Abstract
Glioblastoma multiforme (GBM) is a grade 4 and the most aggressive form of glioma, with a poor response to current treatments. The expression of microRNAs (miRNAs) is widely dysregulated in various cancers, including GBM. One of the overexpressed miRNAs in GBM is miR-21 which promotes proliferation, invasion and metastatic behaviors of tumor cells. With a size of 30–100 nm, the extracellular vesicles “exosomes” have emerged as a novel and powerful drug delivering systems. Recently, exosomal transfer of miRNAs or anti-miRNAs to tumor cells has introduced a new approach for therapeutic application of miRNAs to combat cancer. Here, we have tried to down-regulate miR-21 expression in glioma cell lines, U87-MG, and C6, by using engineered exosomes, packed with a miR-21-sponge construct. Our data revealed that the engineered exosomes have the potential to suppress miR-21 and consequently to upregulate miR-21 target genes, PDCD4 and RECK. Interestingly, in cells treated with miR-21-sponge exosomes we observed a decline in proliferation and also an elevation in apoptotic rates. Finally, in a rat model of glioblastoma, administrating exosomes loaded with a miR-21-sponge construct leads to a significant reduction in the volume of the tumors. In brief, our findings suggest a new therapeutic strategy to use engineered exosomes to deliver a miR-21-sponge construct to GBM cells, in order to block its malignant behavior.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors/gliomas
In stably transfected HEK-293T cells with the recombinant vectors, the expression level of miR-21 was measured via real-time PCR (Supplementary Figure 1)
The overexpressed miR-21-sponge has the potential to reduce miR-21 level in transfected cells (P < 0.05, Figure 1A), in comparison to the cells stably transfected with an empty tracer vector and untransfected HEK-293T cells
Summary
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors/gliomas. In GBM, similar to other cancer types, the communication between tumor cells and its microenvironment has a big impact on tumor progression; and it provided a new approach for cancer treatment [3, 4]. Exosomes are a Effects of miR-21-Sponge on Glioblastoma Cells subclass of EVs with a size of 30–100 nm, with a recognized role as an important mediator of signaling event between tumor cells and other cells in its microenvironment [8, 9]. One of the exosomes’ components with an important signaling role in cancer progression is microRNAs (miRNAs) [10,11,12,13]
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