EBV-LMP1 targeted DNAzyme enhances radiosensitivity by inhibiting tumor angiogenesis via the JNKs/HIF-1 pathway in nasopharyngeal carcinoma

Abstract

// Lifang Yang 1,2,* , Liyu Liu 1,* , Zhijie Xu 1 , Weihua Liao 3 , Deyun Feng 4 , Xin Dong 1 , San Xu 1 , Lanbo Xiao 1 , Jingchen Lu 1 , Xiangjian Luo 1 , Min Tang 1 , Ann M. Bode 5 , Zigang Dong 5 , Lunquan Sun 2 and Ya Cao 1 1 Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China 2 Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China 3 Department of Radiology, Xiangya Hospital, Central South University, Changsha, China 4 Department of Pathology, Xiangya Hospital, Central South University, Changsha, China 5 The Hormel Institute, University of Minnesota, Austin, MN, USA * These authors contributed equally to this work Correspondence to: Ya Cao, email: // Lunquan Sun, email: // Keywords : LMP1, DNAzyme, radiosensitivity, JNK, angiogenesis Received : August 19, 2014 Accepted : January 03, 2015 Published : January 21, 2015 Abstract LMP1, which is encoded by the Epstein-Barr virus, is proposed to be one of the major oncogenic factors involved in nasopharyngeal carcinoma (NPC). Previous studies demonstrated that down-regulation of LMP1 by LMP1-targeted DNAzyme (DZ1) increases the radiosensitivity of NPC. However, the mechanism by which DZ1 contributes to this radiosensitivity remains unclear. In this study, we determined whether a DZ1 blockade of LMP1 expression has an overall positive effect on the radiotherapy of NPCs by repressing HIF-1/VEGF activity and to investigate the mechanisms underlying LMP1-induced HIF-1 activation in NPC cells. The results showed that DZ1 inhibited the microtubule-forming ability of HUVECs co-cultured with NPC cells, which occurs with the down-regulation of VEGF expression and secretion. Moreover, LMP1 increases phosphorylated JNKs/c-Jun signaling, which is involved in the regulation of HIF-1/VEGF activity. After silencing LMP1 and decreasing phosphorylation of JNKs, NPC cells exhibited an enhanced radiosensitivity. Furthermore, in vivo experiments revealed a significant inhibition of tumor growth and a marked reduction of the K trans parameter, which reflects the condition of tumor micro-vascular permeability. Taken together, our data suggested that VEGF expression is increased by LMP1 through the JNKs/c-Jun signaling pathway and indicated that DZ1 enhances the radiosensitivity of NPC cells by inhibiting HIF-1/VEGF activity.