Combinational RNAi gene therapy of hepatocellular carcinoma by targeting human EGFR and TERT.

Abstract:

Both human telomerase reverse transcriptase (hTERT) and epidermal growth factor receptor (hEGFR) are ideal targets for RNA interference (RNAi)-based gene therapy of hepatocellular carcinoma. Two shRNA expression plasmids pU6-shTERT and pU6-shEGFR targeting hTERT and hEGFR, respectively, were separately formulated as pegylated immuno-lipopolyplexes, a novel non-viral gene delivery system. In vitro studies showed that when pU6-shTERT and pU6-shEGFR were combined and applied to SMMC-7721 cells, there was a significant additive effect on cytotoxicity as well as cell apoptosis, compared to pU6-shTERT or pU6-shEGFR alone, with a cell viability of 50.9±7.4%, 79.2±3.6% and 77.1±3.6%, respectively, and with a cell apoptotic rate of 44.8±0.9%, 25.1±0.4% and 29.5±0.8%, respectively. In vivo study in SMMC-7721 xenograft tumor model demonstrated that intravenous administration of PILP-formulated pU6-shTERT and pU6-shEGFR caused an additive effect on tumor growth inhibition, compared to pU6-shTERT or pU6-shEGFR alone, with a tumor growth inhibition rate of 74.0%, 36.3% and 46.1%, respectively, which is consistent with the downregulated EGFR and TERT mRNA expression. The results suggest that combinational RNAi gene therapy of hepatocellular carcinoma by targeting human EGFR and TERT with pegylated immuno-lipopolyplexes is a new and good strategy.

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