Exosomal excretion of miR-3 7 5 promotes glioma progression by activating the CTGF-EGF R pathway

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Abstract
Abstract Background: Exosomes are membrane-bound extracellular vesicles of 40–150 nm produced by many cell types, and playing an important role in the maintenance of cellular homeostasis. Exosome secretion allows for the selective removal of harmful substances from cells. Whether this process also takes place in glioma cells is unknown. Methods: The role of the tumour suppressor miR-375 was explored in human glioma cell lines. Immunoblotting and qRT-PCR experiments demonstrated a functional link between miR-375 and its target, connective tissue growth factor (CTGF), and led to identify the involved molecular pathways. The exosomes secreted by glioma cells were extracted by ultracentrifugation and examined by transmission electron microscopy. The exosomal expression of miR-375 was analyzed by qRT-PCR. The exosome secretion inhibitor, GW4869, was used to study the biological significance of miR-375 release. Moreover, the dynamics of miR-375 release by glioma cells was investigated by using fluorescently labelled exosomes. Finally, exosomal miR-375 release was studied in an orthotopic xenograft model in nude mice. Results: MiR-375 expression was downregulated in gliomas. MiR-375 suppressed glioma proliferation, migration, and invasion by inhibiting the CTGF-epidermal growth factor receptor (EGFR) signalling pathway. MiR-375-containing exosomes were also found in human peripheral blood samples from glioma patients, and their level was correlated with the status of disease progression. Exosomal miR-375 secretion had an impact on the activity of the CTGF-EGFR pathway. Once secreted, exosomal miR-375 was not reuptaken by glioma cells. Conclusions: Exosomal miR-375 secretion allowed for sustained activation of the CTGF-EGFR oncogenic pathway, promoting the proliferation and invasion of glioma cells. These findings enhance our understanding of exosome biology, and may inspire the development of new therapies for glioma.
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