A Sox2:miR-486-5p axis regulates survival of GBM cells by inhibiting tumor suppressor networks Journal Article

Authors: Lopez-Bertoni, H.; Kotchetkov, I. S.; Mihelson, N.; Lal, B.; Rui, Y.; Ames, H.; Lugo-Fagundo, M.; Guerrero-Cazares, H.; Quinones-Hinojosa, A.; Green, J. J.; Laterra, J.
Article Title: A Sox2:miR-486-5p axis regulates survival of GBM cells by inhibiting tumor suppressor networks
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 tumorpropagating 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. © 2020 American Association for Cancer Research.
Keywords: controlled study; unclassified drug; human cell; nonhuman; mouse; phenotype; animal tissue; cell death; cell survival; microrna; gene expression; tumor volume; embryo; animal experiment; animal model; bim protein; genetic association; gene function; in vivo study; cytotoxicity; cancer inhibition; gene activation; gene identification; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; ionizing radiation; upregulation; nerve cell culture; transcription factor sox2; transcription factor fkhr; pten gene; cell self-renewal; neurosphere; human; priority journal; article; foxo1 gene; microrna 486 5p; glioblastoma multiforme cell line
Journal Title: Cancer Research
Volume: 80
Issue: 8
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2020-04-15
Start Page: 1644
End Page: 1655
Language: English
DOI: 10.1158/0008-5472.Can-19-1624
PUBMED: 32094299
PROVIDER: scopus
PMCID: PMC7165043
Notes: Article -- Source: Scopus
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