014). Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma. Neuro-oncology, 16(5), 671-685. https://doi.org/10.1093/neuonc/not239

Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma. / Mahabir, Roshan; Tanino, Mishie; Elmansuri, Aiman; Wang, Lei; Kimura, Taichi; Itoh, Tamio; Ohba, Yusuke; Nishihara, Hiroshi; Shirato, Hiroki; Tsuda, Masumi; Tanaka, Shinya.

In: Neuro-oncology, Vol. 16, No. 5, 01.01.2014, p. 671-685.

Research output: Contribution to journalArticle

Mahabir, R, Tanino, M, Elmansuri, A, Wang, L, Kimura, T, Itoh, T, Ohba, Y, Nishihara, H, Shirato, H, Tsuda, M & Tanaka, S 2014, 'Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma', Neuro-oncology, vol. 16, no. 5, pp. 671-685. https://doi.org/10.1093/neuonc/not239
Mahabir, Roshan ; Tanino, Mishie ; Elmansuri, Aiman ; Wang, Lei ; Kimura, Taichi ; Itoh, Tamio ; Ohba, Yusuke ; Nishihara, Hiroshi ; Shirato, Hiroki ; Tsuda, Masumi ; Tanaka, Shinya. / Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma. In: Neuro-oncology. 2014 ; Vol. 16, No. 5. pp. 671-685.
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abstract = "BackgroundIonizing 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.MethodsTo 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.ResultsIn 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.ConclusionsWe here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.",
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T1 - Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma

AU - Mahabir, Roshan

AU - Tanino, Mishie

AU - Elmansuri, Aiman

AU - Wang, Lei

AU - Kimura, Taichi

AU - Itoh, Tamio

AU - Ohba, Yusuke

AU - Nishihara, Hiroshi

AU - Shirato, Hiroki

AU - Tsuda, Masumi

AU - Tanaka, Shinya

PY - 2014/1/1

Y1 - 2014/1/1

N2 - BackgroundIonizing 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.MethodsTo 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.ResultsIn 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.ConclusionsWe here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.

AB - BackgroundIonizing 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.MethodsTo 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.ResultsIn 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.ConclusionsWe here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.

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KW - The Cancer Genome Atlas (TCGA)

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DO - 10.1093/neuonc/not239

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