Endothelial-Monocyte Activating Polypeptide II Suppresses the In Vitro Glioblastoma-Induced Angiogenesis by Inducing Autophagy.
Endothelial-Monocyte Activating Polypeptide II Suppresses the In Vitro Glioblastoma-Induced Angiogenesis by Inducing Autophagy.
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DOI：
10.3389/fnmol.2017.00208
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发表时间：
2017
影响因子：
4.8
通讯作者：
Xue Y
中科院分区：
文献类型：
--
作者：
Li Z;Ma J;Liu L;Liu X;Wang P;Liu Y;Li Z;Zheng J;Chen J;Tao W;Xue Y
向胶质母细胞瘤（GBM）递送治疗剂的障碍是肿瘤诱导的血管生成，其导致异常血管的形成和功能失调的血液-肿瘤屏障。本研究旨在阐明内皮单核细胞激活多肽II（EMAP II）对GBM诱导的血管生成的影响及其可能的机制。结果表明，EMAP II通过诱导细胞自噬，抑制GBM诱导的内皮细胞（GECs）的存活、线粒体膜电位、迁移和管腔形成。通过透射电镜、免疫荧光和Western blot观察EMAP II诱导细胞自噬，并上调微管相关蛋白-1轻链-3（LC 3）-II和p62/SQSTM 1的表达。EMAP Ⅱ可抑制PI 3 K/AKT/mTOR信号通路的活性。此外，EMAP II上调未折叠蛋白反应（UPR）相关蛋白（GRP 78、eIF 2 α和CHOP），这表明暴露于EMAP II的GEC经历了内质网应激。进一步的机制研究发现，EMAP II可抑制miR-96的表达，miR-96可直接靶向UPR相关蛋白的3′-UTR，而miR-96的过表达可通过下调UPR相关蛋白来抑制LC 3和p62/SQSTM 1的表达。此外，EMAP II与miR-96抑制剂的组合显示出对GECs的活力、迁移和体外管形成的抑制作用，这对于血管生成至关重要。总之，我们已经证明了EMAP II通过诱导自噬导致GBM诱导的血管生成减少的事实，这可能有助于建立用于人GBM治疗的潜在策略。
The obstacle in delivering therapeutics to glioblastoma (GBM) is tumor-induced angiogenesis which leads to the formation of abnormal vessels and a dysfunctional blood-tumor barrier. Here, we elucidated the effect of endothelial-monocyte activating polypeptide II (EMAP II) on the GBM-induced angiogenesis as well as its potential mechanisms. Our results proved that EMAP II inhibited the viability, mitochondrial membrane potential, migration and tube formation of GBM-induced endothelial cells (GECs) by inducing cell autophagy, demonstrated by cell viability assay, JC-1 staining assay, transwell assay and tube formation assay, respectively. Cell autophagy was induced by EMAP II through the observation of autophagic vacuoles formation and the up-regulation of microtubule-associated protein-1 light chain-3 (LC3)-II and p62/SQSTM1 expression, demonstrated by transmission electron microscopy analysis, immunofluorescence assay and Western blot assay. The activity of PI3K/AKT/mTOR signal pathway could be inhibited by the EMAP II treatment. Furthermore, unfolded protein response (UPR)-related proteins (GRP78, eIF2α, and CHOP) were up-regulated by EMAP II, which suggest that GECs exposed to EMAP II experienced endoplasmic reticulum stress. Further, mechanistic investigations found that EMAP II reduced the miR-96 expression which could directly target the 3′-UTR of these UPR-related proteins, and over-expression of miR-96 inhibited LC3 and p62/SQSTM1 expression by down-regulating these UPR-related proteins in GECs. Moreover, the combination of EMAP II with miR-96 inhibitor showed the inhibitory effect on the viability, migration, and in vitro tube formation of GECs, which are critical for angiogenesis. Taken together, we have demonstrated the fact that EMAP II resulted in the decreased GBM-induced angiogenesis by inducing autophagy, which might contribute to establishing potential strategies for human GBM treatment.