M2 macrophage-derived exosomal microRNAs inhibit cell migration and invasion in gliomas through PI3K/AKT/mTOR signaling pathway

Abstract

Background Glioma, the most common primary brain tumor, account Preparing figures for 30 to 40% of all intracranial tumors. Herein, we aimed to study the effects of M2 macrophage-derived exosomal microRNAs (miRNAs) on glioma cells. Methods First, we identified seven differentially expressed miRNAs in infiltrating macrophages and detected the expression of these seven miRNAs in M2 macrophages. We then selected hsa-miR-15a-5p (miR-15a) and hsa-miR-92a-3p (miR-92a) for follow-up studies, and confirmed that miR-15a and miR-92a were under-expressed in M2 macrophage exosomes. Subsequently, we demonstrated that M2 macrophage-derived exosomes promoted migration and invasion of glioma cells, while exosomal miR-15a and miR-92a had the opposite effects on glioma cells. Next, we performed the target gene prediction in four databases and conducted target gene validation by qRT-PCR, western blot and dual luciferase reporter gene assays. Results The results revealed that miR-15a and miR-92a were bound to CCND1 and RAP1B, respectively. Western blot assays demonstrated that interference with the expression of CCND1 or RAP1B reduced the phosphorylation level of AKT and mTOR, indicating that both CCND1 and RAP1B can activate the PI3K/AKT/mTOR signaling pathway. Conclusion Collectively, these findings indicate that M2 macrophage-derived exosomal miR-15a and miR-92a inhibit cell migration and invasion of glioma cells through PI3K/AKT/mTOR signaling pathway.

SNORA70E promotes the occurrence and development of ovarian cancer through pseudouridylation modification of RAP1B and alternative splicing of PARPBP

“…RAP1B is mainly located in the nucleus, and studies have shown that RAP1B expression is associated with tumorigenesis and metastasis in, for example, ovarian cancer, oesophageal squamous cell carcinoma, and gastric cancer, and can act as a tumour promoter by regulating multiple signalling pathways such as Wnt/β‐catenin, PI3K/AKT/mTOR pathway. 18 , 19 , 20 , 21 , 22 We confirmed that the overexpression of SNORA70E induced the expression of the RAP1B protein significantly. Through RIP detection, we found that DKC1 can bind to RAP1B mRNA, thus we suggest that SNORA70E regulates RAP1B mRNA through pseudouracil modification, affecting its protein expression.…”

Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future

“…2-hydroxyglutarate (2HG) produced by IDH1/2 mutation promotes mTOR activity by depleting KDM4A and decreasing DEPTOR protein stability (128), presenting another mechanism of IDH1/2 mutation promoting the genesis of glioma and the possibility of a combination IDH inhibitor and mTOR inhibitor. Simultaneously, the pathway is a hotspot of studies on microRNA, lncRNA, and exosomes because of the extensive functions of noncoding RNA and PI3K/Akt (129)(130)(131)(132). In addition, the downstream targets of the pathway, such as p70S6K, 4EBP1, and eIF-4E, are also druggable targets (133).…”

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

“…It has been verified that M2 macrophages could secret miR-15a and miR-92a via exosomes, and subsequently, miR-15a and miR-92a separately repressed cyclin D1 (CCND1) and Ras-related protein Rap1b (Rap1b). Thus, the PI3K/AKT/mTOR signaling pathway was interfered, and glioma migration and invasion was suppressed (32).…”