Abstract
Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and therapeutic gene in many human cancers. Recently, an adenovirus REIC vector with the super gene expression system (Ad-SGE-REIC) was developed to increase REIC/Dkk-3 expression and enhance therapeutic effects compared with the conventional adenoviral vector (Ad-CAG-REIC). In this study, we investigated the in vitro and in vivo effects of Ad-SGE-REIC on malignant glioma. In U87ΔEGFR and GL261 glioma cells, western blotting confirmed that robust upregulation of REIC/Dkk-3 expression occurred in Ad-SGE-REIC-transduced cells, most notably after transduction at a multiplicity of infection of 10. Cytotoxicity assays showed that Ad-SGE-REIC resulted in a time-dependent and significant reduction in the number of malignant glioma cells attaching to the bottom of culture wells. Xenograft and syngeneic mouse intracranial glioma models treated with Ad-SGE-REIC had significantly longer survival than those treated with the control vector Ad-LacZ or with Ad-CAG-REIC. This study demonstrated the anti-glioma effect of Ad-SGE-REIC, which may represent a promising strategy for the treatment of malignant glioma.
Highlights
There are only a few reports on the immunological reaction to secretory or exogenous REIC/Dkk-3 protein[11,12,13]
This study focused on the anti-glioma activity of Ad-super gene expression (SGE)-REIC, a novel adenoviral vector that produces higher protein expression and a superior therapeutic effect compared with the conventional system (Ad-CAG-REIC)
REIC/Dkk-3 expression was upregulated in Ad-SGE-REIC-transduced glioma cells, and the most prominent effect was obtained after transduction at 10 multiplicity of infection (MOI)
Summary
There are only a few reports on the immunological reaction to secretory or exogenous REIC/Dkk-3 protein[11,12,13]. We developed a novel adenoviral vector expressing REIC/Dkk-3, based on the cytomegalovirus (CMV) promoter-driven super gene expression system (Ad-SGE-REIC), by inserting the triple translational enhancer sequences of human telomerase reverse transcriptase (hTERT), Simian virus 40 (SV40), and CMV, downstream of the bovine growth hormone polyadenylation (BGH polyA) sequence. This gene expression cassette was named the super gene expression (SGE) system[18]. Because the CMV promoter-SGE system facilitates more potent gene expression, Ad-SGE-REIC is superior to conventional adenoviral systems with respect to REIC protein expression and therapeutic effects in prostate, renal, and cervical cancer and in malignant mesothelioma. We further tested the effect of the activated immune system in a syngeneic mouse glioma model
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