Abstract
BackgroundGlioma is the most frequent and lethal primary brain malignancy. Amounting evidence has highlighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma.MethodsBioinformatics analysis was firstly used to predict the target genes of miR-148a-3p. Exosomes were then extracted from normal human astrocytes and glioma cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression patterns of miR-148a-3p and ERBB receptor feedback inhibitor 1 (ERRFI1). Dual-luciferase reporter gene assay was applied to verify the direct binding between miR-148a-3p and ERRFI1. Cell counting kit-8 and tube formation assays were further conducted to assess the proliferation and angiogenic properties of human umbilical vein endothelial cells (HUVECs) in the co-culture system with exosomes. Lastly, glioma tumor models were established in BALB/c nude mice to study the role of exosomal miR-148a-3p in vivo.ResultsmiR-148a-3p was highly expressed, while ERRFI1 was poorly expressed in glioma. miR-148a-3p was found to be enriched in glioma cells-derived exosomes and could be transferred to HUVECs via exosomes to promote their proliferation and angiogenesis. ERRFI1 was identified as a target gene of miR-148a-3p. In addition, miR-148a-3p activated the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting ERRFI1. In the co-culture system, our data demonstrated that glioma cells-derived exosomal miR-148a-3p down-regulated ERRFI1 and activated the EGFR/MAPK signaling pathway, so as to promote cell proliferation and angiogenesis. In vivo experimentation further demonstrated that this mechanism was responsible for the promotive role of exosomal miR-148a-3p in tumorigenesis and angiogenesis.ConclusionTaken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.
Highlights
Glioma is the most frequent and lethal primary brain malignancy
Results miR‐148a‐3p is enriched in glioma cells‐derived exosomes Previous literature showed that miR-148a-3p was highlyexpressed in glioma tissues and cells [19], and its dysregulation was correlated with the histological grade of glioma [21]
The results showed that the expression of miR-148a-3p was higher in tumor tissues of patients with anaplastic astrocytoma, anaplastic oligodendrogliomas, oligodendroglioma, astrocytoma, and glioblastoma relative to that of the non-neoplastic brain tissues, with the highest expression exhibited in glioblastoma tissue samples (Fig. 1a)
Summary
Glioma is the most frequent and lethal primary brain malignancy. Amounting evidence has high‐ lighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma. The hard-done work of researchers has identified that cancer stem cells can potentially release exosomal microRNAs (miRNAs or miRs) to mediate cell–cell communication [7]. One such miRNA, miR-148a-3p may play a key role in regulating glioma and angiogenesis. The aberrant expression of miR-148a-3p in glioblastoma cells, and miR-148a in exosomes derived from glioblastoma cells have been proposed to contribute to promotion of cell proliferation and metastasis in glioblastoma (a subtype of glioma) [8]. Researchers have identified that glioma cells-derived exosomal miR-9 can be internalized by vascular endothelial cells to promote angiogenesis [12]. We speculated whether miR-148a could be carried by exosomes of glioma cells to influence the fate of angiogenesis in gliomas
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