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Title: Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model
Authors: Sia, K.C.
Huynh, H.
Chung, A.Y.F.
Ooi, L.L.P.J.
Lim, K.H.
Hui, K.M. 
Lam, P.Y.P.
Issue Date: Aug-2013
Citation: Sia, K.C., Huynh, H., Chung, A.Y.F., Ooi, L.L.P.J., Lim, K.H., Hui, K.M., Lam, P.Y.P. (2013-08). Preclinical evaluation of transcriptional targeting strategy for human hepatocellular carcinoma in an orthotopic xenograft mouse model. Molecular Cancer Therapeutics 12 (8) : 1651-1664. ScholarBank@NUS Repository.
Abstract: Gene regulation of many key cell-cycle players in S-, G2 phase, and mitosis results from transcriptional repression in their respective promoter regions during theG0 andG1 phases of cell cycle. Within these promoter regions are phylogenetically conserved sequences known as the cell-cycle-dependent element (CDE) and cellcycle genes homology regions (CHR) sites. Thus, we hypothesize that transcriptional regulation of cell-cycle regulation via the CDE/CHR region together with liver-specific apolipoprotein E (apoE)-hAAT promoter could bring about a selective transgene expression in proliferating human hepatocellular carcinoma. We show that the newly generated vector AH-6CC-L2C could mediate hepatocyte-targeted luciferase gene expression in tumor cells and freshly isolated short-term hepatocellular carcinoma cultures from patient biopsy. In contrast, normal murine and human hepatocytes infected with AH-6CC-L2C expressed minimal or low luciferase activities. In the presence of prodrug 5-fluorocytosine (5-FC), AH-6CC-L2C effectively suppressed the growth of orthotopic hepatocellular carcinoma patient-derived xenograft mouse model via the expression of yeast cytosine deaminase (yCD) that converts 5-FC to anticancer metabolite 5-fluoruracil. More importantly, we show that combination treatment of AH-6CC-L2C with an EZH2 inhibitor, DZNep, that targets EpCAMpositive hepatocellular carcinoma, can bring about a greater therapeutic efficacy compared with a single treatment of virus or inhibitor. Our study showed that targeting proliferating human hepatocellular carcinoma cells through the transcriptional control of therapeutic gene could represent a feasible approach against hepatocellular carcinoma. Mol Cancer Ther; 12(8); 1651-64. © 2013 AACR.
Source Title: Molecular Cancer Therapeutics
ISSN: 15357163
DOI: 10.1158/1535-7163.MCT-13-0056
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