TY - JOUR
T1 - miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles
AU - Bier, Ariel
AU - Hong, Xin
AU - Cazacu, Simona
AU - Goldstein, Hodaya
AU - Rand, Daniel
AU - Xiang, Cunli
AU - Jiang, Wei
AU - Ben-Asher, Hiba Waldman
AU - Attia, Moshe
AU - Brodie, Aharon
AU - She, Ruicong
AU - Poisson, Laila M.
AU - Brodie, Chaya
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85093963481&partnerID=8YFLogxK
U2 - 10.1038/s41419-020-03088-3
DO - 10.1038/s41419-020-03088-3
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C2 - 33093452
AN - SCOPUS:85093963481
SN - 2041-4889
VL - 11
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 10
M1 - 899
ER -
