miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles
| Autor: | Moshe Attia, Laila M. Poisson, Hiba Waldman Ben-Asher, Ariel Bier, Daniel Rand, Cunli Xiang, Aharon Brodie, Hodaya Goldstein, Ruicong She, Wei Jiang, Xin Hong, Chaya Brodie, Simona Cazacu |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Cancer Research GRB10 Adaptor Protein Immunology Mice Nude Biology Article Extracellular Vesicles Mice Cellular and Molecular Neuroscience Neural Stem Cells Glioma microRNA Tumor Cells Cultured medicine Bystander effect Animals Humans lcsh:QH573-671 Cancer Oncogene Microglia Brain Neoplasms lcsh:Cytology fungi Mesenchymal stem cell Cell Biology Microarray Analysis medicine.disease Xenograft Model Antitumor Assays Neural stem cell Gene Expression Regulation Neoplastic CNS cancer MicroRNAs medicine.anatomical_structure Neoplastic Stem Cells Cancer research Stem cell Glioblastoma |
| Zdroj: | Cell Death and Disease, Vol 11, Iss 10, Pp 1-14 (2020) Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-020-03088-3 |
| Popis: | Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs. |
| Databáze: | OpenAIRE |
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