miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles.
miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles.
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DOI：
10.1038/s41419-020-03088-3
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发表时间：
2020-10-22
影响因子：
9
通讯作者：
Brodie C
中科院分区：
文献类型：
--
作者：
Bier A;Hong X;Cazacu S;Goldstein H;Rand D;Xiang C;Jiang W;Ben-Asher HW;Attia M;Brodie A;She R;Poisson LM;Brodie C
胶质母细胞瘤（GBM）是一种高度侵袭性的肿瘤，预后差。胶质瘤干细胞（GSC）的一个小亚群与放射抵抗和肿瘤复发有关。在这项研究中，我们分析了与GSC的功能相关的miRNA的表达，这些细胞与人类神经干细胞相比，使用miRNA微阵列分析。这些分析鉴定了与胶质瘤细胞侵袭性、轴突导向和TGF-β信号传导相关的基因簇。miR-504在GSC中的表达明显低于NSC，在GBM中的表达低于正常脑组织，在间充质胶质瘤亚型中的表达进一步降低。miR-504在GSC中的过表达抑制了其自我更新、迁移和间充质标志物的表达。miR-504的抑制作用是通过靶向Grb 10表达介导的，Grb 10在GSC和GBM中充当致癌基因。外源性miR-504的过表达还导致其通过GSC分泌的细胞外囊泡（EV）递送到共培养的小胶质细胞，并且导致GSC诱导的小胶质细胞向M2亚型的极化的消除。最后，miR-504过表达延长了携带GSC衍生的异种移植物的小鼠的存活时间并降低了肿瘤生长。总之，我们确定了在GSC的干细胞和间充质转化中发挥作用的miRNA和潜在的靶网络，以及miR-504/Grb 10通路作为该过程的重要调节因子。miR-504的过表达在GSC中发挥抗肿瘤作用，以及通过EV递送对小胶质细胞极化的旁观者效应。
Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-β signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.
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影响因子：
--
作者：
Giladi ND;Ziv-Av A;Lee HK;Finniss S;Cazacu S;Xiang C;Waldman Ben-Asher H;deCarvalho A;Mikkelsen T;Poisson L;Brodie C
通讯作者：
Brodie C
影响因子：
--
作者：
Jiang W;Finniss S;Cazacu S;Xiang C;Brodie Z;Mikkelsen T;Poisson L;Shackelford DB;Brodie C
通讯作者：
Brodie C
影响因子：
7.3
作者：
Chen Z;Hambardzumyan D
通讯作者：
Hambardzumyan D
影响因子：
14
作者：
Bier, Ariel;Berenstein, Peter;Brodie, Chaya
通讯作者：
Brodie, Chaya
影响因子：
13.3
作者：
Iser, Isabele C.;Pereira, Mariana B.;Wink, Marcia R.
通讯作者：
Wink, Marcia R.