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*, Shi Yuan Cheng

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Scopus citations

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-κ B 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.

Original languageEnglish (US)
Article number12885
JournalNature communications
Volume7
DOIs
StatePublished - Oct 4 2016

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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