Combinational RNAi gene therapy of hepatocellular carcinoma by targeting human EGFR and TERT
Combinational RNAi gene therapy of hepatocellular carcinoma by targeting human EGFR and TERT
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靶向人 EGFR 和 TERT 的肝细胞癌联合 RNAi 基因治疗
DOI：
10.1016/j.ejps.2011.01.004
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发表时间：
2011-03-18
影响因子：
4.6
通讯作者：
Zhang, Yun
中科院分区：
文献类型：
--
作者：
Hu, Yurong;Shen, Yingying;Zhang, Yun
人端粒酶逆转录酶 (hTERT) 和表皮生长因子受体 (hEGFR) 都是基于 RNA 干扰 (RNAi) 的肝细胞癌基因治疗的理想靶点。两个分别靶向 hTERT 和 hEGFR 的 shRNA 表达质粒 pU6-shTERT 和 pU6-shEGFR 分别配制为聚乙二醇化免疫脂多聚复合物，这是一种新型非病毒基因递送系统。体外研究表明，当 pU6-shTERT 和 pU6-shEGFR 联合应用于 SMMC-7721 细胞时，与单独使用 pU6-shTERT 或 pU6-shEGFR 相比，对细胞毒性和细胞凋亡有显着的累加效应，细胞活力分别为 50.9 +/- 7.4%、79.2 +/- 3.6% 和 77.1 +/- 3.6%。细胞凋亡率分别为44.8+/-0.9%、25.1+/-0.4%和29.5+/-0.8%。 SMMC-7721异种移植肿瘤模型的体内研究表明，与单独使用pU6-shTERT或pU6-shEGFR相比，静脉注射PILP配制的pU6-shTERT和pU6-shEGFR对肿瘤生长抑制产生叠加效应，肿瘤生长抑制率分别为74.0%、36.3%和46.1%，这与下调的EGFR和TERT mRNA表达一致。结果表明，通过聚乙二醇化免疫脂多聚复合物靶向人 EGFR 和 TERT 的肝细胞癌组合 RNAi 基因治疗是一种新的良好策略。 (C) 2011 Elsevier B.V. 保留所有权利。
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. (C) 2011 Elsevier B.V. All rights reserved.