Interferon Regulatory Factor 7 and NPC

干扰素调节因子 7 和 NPC

• 批准号: 6852445
• 负责人: LUWEN ZHANG
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852445
• 关键词: DNA binding protein; Epstein Barr virus; RNA interference; antisense nucleic acid; athymic mouse; carcinoma; clinical research; human tissue; interferons; nasopharyngeal neoplasms; neoplastic cell; neoplastic transformation; oncogenes; oncogenic virus; oncoproteins; recombinant virus; respiratory epithelium; viral carcinogenesis; virus antigen; virus protein; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) infection has been closely associated with the development of nasopharyngeal carcinoma (NPC). How EBV interacts with epithelial cells to achieve transformation is poorly known. Although EBV latent membrane protein 1 (LMP-1) is the viral protein required for EBV transformation of resting B cells and proposed to be a critical player in NPC, the exact role of LMP-1 in the development of NPC is still uncertain. One of the genes regulated by LMP-1 is interferon (IFN) regulatory factor 7 (IRF-7). LMP-1 induces the expression of IRF-7, and activates IRF-7 protein by phosphorylation and nuclear translocation. However, little is known about the functions of the LMP-1 and IRF-7 interaction. We have found that IRF-7 has oncogenic potential and is expressed in human cancers, such as NPC. Also, LMP-1 and IRF-7 have a cooperative effect in transforming rodent cells. We hypothesize that IRF-7 is one of the mediators of LMP-l-induced transformation, and plays a role in the pathogenesis of EBV-associated tumors. The proposed experiments in the grant will address whether IRF-7 and in combination with LMP-1 plays a role in the pathogenesis of NPC. In Aim 1, we will examine the possible linkage between IRF-7 and NPC. The expression and activation status of IRF-7 (i.e., nuclear IRF-7) will be compared between normal epithelial and NPC cells. Also, the relation between LMP-1 and IRF-7 in NPC will be examined with the use of immunostaining. The possible role of IRF-7 and LMP-1 in the development of NPC will be tested in Aim 2. We will make recombinant retroviruses carrying small interfering RNA (siRNA) for IRF-7 or LMP-1, and introduce the viruses to NPC cells, and monitor the development of tumors in nude mice. In addition, we will make the dominant mutant for LMP-1 transformation, and test if the dominant mutant could block the growth of NPC. The results from proposed experiments should shed light on the relation among LMP-1, IRF-7, and NPC. This study would lead to a better understanding of how LMP-1 and IRF-7 interact to participate in viral pathogenesis, latency, and transformation.

描述（申请人提供）：EB病毒（EBV）感染与鼻咽癌（NPC）的发生密切相关。 EBV 如何与上皮细胞相互作用以实现转化尚不清楚。尽管 EBV 潜伏膜蛋白 1 (LMP-1) 是静息 B 细胞 EBV 转化所需的病毒蛋白，并且被认为是 NPC 的关键参与者，但 LMP-1 在 NPC 发展中的确切作用仍不确定。 LMP-1 调节的基因之一是干扰素 (IFN) 调节因子 7 (IRF-7)。 LMP-1诱导IRF-7的表达，并通过磷酸化和核转位激活IRF-7蛋白。然而，人们对 LMP-1 和 IRF-7 相互作用的功能知之甚少。我们发现 IRF-7 具有致癌潜力，并在人类癌症（例如鼻咽癌）中表达。此外，LMP-1和IRF-7在啮齿动物细胞转化中具有协同作用。我们假设 IRF-7 是 LMP-1 诱导转化的介质之一，并在 EBV 相关肿瘤的发病机制中发挥作用。该资助计划中的实验将探讨 IRF-7 及其与 LMP-1 的组合是否在 NPC 的发病机制中发挥作用。在目标 1 中，我们将研究 IRF-7 和 NPC 之间可能的联系。将比较正常上皮细胞和鼻咽癌细胞之间 IRF-7（即核 IRF-7）的表达和激活状态。此外，将使用免疫染色检查鼻咽癌中LMP-1和IRF-7之间的关系。 IRF-7和LMP-1在NPC发展中的可能作用将在目标2中进行测试。我们将制造携带IRF-7或LMP-1的小干扰RNA（siRNA）的重组逆转录病毒，并将病毒引入NPC细胞，并监测裸鼠肿瘤的发展。另外，我们将制作显性突变体用于LMP-1转化，并测试显性突变体是否可以阻断NPC的生长。所提出的实验结果应阐明 LMP-1、IRF-7 和 NPC 之间的关系。这项研究将有助于更好地了解 LMP-1 和 IRF-7 如何相互作用以参与病毒发病机制、潜伏期和转化。