Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2

Abstract

Accumulating evidence has implied that microRNAs (miRNAs) are implicated in glioma progression, and genetically engineered mesenchymal stem cells can help to inhibit tumor growth of glioma. Herein we hypothesized that miR-199a could be delivered by mesenchymal stem cells to glioma cells through exosomes and thus prevent the glioma development by down-regulating ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 (AGAP2). The expression pattern of miR-199a and AGAP2 was characterized in glioma tissues and cells using RNA polymerase chain reaction quantification, immunohistochemical staining and Western blot assays. Mesenchymal stem cells transfected with miR-199a mimic or their derived exosomes were co-cultured with U251 cells. The biological behaviors as well as chemosensitivity of U251 cells were assessed to explore the involvement of miR-199a/AGAP2 in glioma. MiR-199a was poorly expressed in glioma tissue and cells while AGAP2 was highly expressed. Mesenchymal stem cells 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, mesenchymal stem cells over-expressing miR-199a enhanced the chemosensitivity to temozolomide and inhibited the tumor growth in vivo . Taken together, mesenchymal stem cell-derived exosomal miR-199a can inhibit the progression of glioma by down-regulating AGAP2.

Role of Exosomes in the Progression, Diagnosis, and Treatment of Gliomas

“…The NK cell-derived exosomes target GBM cells and play an antitumor role. However, the underlying mechanism remains unclear [ 104 , 112 ]. Hao et al [ 107 ] found that exosomes from the human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) exert partial antitumor activity by regulation of the miR-10a-5p/PTEN signaling.…”

“…Lang et al [ 133 ] isolated the exosomes derived from miR-124a-expressing (via lentiviral expression) MSCs that released miR-124a, which could be used as therapeutic agents against gliomas. A study by Yu et al revealed that the exosomes derived from MSCs transport miR-199a to the glioma cells to downregulate AGAP2 and inhibit glioma cell proliferation, invasion, and metastasis [ 104 ].The overexpression of miR-199a in MSCs improved the chemosensitivity to TMZ, and suppressed glioma cell proliferation. Similarly, Munoz et al demonstrated that the anti-miR-9-delivering exosomes increased the multidrug transporter expression and sensitivity to TMZ in drug-resistant GBM cells, resulting in higher rates of cell death and caspase activity [ 110 ].…”

Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent

“…Another study reported that exosomes from MSCs that overexpress a small interfering RNA against GRP78, which is overexpressed in sorafenib-resistant cancer cells, re-sensitize HCC to sorafenib in vitro and in vivo [150]. Exosomes from miR-119a-overexpressing MSCs suppressed the proliferative, invasive, and migrative activities of glioma cells, resulted in suppression of glioma progression by downregulating ankyrin repeat and PH domain 2 in vitro [151]. Exosomes from miR-16-5p-overexpressing MSCs inhibit the proliferation, migration, and invasion of colorectal cancer cells (CRCs) and promote the apoptosis of such cells by decreasing the expression of integrin α2 in vitro [28].…”

Genetic Engineering as a Strategy to Improve the Therapeutic Efficacy of Mesenchymal Stem/Stromal Cells in Regenerative Medicine

“…Exosomes from BMSCs overexpressing miR-34 were 2-fold more potent than control MSCs in inducing the inhibition of invasion, migration, proliferation and tumorigenesis of glioblastoma cells, in vitro and in vivo ( Wang B. et al, 2019 ). Exosomes from miR-101-3p and miR-199a-overexpressing BMSCs also inhibited invasion, migration and proliferation of oral cancer cells ( Xie et al, 2019 ) and glioma cells ( Yu et al, 2019 ). Furthermore, inhibition of the tumor progression was also observed in vivo in a glioma model ( Yu et al, 2019 ).…”

“…Exosomes from miR-101-3p and miR-199a-overexpressing BMSCs also inhibited invasion, migration and proliferation of oral cancer cells ( Xie et al, 2019 ) and glioma cells ( Yu et al, 2019 ). Furthermore, inhibition of the tumor progression was also observed in vivo in a glioma model ( Yu et al, 2019 ).…”