Inhibition of hypoxia inducible factor-1α (HIF-1α) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas
Inhibition of hypoxia inducible factor-1α (HIF-1α) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas
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DOI：
10.1007/s11060-005-9103-z
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发表时间：
2006-07-01
影响因子：
3.9
通讯作者：
Gillespie, David
中科院分区：
文献类型：
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作者：
Jensen, Randy L.;Ragel, Brian T.;Gillespie, David
简介：在正常生理条件下，缺氧诱导因子-1 α（HIF-1 α）调节血管内皮生长因子（VEGF），该因子被认为是恶性胶质瘤血管生成的主要介质。我们研究了HIF-1 α对VEGF分泌、肿瘤生长和恶性胶质瘤血管生成的影响。方法：我们研究了175例人脑胶质瘤HIF-1 α及其下游调节蛋白的表达。采用ELISA和Western印迹法检测常氧和缺氧条件下胶质瘤细胞系中HIF-1 α的表达和VEGF的分泌。恶性胶质瘤细胞系用显性阴性HIF-1 α（DN-HIF-1 α）表达载体或针对HIF-1 α基因的siRNA构建体转染。对分离自稳定转染细胞系的具有最高VEGF/HIF-1 α抑制的细胞进行生长研究。MIB-1标记指数和微血管密度（MVD）的测量进行了在体内tumors.Results：HIF-1表达与恶性胶质瘤表型，并不局限于周围坏死，pseudopalisading细胞。VEGF和HIF-1表达在胶质瘤细胞系中即使在常氧下也是高的，并且在暴露于缺氧或生长因子刺激后增加。用DN-HIF-1 α或HIF-1 α siRNA转染的细胞显示HIF-1 α和VEGF分泌减少。在体内，但不是在体外生长减少响应VEGF和HIF-1抑制。HIF-1 siRNA研究显示，胶质瘤细胞系的VEGF分泌以及体外和体内生长减少。两种HIF-1抑制剂均使MVD无变化，但MIB-1增殖指数下降。结论：VEGF和HIF-1 α在恶性胶质瘤中升高。HIF-1 α抑制导致VEGF分泌抑制。HIF-1 α表达影响胶质瘤肿瘤生长，提示其在恶性胶质瘤治疗中的临床应用。
Introduction: Hypoxia inducible factor-1 alpha (HIF-1 alpha) regulates vascular endothelial growth factor (VEGF), the presumed principal mediator of angiogenesis in malignant gliomas, under normal physiologic conditions. We examined the effect of HIF-1 alpha on VEGF secretion, tumor growth, and angiogenesis in malignant gliomas.Methods: We examined 175 human gliomas for expression of HIF-1 alpha and its downstream-regulated proteins. HIF-1 alpha expression and VEGF secretion in glioma cell lines under normoxia and hypoxia were examined using ELISA and Western blot. Malignant glioma cell lines were transfected with dominant-negative HIF-1 alpha (DN-HIF-1 alpha) expression vector or siRNA constructs against the HIF-1 alpha gene. Growth studies were conducted on cells with the highest VEGF/HIF-1 alpha inhibition isolated from stable transfected cell lines. MIB-1-labeling index and microvascular density (MVD) measurements were performed on the in vivo tumors.Results: HIF-1 expression correlates with malignant glioma phenotype and was not confined to perinecrotic, pseudopalisading cells. VEGF and HIF-1 expression was high in glioma cell lines even under normoxia, and increased after exposure to hypoxia or growth factor stimulation. Cells transfected with DN-HIF-1 alpha or HIF-1 alpha siRNA demonstrated decreased HIF-1 alpha and VEGF secretion. In vivo but not in vitro growth decreased in response to VEGF and HIF-1 inhibition. HIF-1 siRNA studies showed decreased VEGF secretion and in vitro and in vivo growth of glioma cell lines. MVD was unchanged but MIB-1 proliferation index decreased for both types of HIF-1 inhibition.Conclusions: VEGF and HIF-1 alpha are elevated in malignant gliomas. HIF-1 alpha inhibition results in VEGF secretion inhibition. HIF-1 alpha expression affects glioma tumor growth, suggesting clinical applications for malignant glioma treatment.