Abstract
Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has been known to have oncogenic properties during latent infection in nasopharyngeal carcinoma (NPC). Genetic manipulation of LMP1 expression may provide a novel strategy for the treatment of NPC. DNAzymes are synthetic, single-stranded DNA catalysts that can be engineered to bind and cleave the target mRNA of a disease-causing gene. By targeting the LMP1 mRNA, we successfully obtained a phosphorothioate-modified ‘‘10–23’’ DNAzyme namely DZ1, through screening a series of DNAzymes. DZ1 could significantly down-regulate the expression of LMP1 in NPC cells, inhibit cell proliferation, metastasis, promote apoptosis and enhance radiosensitivity of NPC through interfering signal pathways which are abnormally activated by LMP1, including NF-κB, AP-1 and STAT3 signal pathways. Together, interfering LMP1 signaling pathway could be a promising strategy to target the malignant phenotypes of NPC.
Highlights
Nasopharyngeal carcinoma (NPC), a malignancy arising from the epithelium lining of the posterior nasopharynx, is endemic in Southern China and Southeast Asia, with a striking racial and geographic distribution and has caused very serious health problem in these areas [1]
Epstein-Barr virus (EBV) has been shown to possess some mutations in the latent membrane protein 1 (LMP1) gene and these sequence changes may be associated with the viral oncogenic potential
By targeting the LMP1 mRNA, 13 DNAzymes were transfected into LMP1 positive cells, the data showed that DNAzymes DZ1, DZ7 and DZ10 strongly inhibited LMP1 protein expression compared with the controls, and confirmed that DNAzymes could inhibit LMP1 expression in a dose-dependent manner
Summary
Nasopharyngeal carcinoma (NPC), a malignancy arising from the epithelium lining of the posterior nasopharynx, is endemic in Southern China and Southeast Asia, with a striking racial and geographic distribution and has caused very serious health problem in these areas [1]. This enzyme has a number of features, which endow it with tremendous potential for applications both in vitro and in vivo These include its ability to cleave almost any RNA sequence with high specificity provided it contains a purine-pyrimidine dinucleotide. The ability of the 10-23 DNAzyme to cleave RNA with high efficiency under simulated physiological conditions has fuelled expectation that this agent may have useful biological application in a gene inactivation strategy [18,19]. To explore this potential a number of groups have attempted to examine the activity of DNAzymes in biological systems [20,21,22]. We canvass the use of catalytic DNA in the inhibition of EBV LMP1 gene expression and provide a summary of our research in the field, followed by a discussion of the potential for the use of DNAzymes for therapeutic approaches to NPC
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