Yu H, Xue Y, Wang P, Liu X, Ma J, Zheng J, Li Z, Li Z, Cai H, Liu Y
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.
Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang, People's Republic of China.
Oncogenesis. 2017 Mar 13;6(3):e303. doi: 10.1038/oncsis.2017.7.
Antiangiogenic therapy plays a significant role in combined glioma treatment. However, poor permeability of the blood-tumor barrier (BTB) limits the transport of chemotherapeutic agents, including antiangiogenic drugs, into tumor tissues. Long non-coding RNAs (lncRNAs) have been implicated in various diseases, especially malignant tumors. The present study found that lncRNA X-inactive-specific transcript (XIST) was upregulated in endothelial cells that were obtained in a BTB model in vitro. XIST knockdown increased BTB permeability and inhibited glioma angiogenesis. The analysis of the mechanism of action revealed that the reduction of XIST inhibited the expression of the transcription factor forkhead box C1 (FOXC1) and zonula occludens 2 (ZO-2) by upregulating miR-137. FOXC1 decreased BTB permeability by increasing the promoter activity and expression of ZO-1 and occludin, and promoted glioma angiogenesis by increasing the promoter activity and expression of chemokine (C-X-C motif) receptor 7b (CXCR7). Overall, the present study demonstrates that XIST plays a pivotal role in BTB permeability and glioma angiogenesis, and the inhibition of XIST may be a potential target for the clinical management of glioma.
抗血管生成疗法在联合治疗胶质瘤中发挥着重要作用。然而，血脑肿瘤屏障（BTB）的低通透性限制了包括抗血管生成药物在内的化疗药物向肿瘤组织的转运。长链非编码RNA（lncRNAs）与多种疾病有关，尤其是恶性肿瘤。本研究发现，在体外BTB模型中获得的内皮细胞中，长链非编码RNA X染色体失活特异性转录本（XIST）上调。敲低XIST可增加BTB通透性并抑制胶质瘤血管生成。作用机制分析显示，XIST的减少通过上调miR-137抑制转录因子叉头框C1（FOXC1）和紧密连接蛋白2（ZO-2）的表达。FOXC1通过增加紧密连接蛋白1（ZO-1）和闭合蛋白的启动子活性及表达来降低BTB通透性，并通过增加趋化因子（C-X-C基序）受体7b（CXCR7）的启动子活性及表达来促进胶质瘤血管生成。总体而言，本研究表明XIST在BTB通透性和胶质瘤血管生成中起关键作用，抑制XIST可能是胶质瘤临床治疗的一个潜在靶点。
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