Glioma exosomal microRNA-148a-3p promotes tumor angiogenesis through activating the EGFR/MAPK signaling pathway via inhibiting ERRFI1

Abstract

Background Glioma 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. Methods Bioinformatics 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. Results miR-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. Conclusion Taken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.

The Activation of Mesenchymal Stem Cells by Glioblastoma Microvesicles Alters Their Exosomal Secretion of miR-100-5p, miR-9-5p and let-7d-5p

“…In parallel, while the difference did not appear significant, we found interesting that miR-148a-3p and miR-335-5p were upregulated in TA-MSCs. MiR-148a-3p is a crucial regulator of GBM progression, by promoting tumor stem cell proliferation, migration, invasion and angiogenesis [ 67 , 68 , 69 , 70 , 71 , 72 ], while miR-335-5p has been shown to be upregulated in GBM [ 73 , 74 ].…”

Current Understanding of Exosomal MicroRNAs in Glioma Immune Regulation and Therapeutic Responses

“…Mechanically, miR-9 could target collagen type XVIII alpha 1 chain (COL18A1), thrombospondin 2 (THBS2), patched 1 (PTCH1), and egl-9 family hypoxia-inducible factor 3 (PHD3) to degrade these mRNA, contributing to initiating HIF-1a/VEGF signaling transduction (34). Besides, glioma-derived exosomal miR-148a-3p reinforced angiogenesis through activating the EGFR/MAPK signaling pathway with the ERBB receptor feedback inhibitor 1 (ERRFI1) (35).…”

Roles of Non-coding RNAs and Angiogenesis in Glioblastoma

“…The EGFR/mitogen activated protein kinase (MAPK) pathway is known to contribute to glioma progression (Qu et al, 2012). Recently, Wang et al (2020) evaluated the regulatory role of exosomal miR-148a-3p in glioma. In this research, the exosomes were isolated from glioma cells and healthy human astrocytes, and the expression level of exosomal miR-148a-3p was measured by RT-qPCR.…”

“…Furthermore, inhibition of ERRFI1 activated the EGFR/MAPK pathway via miR-148a-3p. This mechanism was suggested to be responsible for the promotion of angiogenesis and tumorigenesis by exosomal miR-148a-3p (Wang et al, 2020).…”