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A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks
Hernando Lopez-Bertoni1,2, Ivan S Kotchetkov3, Nicole Mihelson4
1Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland. Laterra@kennedykrieger.org Lopezbertoni@kennedykrieger.org.
Abstract:
Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways. SIGNIFICANCE: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p-dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival.
Insights
Researchers discovered a new pathway involving Sox2 and miR-486-5p that helps glioblastoma stem cells survive by suppressing tumor suppressor genes. Inhibiting this pathway may offer a new therapeutic strategy for glioblastoma multiforme (GBM).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma multiforme (GBM) is a heterogeneous cancer with stem-like cells driving tumor propagation.
- Reprogramming factors Oct4 and Sox2 are implicated in GBM stemness, partly via microRNA (miRNA) regulation.
- The precise mechanisms linking transcription factors, miRNAs, and cancer stem cell (CSC) tumor-propagating capacity remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which transcription factors and miRNAs coordinate CSC tumor-propagating capacity in GBM.
- To identify specific miRNAs regulated by Sox2 that contribute to the GBM stem-like phenotype.
- To investigate the therapeutic potential of targeting the identified Sox2-miRNA axis.
Main Methods:
- Identified miR-486-5p as a Sox2-induced miRNA in glioma cell lines and patient-derived neurospheres.
- Assessed the effect of miR-486-5p on self-renewal capacity and apoptosis in GBM neurospheres.
- Utilized nanoparticle delivery of miR-486-5p antagomirs in orthotopic GBM xenografts for in vivo studies.
- Investigated the regulatory relationship between miR-486-5p, PTEN, FoxO1, and BIM.
Main Results:
- miR-486-5p was identified as a Sox2-induced miRNA targeting tumor suppressor genes PTEN and FoxO1.
- Forced miR-486-5p expression enhanced GBM neurosphere self-renewal; inhibition induced cell death via PTEN/BIM.
- In vivo delivery of miR-486-5p antagomirs reduced tumor size and enhanced radiation response in GBM xenografts.
Conclusions:
- A novel Sox2:miR-486-5p axis was defined, crucial for GBM stem cell survival by repressing tumor suppressor pathways.
- miR-486-5p directly links transcriptional drivers of stemness to miRNA-mediated regulation of tumor suppressors.
- This axis represents a potential therapeutic target for glioblastoma treatment.
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