Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact.

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Version: Final published version
Serval ID
serval:BIB_307FA56491DD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact.
Journal
Journal of Neuroscience
Author(s)
Sathyan P., Zinn P.O., Marisetty A.L., Liu B., Kamal M.M., Singh S.K., Bady P., Lu L., Wani K.M., Veo B.L., Gumin J., Kassem D.H., Robinson F., Weng C., Baladandayuthapani V., Suki D., Colman H., Bhat K.P., Sulman E.P., Aldape K., Colen R.R., Verhaak R.G., Lu Z., Fuller G.N., Huang S., Lang F.F., Sawaya R., Hegi M., Majumder S.
ISSN
1529-2401 (Electronic)
ISSN-L
0270-6474
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
35
Number
45
Pages
15097-15112
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish
Abstract
UNLABELLED: Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21-Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with Class B tumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21-Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21-Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes.
SIGNIFICANCE STATEMENT: Molecular profiling-based classification of glioblastoma (GBM) into four subtypes has substantially increased our understanding of the biology of the disease and has pointed to the heterogeneous nature of GBM. However, this classification is not mechanism based and its prognostic value is limited. Here, we identify a new mechanism in GBM (the miR-21-Sox2 axis) that can classify ∼50% of patients into two subtypes with distinct molecular, radiological, and pathological characteristics. Importantly, this classification can predict patient survival better than the currently used parameters. Further, analysis of the miR-21-Sox2 relationship in mouse neural stem cells and in the mouse brain at different developmental stages indicates that miR-21 and Sox2 are predominantly expressed in mutually exclusive patterns, suggesting a role in normal neural development.
Keywords
glioblastoma, microRNA-21, neuronal subtype, SOX2
Pubmed
Web of science
Open Access
Yes
Create date
10/01/2016 15:35
Last modification date
20/08/2019 13:15
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