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

Tianzhi Huang, Angel A. Alvarez, Rajendra P. Pangeni, Craig M. Horbinski, Songjian Lu, Sung-Hak Kim, C. David James, Jeffery J. Raizer, John A. Kessler, Cameron W. Brenann, Erik P. Sulman, Gaetano Finocchiaro, Ming Tan, Ryo Nishikawa, Xinghua Lu, Ichiro Nakano, Bo Hu () and Shi-Yuan Cheng ()
Additional contact information
Tianzhi Huang: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Angel A. Alvarez: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Rajendra P. Pangeni: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Craig M. Horbinski: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Songjian Lu: University of Pittsburgh
Sung-Hak Kim: University of Alabama at Birmingham
C. David James: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Jeffery J. Raizer: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
John A. Kessler: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Cameron W. Brenann: Human Oncology and Pathogenesis Program, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center
Erik P. Sulman: The University of Texas M.D. Anderson Cancer Center
Gaetano Finocchiaro: Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico, Via Celoria 11
Ming Tan: Mitchell Cancer Institute, University of South Alabama
Ryo Nishikawa: Saitama Medical University International Medical Center
Xinghua Lu: University of Pittsburgh
Ichiro Nakano: University of Alabama at Birmingham
Bo Hu: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Shi-Yuan Cheng: Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12885

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