Abstract
The underlying molecular mechanisms that the hypoxic microenvironment could aggravate neuronal injury are still not clear. In this study, we hypothesized that the exosomes, exosomal miRNAs, and the mTOR signaling pathway might be involved in hypoxic peritumoral neuronal injury in glioma. Multimodal radiological images, HE, and HIF-1α staining of high-grade glioma (HGG) samples revealed that the peritumoral hypoxic area overlapped with the cytotoxic edema region and directly contacted with normal neurons. In either direct or indirect coculture system, hypoxia could promote normal mouse hippocampal neuronal cell (HT22) injury, and the growth of HT22 cells was suppressed by C6 glioma cells under hypoxic condition. For administrating hypoxia-induced glioma-derived exosomes (HIGDE) that could aggravate oxygen-glucose deprivation (OGD)/reperfusion neuronal injury, we identified that exosomes may be the communication medium between glioma cells and peritumoral neurons, and we furtherly found that exosomal miR-199a-3p mediated the OGD/reperfusion neuronal injury process by suppressing the mTOR signaling pathway. Moreover, the upregulation of miRNA-199a-3p in exosomes from glioma cells was induced by hypoxia-related HIF-1α activation. To sum up, hypoxia-induced glioma-derived exosomal miRNA-199a-3p can be upregulated by the activation of HIF-1α and is able to increase the ischemic injury of peritumoral neurons by inhibiting the mTOR pathway.
Highlights
Glioblastoma multiforme (GBM) is the most common primary brain malignancy in adults with consistently very poor outcomes [1]
In MRI, the tumor lesion is best defined on contrast-enhanced T1W sequence, while paratumoral vasogenic and/or cytotoxic edema can be clearly identified as hyperintense signals on T2 and Flair sequences (Figure 1(a))
Further 18F-FDG and 18F-FMISO PET/CT scannings were performed in this glioma patient and clearly showed that the regions of paratumoral hypoxia were the same as the regions of edema identified on T2 and Flair
Summary
Glioblastoma multiforme (GBM) is the most common primary brain malignancy in adults with consistently very poor outcomes [1]. It has been reported that the peritumoral hypoxic microenvironment could promote the growth of glioma cells [5]; its underlying molecular mechanisms are still not clear. Exosomes are 40–100 nm nanosized vesicles released into the extracellular space from many cell types, including blood cells [6], and have been reported to play important roles in tumor progression [7]. The mechanism of exosomes in the occurrence and/or regulation of hypoxiainduced glioma cell proliferation and neuronal injury remains unclear. MiRNAs have been confirmed to be altered by hypoxia to target crucial oncogenes and tumor suppressors, which are the hallmarks of tumorigenic processes [9]. It is reasonable to hypothesize that exosomal miRNAs participate in hypoxic exosomal phenomena.
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