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Nat Commun. 2016 Oct 4;7:12885. doi: 10.1038/ncomms12885.

A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways.

Author information

1
Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
2
Department of Neurological Surgery, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
3
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania 15206, USA.
4
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
5
Human Oncology and Pathogenesis Program, Department of Neurosurgery, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
6
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
7
Unit of Molecular Neuro-Oncology, Department of Neuro-Oncology, Fondazione IRCCS Istituto Neurologico, Via Celoria 11, 20133 Milano, Italy.
8
Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
9
Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, 350-1298, Japan.

Abstract

Molecularly defined subclassification is associated with phenotypic malignancy of glioblastoma (GBM). However, current understanding of the molecular basis of subclass conversion that is often involved in GBM recurrence remain rudimentary at best. Here we report that canonical Wnt signalling that is active in proneural (PN) but inactive in mesenchymal (MES) GBM, along with miR-125b and miR-20b that are expressed at high levels in PN compared with MES GBM, comprise a regulatory circuit involving TCF4-miR-125b/miR-20b-FZD6. FZD6 acts as a negative regulator of this circuit by activating CaMKII-TAK1-NLK signalling, which, in turn, attenuates Wnt pathway activity while promoting STAT3 and NF-κB signalling that are important regulators of the MES-associated phenotype. These findings are confirmed by targeting differentially enriched pathways in PN versus MES GBM that results in inhibition of distinct GBM subtypes. Correlative expressions of the components of this circuit are prognostic relevant for clinical GBM. Our findings provide insights for understanding GBM pathogenesis and for improving treatment of GBM.

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