Epstein-Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro
Epstein-Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro
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DOI：
10.1099/vir.0.2008/003392-0
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发表时间：
2008-11-01
影响因子：
3.8
通讯作者：
Young, Lawrence S.
中科院分区：
文献类型：
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作者：
O'Neil, John D.;Owen, Thomas J.;Young, Lawrence S.
EB病毒（EBV）编码的EBNA 1蛋白在所有病毒相关肿瘤中表达，包括鼻咽癌（NPC），在EBV基因组维持，复制和转录中发挥重要作用。先前的研究表明，EBNA 1可能具有与肿瘤发生相关的额外作用，包括增强细胞存活，提高了EBNA 1可能影响细胞基因表达的可能性。我们最近通过基因表达微阵列分析在NPC细胞模型中证明EBNA 1影响一系列细胞基因的表达，包括那些参与转录、翻译和细胞信号传导的基因。在这里，我们首次报道EBNA 1增强了NPC细胞中AP-1转录因子的活性，并证明这是通过EBNA 1与c-Jun和ATF 2的启动子结合，增强其表达来实现的。此外，我们证明了AP-1靶向白细胞介素8，血管内皮生长因子（VEGF）和缺氧不可逆因子-1 α的表达升高，以响应EBNA 1的表达，这增强了体外血管生成试验中微管的形成。此外，我们证实了鼻咽癌活检组织中VEGF和c-Jun和ATF 2磷酸化亚型的升高。这些发现暗示EBNA 1在血管生成过程中，并表明这种病毒蛋白可能直接有助于NPC的发展和侵袭性转移的性质。
The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumours, including nasopharyngeal carcinoma (NPC), where it plays an essential role in EBV genome maintenance, replication and transcription. Previous studies suggest that EBNA1 may have additional effects relevant to oncogenesis, including enhancement of cell survival, raising the possibility that EBNA1 may influence cellular gene expression. We have recently demonstrated by gene expression microarray profiling in an NPC cell model that EBNA1 influences the expression of a range of cellular genes, including those involved in transcription, translation and cell signalling. Here, we report for the first time that EBNA1 enhances activity of the AP-1 transcription factor in NPC cells and demonstrate that this is achieved by EBNA1 binding to the promoters of c-Jun and ATF2, enhancing their expression. In addition, we demonstrate elevated expression of the AP-1 targets interleukin 8, vascular endothelial growth factor (VEGF) and hypoxia-inclucible factor-1 alpha in response to EBNA1 expression, which enhances microtubule formation in an in vitro angiogenesis assay. Furthermore, we confirm elevation of VEGF and the phosphorylated isoforms of c-Jun and ATF2 in NPC biopsies. These findings implicate EBNA1 in the angiogenic process and suggest that this viral protein might directly contribute to the development and aggressively metastatic nature of NPC.