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

Lifang Yang, Liyu Liu, Zhijie Xu, Weihua Liao, Deyun Feng, Xin Dong, San Xu, Lanbo Xiao, Jingchen Lu, Xiangjian Luo, Min Tang, Ann M. Bode, Zigang Dong, Lunquan Sun, Ya Cao

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 Ktrans 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.

Original languageEnglish (US)
Pages (from-to)5804-5817
Number of pages14
JournalOncotarget
Volume6
Issue number8
DOIs
StatePublished - 2015

Keywords

  • Angiogenesis
  • DNAzyme
  • JNK
  • LMP1
  • NPC
  • Radiosensitivity

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