Hypoxia-Induced Glioma-Derived Exosomal miRNA-199a-3p Promotes Ischemic Injury of Peritumoral Neurons by Inhibiting the mTOR Pathway.
Hypoxia-Induced Glioma-Derived Exosomal miRNA-199a-3p Promotes Ischemic Injury of Peritumoral Neurons by Inhibiting the mTOR Pathway.
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缺氧诱导的胶质瘤来源的外泌体 miRNA-199a-3p 通过抑制 mTOR 通路促进瘤周神经元缺血性损伤
DOI：
10.1155/2020/5609637
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发表时间：
2020
影响因子：
--
通讯作者：
Xie R
中科院分区：
文献类型：
--
作者：
Zhao JL;Tan B;Chen G;Che XM;Du ZY;Yuan Q;Yu J;Sun YR;Li XM;Hu J;Xie R
缺氧微环境加重神经元损伤的分子机制尚不清楚。在这项研究中，我们假设外泌体、外泌体mirna和mTOR信号通路可能参与了胶质瘤中低氧性瘤周神经元损伤。高级别胶质瘤（HGG）标本的多模态放射图像、HE和HIF-1α染色显示，瘤周缺氧区与细胞毒性水肿区重叠，并直接与正常神经元接触。在直接或间接共培养系统中，缺氧均可促进正常小鼠海马神经元细胞（HT22）损伤，且缺氧条件下HT22细胞的生长受到C6胶质瘤细胞的抑制。为了给药缺氧诱导的胶质瘤源性外泌体（HIGDE）可能会加重氧糖剥夺(OGD)/再灌注神经元损伤，我们发现外泌体可能是胶质瘤细胞和瘤周围神经元之间的通讯介质，我们进一步发现外泌体miR-199a-3p通过抑制mTOR信号通路介导OGD/再灌注神经元损伤过程。此外，缺氧相关的HIF-1α激活可诱导胶质瘤细胞外泌体中miRNA-199a-3p的上调。综上所述，缺氧诱导的胶质瘤源性外泌体miRNA-199a-3p可通过激活HIF-1α而上调，并可通过抑制mTOR通路加重肿瘤周围神经元的缺血性损伤。
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.
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