Tenascin-cmediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma
Tenascin-cmediated vasculogenic mimicry formation via regulation of MMP2/MMP9 in glioma
复制标题
胶质瘤中腱蛋白通过调节 MMP2/MMP9 介导的血管生成拟态形成
DOI：
10.1038/s41419-019-2102-3
复制
发表时间：
2019-11-21
影响因子：
9
通讯作者：
Chen, Zhong-ping
中科院分区：
文献类型：
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作者：
Cai, Hai-ping;Wang, Jing;Chen, Zhong-ping
血管生成模拟（VM）是高度侵袭性肿瘤细胞形成的血管样结构，被认为是导致胶质瘤患者抗血管生成治疗失败的几种机制之一。因此，抑制血管生成可能是对抗血管生成阻力的有效治疗方法。本研究旨在证明一种名为Tenascin-c （TNC）的细胞外蛋白参与了VM的形成，TNC敲低可抑制胶质瘤中的VM。TNC随着胶质瘤级别的增加而上调。TNC和VM形成是胶质瘤患者生存的潜在独立预测因子。TNC上调与VM形成相关，外源TNC刺激VM形成。此外，TNC敲低可显著抑制胶质瘤细胞内VM的形成和增殖，降低细胞侵袭性和迁移性。从机制上说，TNC敲低降低了Akt在Ser（473）和Thr（308）位点的磷酸化，随后下调了基质金属蛋白酶2和9，这两种蛋白都是与VM形成和迁移相关的重要蛋白。我们的研究结果表明，TNC在胶质瘤VM的形成中起着重要作用，提示TNC是胶质瘤抗血管生成治疗的潜在治疗靶点。
Vasculogenic mimicry (VM), the formation of vessel-like structures by highly invasive tumor cells, has been considered one of several mechanisms responsible for the failure of anti-angiogenesis therapy in glioma patients. Therefore, inhibiting VM formation might be an effective therapeutic method to antagonize the angiogenesis resistance. This study aimed to show that an extracellular protein called Tenascin-c (TNC) is involved in VM formation and that TNC knockdown inhibits VM in glioma. TNC was upregulated with an increase in glioma grade. TNC and VM formation are potential independent predictors of survival of glioma patients. TNC upregulation was correlated with VM formation, and exogenous TNC stimulated VM formation. Furthermore, TNC knockdown significantly suppressed VM formation and proliferation in glioma cells in vitro and in vivo, with a reduction in cellular invasiveness and migration. Mechanistically, TNC knockdown decreased Akt phosphorylation at Ser(473) and Thr(308) and subsequently downregulated matrix metalloproteinase 2 and 9, both of which are important proteins associated with VM formation and migration. Our results indicate that TNC plays an important role in VM formation in glioma, suggesting that TNC is a potential therapeutic target for anti-angiogenesis therapy for glioma.