title: EBV-LMP1 targeted DNAzyme enhances radiosensitivity by inhibiting tumor angiogenesis via the JNKs/HIF-1 pathway in nasopharyngeal carcinoma.
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.
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.|Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Liyu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Radiology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Liao
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Deyun
authors.initials: D
authors.lastname: Feng
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: San
authors.initials: S
authors.lastname: Xu
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Lanbo
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Jingchen
authors.initials: J
authors.lastname: Lu
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Luo
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Lunquan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Cancer Research Institute, Key Laboratory of Chinese Ministry of Education, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002277:Carcinoma; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D021881:DNA, Catalytic / Q000494:pharmacology*; D005260:Female; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D010766:Phosphorylation; D011836:Radiation Tolerance; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D021881:DNA, Catalytic; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D051793:Hypoxia-Inducible Factor 1; D014763:Viral Matrix Proteins
keywords: DNAzyme; JNK; LMP1; angiogenesis; radiosensitivity