CSIG-08. A REGULATORY CIRCUIT OF miR-125b/miR-20b AND Wnt SIGNALING CONTROLS GBM PHENOTYPES THROUGH FZD6-MEDIATED PATHWAYS
Year: 2016
Type: conference-abstract
Abstract: Molecular profiling of Glioblastomas (GBM) can segregate patients into distinct subtypes associated with tumor phenotype and tumor recurrence. However, the mechanism underlying subtype conversion, that is associated with recurrence, are poorly understood. Here we report that canonical Wnt signaling induces transcription of miR-125b and miR-20b, and both Wnt signaling and their target miRNAs are enriched in proneural (PN) compared to mesenchymal (MES) GBM. Mechanistically, miR-125b and miR-20b enhance Wnt signaling by simultaneously targeting two negative regulators of the Wnt/β-catenin pathway, APC and FZD6, thereby creating a positive feedback loop. Overexpression of miR-125b and miR-20b in MES GBM spheres markedly reduce their capacity for self-renewal in vitro and the in vivo growth of tumor xenografts. Contrastingly, antagonizing miR-125b or miR-20b by specific inhibitory miRZIPs significantly enhances the ability of PN sphere self-renewal and tumor-initiation, while inducing MES-like properties. FZD6 acts as a major downstream effector for miR-125b and miR-20b in regulating phenotypic properties of GBM. Overexpression of FZD6, but not other members of the FZD family, stimulated CaMKII-TAK1-NLK signaling, which attenuates the canonical Wnt pathway, while promoting mesenchymal-enriched Stat3 and NF-kB signaling. These novel findings are further confirmed in vitro and in vivo, with our tumor xenograft models, which demonstrate targeting differentially enriched signaling pathways in PN versus MES GBM effectively inhibits their capacity for self-renewal and tumor growth. Furthermore, analysis of our own patient samples in addition to The Cancer Genome Atlas (TCGA) GBM data sets reveals the expression of the components of TCF4-miR-125b/20b-FZD6 circuit are prognostic for clinical GBM. Our findings provide critical insights for understanding GBM pathobiology and for improving the treatment of GBM.
Source: Neuro-Oncology
Institutions: Northwestern University, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University of Pittsburgh, Memorial Sloan Kettering Cancer Center, The University of Texas MD Anderson Cancer Center, Fondazione IRCCS Istituto Neurologico Carlo Besta, University of South Alabama, Saitama International Medical Center, Saitama Medical University, University of Alabama at Birmingham
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2587627050