1. A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks.
- Author
-
Lopez-Bertoni H, Kotchetkov IS, Mihelson N, Lal B, Rui Y, Ames H, Lugo-Fagundo M, Guerrero-Cazares H, Quiñones-Hinojosa A, Green JJ, and Laterra J
- Subjects
- Animals, Bcl-2-Like Protein 11 metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms radiotherapy, Cell Death, Cell Dedifferentiation genetics, Cell Line, Tumor, Cellular Reprogramming physiology, Epigenetic Repression, Female, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma radiotherapy, Heterografts, Humans, Mice, Mice, Nude, MicroRNAs administration & dosage, MicroRNAs antagonists & inhibitors, MicroRNAs genetics, Nanoparticles administration & dosage, Neoplasm Proteins genetics, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Neoplastic Stem Cells radiation effects, Neural Stem Cells, Octamer Transcription Factor-3 metabolism, Radiation Tolerance, Random Allocation, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Transfection methods, Tumor Burden, Tumor Stem Cell Assay methods, Up-Regulation, Brain Neoplasms pathology, Cell Survival, Forkhead Box Protein O1 genetics, Genes, Tumor Suppressor, Glioblastoma pathology, MicroRNAs metabolism, Neoplasm Proteins physiology, PTEN Phosphohydrolase genetics, SOXB1 Transcription Factors physiology
- 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., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF