Down-regulation of EBV-LMP1 radio-sensitizes nasal pharyngeal carcinoma cells via NF-κB regulated ATM expression.
Down-regulation of EBV-LMP1 radio-sensitizes nasal pharyngeal carcinoma cells via NF-κB regulated ATM expression.
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DOI：
10.1371/journal.pone.0024647
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Cao Y
中科院分区：
文献类型：
--
作者：
Ma X;Yang L;Xiao L;Tang M;Liu L;Li Z;Deng M;Sun L;Cao Y
EB病毒编码的潜伏膜蛋白1（LMP 1）在大多数与EB病毒相关的人类恶性肿瘤中表达，并且已被认为是EB病毒介导的致癌作用中的主要致癌因子之一。在以前的研究中，我们通过实验证明，DNA酶下调LMP 1表达可以增加细胞和小鼠异种移植NPC模型的放射敏感性。本研究旨在探讨LMP 1基因表达下调对鼻咽癌放射增敏作用的分子机制。结果表明，LMP 1能够上调ATM在NPC中的表达。ATM柔性运动区的生物信息学分析揭示了NF-κB的三个初步结合位点。通过使用NF-κB信号传导的特异性抑制剂和Ikappa B的显性负突变体，显示可以有效地抑制CNE 1-LMP 1细胞中ATM的表达。DNA酶抑制LMP 1表达导致NF-κB DNA结合活性减弱。我们进一步表明，ATM靶向siRNA沉默ATM表达可以增强LMP 1阳性NPC细胞的放射敏感性。总之，我们的研究结果表明，ATM的表达可以通过NF-κB途径由LMP 1通过直接的启动子结合来调节，从而导致NPC的辐射敏感性的改变。
The latent membrane protein 1 (LMP1) encoded by EBV is expressed in the majority of EBV-associated human malignancies and has been suggested to be one of the major oncogenic factors in EBV-mediated carcinogenesis. In previous studies we experimentally demonstrated that down-regulation of LMP1 expression by DNAzymes could increase radiosensitivity both in cells and in a xenograft NPC model in mice. In this study we explored the molecular mechanisms underlying the radiosensitization caused by the down-regulation of LMP1 in nasopharyngeal carcinoma. It was confirmed that LMP1 could up-regulate ATM expression in NPCs. Bioinformatic analysis of the ATM ptomoter region revealed three tentative binding sites for NF-κB. By using a specific inhibitor of NF-κB signaling and the dominant negative mutant of IkappaB, it was shown that the ATM expression in CNE1-LMP1 cells could be efficiently suppressed. Inhibition of LMP1 expression by the DNAzyme led to attenuation of the NF-κB DNA binding activity. We further showed that the silence of ATM expression by ATM-targeted siRNA could enhance the radiosensitivity in LMP1 positive NPC cells. Together, our results indicate that ATM expression can be regulated by LMP1 via the NF-κB pathways through direct promoter binding, which resulted in the change of radiosensitivity in NPCs.
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