Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells
Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells
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DOI：
10.2353/ajpath.2010.091164
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发表时间：
2010-07-01
影响因子：
6
通讯作者：
Kitamura, Hitoshi
中科院分区：
文献类型：
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作者：
Shimoyamada, Hiroaki;Yazawa, Takuya;Kitamura, Hitoshi
血管内皮生长因子- a （VEGF-A）在肿瘤发生过程中对血管生成、血管通透性和转移至关重要。我们在这里证明，由细胞外信号调节激酶（ERK）途径激活诱导的早期生长反应-1 （EGR-1）激活肺癌细胞中的VEGF-A。在携带突变K-RAS或EGFR基因的腺癌细胞中发现EGR-1表达增加。利用EGR-1诱导的肺癌细胞进行缺氧培养、siRNA实验、荧光素酶测定、染色质免疫沉淀、电泳迁移转移测定和定量RT-PCR等实验表明，EGR-1结合到VEGF-A启动子的近端区域，激活VEGF-A表达，并增强缺氧诱导因子1 α (hi1 α)介导的VEGF-A表达。EGR-1调制器。EGR-1水平升高可迅速诱导NAB-2。人肺腺癌病理样本显示，在携带K-RAS-或egfr -的突变型腺癌中，EGR-1/HIF-1 α和VEGF-A的表达存在相关性，EGR-1和VEGF-A的表达相对升高。EGR-1和VEGF-A的表达随着肿瘤去分化而增加，而HIF-1 α的表达则没有增加。虽然整体上EGR-1与NAB-2表达呈弱相关，但随着肿瘤去分化，NAB-2表达下降，抑制DNA甲基转移酶/组蛋白去乙酰化酶可增加NAB-2在肺癌细胞中的表达，尽管NAB-2启动子未发生表观遗传改变。这些发现表明，EGR-1在肺癌细胞中对VEGF-A的表达起重要作用，而与nab2表达相关的反激活子的表观遗传沉默也可能有助于上调VEGF-A的表达。（美国病理学杂志，2010,177:70-83;DOI: 10.2353/ajpath.2010.091164）
Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1 alpha (HIE-1 alpha)-mediated VEGF-A expression. The EGR-1 modulator,.NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1 alpha and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1 alpha expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression. (Am J Pathol 2010, 177:70-83; DOI: 10.2353/ajpath.2010.091164)