M2-like tumor-associated macrophages transmit exosomal miR-27b-3p and maintain glioblastoma stem-like cell properties

Abstract

AbstractThere is growing evidence supporting the implications of exosomes-shuttled microRNAs (miRs) in the phenotypes of glioblastoma stem cells (GSCs), whilst the role of exosomal miR-27b-3p remains to be established. Herein, the aim of this study was to investigate the effect of M2 tumor-associated macrophage (TAM)-derived exosomal miR-27b-3p on the function of GSCs. Clinical glioblastoma (GBM) specimens were obtained and GSCs and M2-TAMs were isolated by fluorescence-activated cell sorting (FACS), and exosomes were separated from M2-TAMs. It was observed that M2-TAM-derived exosomes promoted the stem-like properties of GSCs. Gain- and loss- of function assays were then conducted to explore the effects of exosomal miR-27b-3p and the miR-27b-3p/MLL4/PRDM1 axis on GSC phenotypes. A xenograft tumor model of GBM was further established for in vivo substantiation. Inhibition of miR-27b-3p in M2-TAMs reduced exosomal miR-27b-3p transferred into GSCs and consequently diminished GSC viability in vitro and tumor-promoting effects of GSCs in vivo. The interaction among miR-27b-3p, mixed linked leukemia 4 (MLL4), positive regulatory domain I (PRDM1) was validated by dual-luciferase and ChIP assays. MLL4 positively regulated PRDM1 expression by inducing methylation in the PRDM1 enhancer region and ultimately reduced IL-33 expression. miR-27b-3p targeted MLL4/PRDM1 to activate IL-33 and maintain the stem-like function of GSCs. In conclusion, our study elucidated that M2-TAM-derived exosomal miR-27b-3p enhanced the tumorigenicity of GSCs through the MLL4/PRDM1/IL-33 axis.