Abstract
BackgroundTo investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)-associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-κB (NF-κB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-κB.MethodsFirst, we constructed the plasmid pVLTR-tk, which was regulated by EBV-LMP1 via NF-κB, and then investigated the cytotoxic effect of the pVLTR-tk/GCV on cancer cells, using MTT assays, clonogenic assays, flow cytometry, and animal experiments.ResultsThe activation of TK was increased after transfection of the pVLTR-tk into the EBV-LMP1 positive cells. After GCV treatment, the clonogenicity and survival of the cells substantially declined, and a bystander effect was also observed. The LMP1 positive cells exhibited remarkable apoptosis following pVLTR-tk/GCV treatment, and the pVLTR-tk/GCV restrained tumor growth in vivo for EBV-LMP1 positive cancers.ConclusionThe pVLTR-tk/GCV suicide gene system may be used as a new gene targeting strategy for EBV-associated cancer.
Highlights
To investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-κB (NF-κB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-κB
The pVLTR-tk/GCV suicide gene system may be used as a new gene targeting strategy for EBV-associated cancer
When the effects at the same concentration of GCV are compared, these cells seem to be EBV-LMP1 promote the TK activity of the pVLTR-tk As shown in Figure 1, the TK enzymatic activity of CNE1 cells transfected with the pVLTR-tk was similar to that of untransfected cells, with the cpm volume being about 1 × 105, indicating that the expression of the endogenous tk gene was at a low level
Summary
To investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-κB (NF-κB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-κB. EBV-encoded latent membrane protein 1 (LMP1), which is considered an oncoprotein, plays an important role in the progress of carcinogenesis via regulation of transformation, proliferation, apoptosis, and other biological processes of the cell [2]. EBV-LMP1 has been found to regulate the development and progression of tumors via activated nuclear factor-κB (NF-κB) [3]. Many cis-acting elements are associated with the expression of charge of the HIV gene in the LTR, including two NF-κB motifs. Several studies have indicated that (page number not for citation purposes)
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