Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
PLoS One. 2011;6(11):e24647. doi: 10.1371/journal.pone.0024647. Epub 2011 Nov 9.
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.
EBV 编码的潜伏膜蛋白 1（LMP1）在大多数 EBV 相关的人类恶性肿瘤中表达，被认为是 EBV 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，通过 DNA 酶下调 LMP1 的表达可以提高细胞和小鼠异种移植 NPC 模型中的放射敏感性。
在这项研究中，我们探讨了下调 LMP1 表达在鼻咽癌中引起放射增敏的分子机制。证实 LMP1 可以在上皮性鼻咽癌细胞中上调 ATM 的表达。对 ATM 启动子区域的生物信息学分析显示出三个可能的 NF-κB 结合位点。通过使用 NF-κB 信号的特异性抑制剂和 IkappaB 的显性负突变体，表明 CNE1-LMP1 细胞中的 ATM 表达可以被有效地抑制。DNA 酶下调 LMP1 的表达导致 NF-κB DNA 结合活性的衰减。我们进一步表明，ATM 靶向 siRNA 沉默 ATM 表达可增强 LMP1 阳性 NPC 细胞的放射敏感性。
总之，我们的结果表明，ATM 表达可以通过 LMP1 通过 NF-κB 途径进行调节，通过直接启动子结合，导致 NPC 中放射敏感性的改变。
