Selective exosome exclusion of miR-375 by glioma cells promotes glioma progression by activating the CTGF-EGFR pathway.
Selective exosome exclusion of miR-375 by glioma cells promotes glioma progression by activating the CTGF-EGFR pathway.
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神经胶质瘤细胞选择性外泌体排除 miR-375 通过激活 CTGF-EGFR 通路促进神经胶质瘤进展
DOI：
10.1186/s13046-020-01810-9
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发表时间：
2021-01-06
期刊：
影响因子：
--
通讯作者：
Ke Y
中科院分区：
文献类型：
--
作者：
Xu X;Liu Y;Li Y;Chen H;Zhang Y;Liu J;Deng S;Zheng Y;Sun X;Wang J;Chen T;Huang M;Ke Y
外泌体是一种40 - 150nm大小的膜结合细胞外囊泡，由许多细胞类型产生，在维持细胞稳态中起重要作用。外泌体的分泌允许从细胞中选择性地去除有害物质。然而，尚不清楚这一过程是否也发生在胶质瘤细胞中。本文探讨了肿瘤抑制因子miR-375在人胶质瘤细胞中的作用。免疫印迹和qRT-PCR实验证明了miR-375与其靶标结缔组织生长因子（CTGF）之间的功能联系，从而鉴定了潜在的分子途径。用超离心法提取胶质瘤细胞分泌的外泌体，透射电镜观察。然后用qRT-PCR分析miR-375的外泌体表达；外泌体分泌抑制剂GW4869检测miR-375释放的生物学意义。此外，使用荧光标记的外泌体研究了胶质瘤细胞释放miR-375的动力学。最后，在裸鼠原位异种移植模型中检测外泌体miR-375的释放。MiR-375在胶质瘤中表达下调。MiR-375通过抑制ctgf -表皮生长因子受体（EGFR）信号通路抑制胶质瘤的增殖、迁移和侵袭。在胶质瘤患者的人外周血样本中也发现了含有mir -375的外泌体，其水平与疾病进展状态相关。外泌体miR-375分泌影响CTGF-EGFR通路活性。一旦分泌，外泌体miR-375不会被胶质瘤细胞收回。外泌体miR-375的分泌允许持续激活CTGF-EGFR致癌途径，促进胶质瘤细胞的增殖和侵袭。这些发现增强了我们对外泌体生物学的理解，并可能激发新的胶质瘤治疗方法的发展。在线版本包含补充材料，可在10.1186/s13046-020-01810-9获得。
Exosomes are membrane-bound extracellular vesicles of 40–150 nm in size, that are produced by many cell types, and play an important role in the maintenance of cellular homeostasis. Exosome secretion allows for the selective removal of harmful substances from cells. However, it remains unclear whether this process also takes place in glioma cells. Herein, the role of the tumour-suppressor miR-375 was explored in human glioma cells. Immunoblotting and qRT-PCR experiments demonstrated a functional link between miR-375 and its target, connective tissue growth factor (CTGF), which led to the identification of the underlying molecular pathways. The exosomes secreted by glioma cells were extracted by ultracentrifugation and examined by transmission electron microscopy. Exosomal expression of miR-375 was then analysed by qRT-PCR; while the exosome secretion inhibitor, GW4869, was used to examine the biological significance of miR-375 release. Moreover, the dynamics of miR-375 release by glioma cells was investigated using fluorescently labelled exosomes. Finally, exosomal miR-375 release was examined in an orthotopic xenograft model in nude mice. 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 identified in human peripheral blood samples from glioma patients, and their level correlated with disease progression status. Exosomal miR-375 secretion impacted the CTGF-EGFR pathway activity. Once secreted, exosomal miR-375 was not taken back up by glioma cells. 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 development of new glioma therapies. The online version contains supplementary material available at 10.1186/s13046-020-01810-9.
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DOI：
10.3322/caac.21244
发表时间：
2014-09
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Berindan-Neagoe I;Monroig Pdel C;Pasculli B;Calin GA
通讯作者：
Calin GA
神经内分泌肿瘤中的EGFR/TGFα和TGFβ/CTGF信号传导：理论治疗靶标。
影响因子：
4.1
作者：
Kidd M;Schimmack S;Lawrence B;Alaimo D;Modlin IM
通讯作者：
Modlin IM
影响因子：
4.2
作者：
Dinkins MB;Dasgupta S;Wang G;Zhu G;Bieberich E
通讯作者：
Bieberich E
影响因子：
11.8
作者：
Hayashi T;Lombaert IM;Hauser BR;Patel VN;Hoffman MP
通讯作者：
Hoffman MP
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D