Linkage between STAT regulation and Epstein-Barr virus gene expression in tumors
Linkage between STAT regulation and Epstein-Barr virus gene expression in tumors
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DOI：
10.1128/jvi.75.6.2929-2937.2001
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发表时间：
2001-03-01
影响因子：
5.4
通讯作者：
Hayward, SD
中科院分区：
文献类型：
--
作者：
Chen, HL;Lee, JM;Hayward, SD
EB病毒(EBV)潜伏基因在淋巴母细胞系中的表达受EBNA2调控。然而，调控EBV相关肿瘤中不表达EBNA2的病毒表达的因素却知之甚少。在EBV相关肿瘤中，EBNA1和LMP1经常被合成。我们发现，位于末端重复序列中的另一个潜伏膜蛋白1(LMP1)启动子L1-tr在鼻咽癌和霍奇金病组织中都是活跃的。对L1-TR和标准ED-L1 LMP1启动子在凝胶迁移率改变分析中的检测表明，这两个启动子都含有功能STAT结合位点。此外，两个LMP1启动子都在报告实验中对JAK-STAT信号的激活做出了反应。共转染JAK1或v-Src或用细胞因子IL-6处理细胞可上调ED-L1和L1-tR报告质粒的表达。共转染显性负的STAT3β表明，STAT3可能是调控EBNA1 QP和LMP1 L1-TR启动子的生物学相关的STAT。相反，ED-L1的LMP1表达没有被STAT3β所抑制，这表明这两个LMP1启动子受不同的STAT家族成员的调控。结合先前JAK-STAT激活QP驱动的EBNA1表达的演示，这将两个在肿瘤中最常见表达的EBV基因置于同一信号转导途径的控制之下。免疫组织化学分析显示，STAT3、STAT5和STAT1在鼻咽癌中呈结构性激活，而在霍奇金病的恶性细胞中则呈结构性激活。我们假设，在免疫能力强的个体中，慢性或异常的STAT激活可能是EBV驱动的肿瘤发生的必要和易感事件。
Epstein-Barr virus (EBV) latency gene expression in lymphoblastoid cell lines is regulated by EBNA2. However, the factors regulating viral expression in EBV-associated tumors that do not express EBNA2 are poorly understood. In EBV-associated tumors, EBNA1 and frequently LMP1 are synthesized. We found that an alternative latent membrane protein 1 (LMP1) promoter, L1-TR, located within the terminal repeats is active in both nasopharyngeal carcinoma and Hodgkin's disease tissues. Examination of the L1-TR and the standard ED-L1 LMP1 promoters in electrophoretic mobility shift assays revealed that both promoters contain functional STAT binding sites. Further, both LMP1 promoters responded in reporter assays to activation of JAK-STAT signaling. Cotransfection of JAK1 or v-Src or treatment of cells with the cytokine interleukin-6 upregulated expression from ED-L1 and L1-TR reporter plasmids. Cotransfection of a dominant negative STAT3 beta revealed that STAT3 is likely to be the biologically relevant STAT for EBNA1 Qp and LMP1 L1-TR promoter regulation. In contrast, LMP1 expression from ED-L1 was not abrogated by STAT3 beta, indicating that the two LMP1 promoters are regulated by different STAT family members. Taken together with the previous demonstration of JAK-STAT activation of Qp driven EBNA1 expression, this places two of the EBV genes most commonly expressed in tumors under the control of the same signal transduction pathway. Immunohistochemical analyses of nasopharyngeal carcinoma tumors revealed that STAT3, STAT5, and STAT1 are constitutively activated in these tumors while STAT3 is constitutively activated in the malignant cells of Hodgkin's disease. We hypothesize that chronic or aberrant STAT activation may be both a necessary and predisposing event for EBV-driven tumorigenesis in immunocompetent individuals.