Epstein-Barr virus lytic transactivator Zta enhances chemotactic activity through induction of interleukin-8 in nasopharyngeal carcinoma cells
Epstein-Barr virus lytic transactivator Zta enhances chemotactic activity through induction of interleukin-8 in nasopharyngeal carcinoma cells
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DOI：
10.1128/jvi.02301-07
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发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Chang, Yao
中科院分区：
文献类型：
--
作者：
Hsu, Meichi;Wu, Shih-Yi;Chang, Yao
EB病毒（Epstein-Barr virus，EBV）相关的未分化型鼻咽癌（nasopharyngeal carcinoma，NPC）是一种以白细胞浸润为特征的恶性肿瘤。浸润细胞和肿瘤细胞之间的相互作用被认为是NPC发展的关键。浸润细胞的募集可以由NPC组织中存在的某些趋化因子指导。目前还不清楚EBV裂解性感染是否以及如何调节趋化因子的表达。使用抗体阵列，我们首先发现，从EBV感染的NPC细胞分泌的几种趋化因子在EBV重新激活进入裂解周期后增加，并且白细胞介素-8（IL-8）是上调最显著和一致的趋化因子。进一步的研究表明，EBV裂解性反式激活因子Zta是NPC细胞中IL-8的有效诱导剂，增加分泌的和细胞内的IL-8蛋白以及IL-8 RNA。Zta上调Egr-1，一种参与IL-8上调的细胞转录因子，但Zta诱导的IL-8表达不依赖于Egr-1。Zta反式激活IL-8启动子的能力对于IL-8的诱导是重要的，并且我们已经鉴定了启动子中的两个Zta响应元件。Zta可以在体外与这两种元件结合，也可以在体内被募集到IL-8启动子。DNA结合缺陷型Zta突变体既不能激活IL-8启动子也不能诱导IL-8产生。此外，表达Zta的NPC细胞发挥主要由IL-8介导的增强的趋化活性。由于IL-8不仅参与白细胞浸润，而且参与多种致癌过程，因此本研究提供了EBV裂解性感染与NPC发病之间的潜在联系。
Epstein-Barr virus (EBV)-associated, undifferentiated type of nasopharyngeal carcinoma (NPC) is characterized by intensive leukocyte infiltration. Interaction between the infiltrating cells and the tumor cells has been considered crucial for NPC development. Recruitment of the infiltrates can be directed by certain chemokines present in the NPC tissues. It is unknown whether and how EBV lytic infection regulates expression of the chemokines. Using an antibody array, we first found that several chemokines secreted from EBV-infected NPC cells are increased upon EBV reactivation into the lytic cycle, and interleukin-8 (IL-8) is the chemokine upregulated most significantly and consistently. Further studies showed that the EBV lytic transactivator Zta is a potent inducer of IL-8 in NPC cells, augmenting secreted and intracellular IL-8 proteins, as well as IL-8 RNA. Zta upregulates Egr-1, a cellular transcription factor that has been involved in upregulation of IL-8, but the Zta-induced IL-8 expression is independent of Egr-1. The ability of Zta to transactivate the IL-8 promoter is important for the induction of IL-8, and we have identified two Zta-responsive elements in the promoter. Zta can bind to these two elements in vitro and can also be recruited to the IL-8 promoter in vivo. DNA-binding-defective Zta mutants can neither activate the IL-8 promoter nor induce IL-8 production. In addition, Zta-expressing NPC cells exert enhanced chemotactic activity that is mainly mediated by IL-8. Since IL-8 may contribute to not only leukocyte infiltration but also multiple oncogenic processes, the present study provides a potential link between EBV lytic infection and pathogenesis of NPC.