Glial Cell Line-Derived Neurotrophic Factor (GDNF) Promotes Angiogenesis through the Demethylation of the Fibromodulin (FMOD) Promoter in Glioblastoma.
Glial Cell Line-Derived Neurotrophic Factor (GDNF) Promotes Angiogenesis through the Demethylation of the Fibromodulin (FMOD) Promoter in Glioblastoma.
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DOI：
10.12659/msm.911669
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发表时间：
2018-09-03
期刊：
影响因子：
--
通讯作者：
Sun J
中科院分区：
文献类型：
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作者：
Chen M;Ba H;Lu C;Dai J;Sun J
血管生成在恶性程度高的胶质母细胞瘤的发展过程中起重要作用。以往的研究证实，胶质细胞系来源的神经营养因子（GDNF）和纤维调节素（FMOD）在人胶质母细胞瘤中强烈表达。本研究的目的是探讨GDNF和FMOD在人胶质母细胞瘤血管生成中的作用及其作用的分子机制。研究了GDNF对人胶质瘤细胞系U251血管内皮生长因子（VEGF）的表达和分泌以及人脐静脉内皮细胞（HUVECs）血管生成的影响。探讨gdnf诱导FMOD表达的分子机制。FMOD在gdnf诱导的VEGF表达、分泌和血管生成中的作用也被检测。在本研究中，我们发现GDNF促进了U251细胞中VEGF的表达和分泌。VEGF介导的gdnf诱导的人胶质母细胞瘤血管生成。此外，GDNF显著上调U251细胞中FMOD的表达。从机制上讲，荧光素酶报告基因检测和甲基化特异性PCR （MSP）的结果表明，GDNF促进了FMOD启动子的去甲基化。更重要的是，我们发现FMOD在人胶质母细胞瘤中是GDNF诱导的VEGF表达和血管生成的重要介质。总的来说，我们的数据表明，GDNF通过人胶质母细胞瘤中FMOD启动子的去甲基化促进血管生成，这表明GDNF和FMOD可能是胶质母细胞瘤的潜在治疗靶点。
Angiogenesis plays an important role in the progression of glioblastoma, with a high degree of malignancy. Previous studies have proved that glial cell line-derived neurotrophic factor (GDNF) and fibromodulin (FMOD) are strongly expressed in human glioblastoma. The purpose of this study was to explore the roles of GDNF and FMOD in angiogenesis and the molecular mechanisms underlying these roles in human glioblastoma. The effects of GDNF on the expression and secretion of vascular endothelial growth factor (VEGF) in human glioblastoma cell line U251 and angiogenesis in human umbilical vein endothelial cells (HUVECs) were investigated. The molecular mechanism of GDNF-induced expression of FMOD was explored. The roles of FMOD in GDNF-induced expression and secretion of VEGF and angiogenesis were also examined. In the present study, we showed that GDNF promoted the expression and secretion of VEGF in U251 cells. VEGF mediated GDNF-induced angiogenesis in human glioblastoma. In addition, GDNF significantly upregulated the expression of FMOD in U251 cells. Mechanistically, the results of luciferase reporter assay and methylation-specific PCR (MSP) demonstrated that GDNF facilitated the demethylation of the FMOD promoter. More importantly, we found that FMOD acted as an important mediator in VEGF expression and angiogenesis induced by GDNF in human glioblastoma. Collectively, our data show that GDNF promotes angiogenesis through demethylation of the FMOD promoter in human glioblastoma, indicating that GDNF and FMOD may be potential therapeutic targets for glioblastoma.