EBV-LMP1-targeted DNAzyme restrains nasopharyngeal carcinoma growth in a mouse C666-1 xenograft model.

摘要

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has been demonstrated to be linked to the pathogenesis of nasopharyngeal carcinoma (NPC), one of the most common cancers in southeast Asia as well as in the areas of southern China. RNA-cleaving DNAzymes are catalytic nucleic acids that bind and cleave a target RNA and have been increasingly used to inhibit gene expression. In this study, we aimed to explore the effects of down-regulation of LMP1 by DNAzymes on the NPC growth using a mouse xenograft model derived from human NPC C666-1 cells that constitutively express the LMP1. A specific LMP1-targeted DNAzyme, named DZ509, was synthesized, showing high activities in the inhibition of LMP1 expression, while the control DNAzyme (mutDZ509) had little effect on LMP1 expression. Knockdown of the LMP1 expression by DZ509 reduced cell proliferation and increased apoptosis compared to the cells transfected with mutDZ509. Intratumoral injections of DZ509 into C666-1 xenografts caused a significant suppression of tumor growth compared to mutDZ509-treated xenografts. Examination of the LMP1 expression in the xenografts demonstrated a marked inhibition of LMP1 by DZ509. An antisense oligonucleotide targeting the same site of the LMP1 transcripts was employed in parallel and produced a comparable inhibition on cell proliferation in vitro and tumor growth in vivo. These data demonstrate that LMP1-targeted DNAzyme is efficient in controlling tumor growth in vivo, and thus may have therapeutic implications in the treatment of NPC.