title: A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways.
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.
authors.affiliation: Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Angel A
authors.initials: AA
authors.lastname: Alvarez
authors.affiliation: Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Pangeni
authors.affiliation: 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.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Horbinski
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania 15206, USA.
authors.forename: Songjian
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: J Raizer
authors.affiliation: Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: John
authors.initials: J
authors.lastname: A Kessler
authors.affiliation: Human Oncology and Pathogenesis Program, Department of Neurosurgery, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brenann
authors.affiliation: Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Unit of Molecular Neuro-Oncology, Department of Neuro-Oncology, Fondazione IRCCS Istituto Neurologico, Via Celoria 11, 20133 Milano, Italy.
authors.forename: Gaetano
authors.identifier: 0000-0003-3583-4040
authors.initials: G
authors.lastname: Finocchiaro
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, 350-1298, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania 15206, USA.
authors.forename: Xinghua
authors.identifier: 0000-0002-8599-2269
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D016000:Cluster Analysis; D019295:Computational Biology; D005260:Female; D051157:Frizzled Receptors / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009368:Neoplasm Transplantation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D025341:Principal Component Analysis; D000073940:Transcription Factor 4 / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051157:Frizzled Receptors; D020930:MAP Kinase Kinase Kinases; D035683:MicroRNAs; D000073940:Transcription Factor 4; D000099151:MAP Kinase Kinase Kinase 7; C484687:FZD6 protein, human; C531888:MIRN125 microRNA, human; C000628461:MIRN20b microRNA, human; C532096:TCF4 protein, human