down-regulation of ebv-lmp1 radio-sensitizes nasal pharyngeal carcinoma cells via nf-κb regulated atm expression下调的ebv-lmp1 radio-sensitizes鼻咽癌的细胞通过nf-κb监管atm表达式.pdfVIP

Down-Regulation of EBV-LMP1 Radio-Sensitizes Nasal Pharyngeal Carcinoma Cells via NF-kB Regulated ATM Expression 1.¤ 1,2. 1 1 1 1 1 Xiaoqian Ma , Lifang Yang , Lanbo Xiao , Min Tang , Liyu Liu , Zijian Li , Mengyao Deng , Lunquan Sun2,4*, Ya Cao1,3,4* 1 Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China, 2 Center for Molecular Medicine, Central South University, Xiangya Hospital, Changsha, China, 3 Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, China, 4 Center for Molecular Imaging, Central South University, Changsha, China Abstract Background: 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. Results: 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-kB. By using a specific inhibitor of NF-kB 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-kB DNA binding activity. We further showed tha