Epstein-Barr virus latent membrane protein 1 induces the chemotherapeutic target, thymidine phosphorylase, via NF-κB and p38 MAPK pathways
Epstein-Barr virus latent membrane protein 1 induces the chemotherapeutic target, thymidine phosphorylase, via NF-κB and p38 MAPK pathways
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DOI：
10.1016/j.cellsig.2010.03.008
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发表时间：
2010-07-01
影响因子：
4.8
通讯作者：
Chang, Yu-Sun
中科院分区：
文献类型：
--
作者：
Chen, Chia-Chun;Chen, Lih-Chyang;Chang, Yu-Sun
在鼻咽癌患者中，胸苷磷酸化酶(TP)的高表达与预后不良密切相关。鼻咽癌是一种与EB病毒(EBV)相关的肿瘤，EBV编码的癌基因产物潜伏膜蛋白1(LMP1)在大约60%的肿瘤组织中表达。然而，以前没有研究研究LMP1是否参与上调鼻咽癌组织中TP的表达。我们在此通过定量RT-PCR和免疫组织化学染色检测表明，LMP1的表达与肿瘤细胞中TP的表达相关。我们进一步证明，LMP1的CTAR1和CTAR2结构域介导了TP的诱导，通过使用LMP1缺失和定点突变的定量RT-PCR和Western印迹分析表明。从机制上讲，LMP1介导的TP诱导可被核因子-kappaB和p38MAPK、显性负性ikappa B和p38的抑制剂以及siRNA介导的p38MAPK的下调所阻断。临床上，鼻咽癌组织中TP、激活的p65和磷酸化的p38MAPK的表达水平之间存在显著的相关性。在功能上，LMP1介导的TP表达增强了鼻咽癌细胞对化疗前体药物5‘-DFUR的敏感性。我们的结果为LMP1介导的NF-kappa B和p38 MAPK信号通路在TP诱导中的作用提供了新的见解，可能为鼻咽癌的治疗提供新的治疗策略。(C)2010 Elsevier Inc.保留所有权利。
High thymidine phosphorylase (TP) expression is significantly correlated with poor prognosis in patients with nasopharyngeal carcinoma (NPC). NPC is an Epstein-Barr Virus (EBV)-associated cancer in which the EBV-encoded oncogene product, latent membrane protein 1 (LMP1), is expressed in approximately 60% of tumor tissues. However, no previous study has examined whether LMP1 is involved in up-regulating TP expression in NPC tissues. We herein show that LMP1 expression is correlated with TP expression in tumor cells, as examined by quantitative RT-PCR and immunohistochemical staining. We further show that the CTAR1 and CTAR2 domains of LMP1 mediate TP induction, as demonstrated by quantitative RT-PCR and Western blot analyses using LMP1 deletion and site-specific mutants. Mechanistically, LMP1-mediated TP induction is abolished by inhibitors of NF-kappa B and p38 MAPK, dominant-negative I kappa B and p38, and siRNA-mediated knockdown of p38 MAPK. Clinically, there were significant correlations among the expression levels of TP, activated p65, and phospho-p38 MAPK in NPC biopsy samples. Functionally, LMP1-mediated induction of TP expression enhanced the sensitivity of NPC cells to the chemotherapeutic prodrug, 5'-DFUR. Our results provide new insights into the roles of LMP1-mediated NF-kappa B and p38 MAPK signaling pathways in TP induction, potentially suggesting new therapeutic strategies for the treatment of NPC. (C) 2010 Elsevier Inc. All rights reserved.