Exosomes Derived from microRNA-199a-Overexpressing Mesenchymal Stem Cells Inhibit Glioma Progression by Down-Regulating AGAP2

Background: Glioma is responsible for a high mortality rate globally. Accumulating evidence reveals that microRNAs (miRs) are implicated in glioma progression, and mesenchymal stem cells (MSCs) play a significant part in glioma treatment. Herein we hypothesized that microRNA-199a (miR-199a) could be delivered by MSCs to glioma cells through exosomes and thus affect the glioma progression by regulating Arf GTPase-activating protein-2 (AGAP2). Methods: Bioinformatics analysis was conducted in an attempt to identify the differential genes in glioma. MSCs were infected with overexpressed miR-199a and the exosomes were extracted to co-culture with U251 cells. The expression of AGAP2 was quantified in glioma. The proliferation, invasion, migration and apoptosis of U251 cells were assessed to explore the involvement of miR-199a/AGAP2 in glioma. Furthermore, xenograft in nude mice was employed to evaluate the effect of MSCs-derived exosomal miR-199a on glioma in vivo. Results: MiR-199a was low expressed in glioma tissue and the cell lines while AGAP2 was highly expressed. MiR-199a could target AGAP2. miR-199a over-expression or AGAP2 silencing inhibited the glioma cell invasion, migration as well as proliferation. MSCs delivered miR-199a to the glioma cells via the exosomes, which resulted in the suppression of the proliferation, invasion and migration of glioma cells. Besides, the combination of miR-199a and MSCs enhanced the chemosensitivity to glioma and inhibited the tumor growth in vivo. Conclusion: Taken together, this study provides evidence that miR-199a can be delivered from MSC to the glioma cells through the exosomes and inhibits the progression of glioma by down-regulating AGAP2. This finding is potential to provide a novel target for glioma treatment.   Funding: None. Declaration of Interest: The authors declare that they have no conflict of interest. Ethical Approval: This study was conducted with the approval of the Ethics Committee of Nanfang Hospital, Southern Medical University. All patients signed the informed consent. The animal experiment procedures were performed in strict accordance with the protocols approved by the Institutional Animal Care and Use Committee.