A Double-Switch Cell Fusion-Inducible Transgene Expression System for Neural Stem Cell-Based Antiglioma Gene Therapy.
A Double-Switch Cell Fusion-Inducible Transgene Expression System for Neural Stem Cell-Based Antiglioma Gene Therapy.
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用于基于神经干细胞的抗神经胶质瘤基因治疗的双开关细胞融合诱导转基因表达系统
DOI：
10.1155/2015/649080
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发表时间：
2015
影响因子：
4.3
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Luo Y;Zhu D;Lam DH;Huang J;Tang Y;Luo X;Wang S
基于神经干细胞(NSC)的肿瘤靶向基因治疗的最新进展表明，表达人工工程病毒融合蛋白VSV-G H162R的NSC载体可在酸性肿瘤微环境中通过形成合胞体特异性地导致肿瘤细胞死亡，但杀伤效率仍有很大提高空间。鉴于另一种抗肿瘤基因与VSV-G共表达可以增强旁观者效应的观点，提出了一种以细胞融合诱导的方式触发转基因表达的合成调控系统。在这里，我们开发了一个双开关细胞融合诱导转基因表达系统(DoFIT)来驱动VSV-G介导的神经胶质瘤细胞融合的转基因表达。在这个二元系统中，转基因表达由胶质瘤特异性启动子和在神经干细胞中高表达但在胶质瘤细胞中低表达的microRNA(MiR)的靶向序列共同调节。因此，转基因表达被NSC载体中的miR“关闭”，但在与胶质瘤细胞融合后，miR被稀释并失去其抑制作用。同时，在合胞体中，转基因表达被胶质瘤特异性启动子“启动”。我们的体外和体内实验数据表明，DoFIT成功地取消了荧光素酶报告基因在NSC载体中的表达，但在VSV-G介导的NSC-胶质瘤细胞融合后特异性地激活了它。
Recent progress in neural stem cell- (NSC-) based tumor-targeted gene therapy showed that NSC vectors expressing an artificially engineered viral fusogenic protein, VSV-G H162R, could cause tumor cell death specifically under acidic tumor microenvironment by syncytia formation; however, the killing efficiency still had much room to improve. In the view that coexpression of another antitumoral gene with VSV-G can augment the bystander effect, a synthetic regulatory system that triggers transgene expression in a cell fusion-inducible manner has been proposed. Here we have developed a double-switch cell fusion-inducible transgene expression system (DoFIT) to drive transgene expression upon VSV-G-mediated NSC-glioma cell fusion. In this binary system, transgene expression is coregulated by a glioma-specific promoter and targeting sequences of a microRNA (miR) that is highly expressed in NSCs but lowly expressed in glioma cells. Thus, transgene expression is “switched off” by the miR in NSC vectors, but after cell fusion with glioma cells, the miR is diluted and loses its suppressive effect. Meanwhile, in the syncytia, transgene expression is “switched on” by the glioma-specific promoter. Our in vitro and in vivo experimental data show that DoFIT successfully abolishes luciferase reporter gene expression in NSC vectors but activates it specifically after VSV-G-mediated NSC-glioma cell fusion.
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影响因子：
7.5
作者：
Luo Y;Li J;Zhu D;Fan Y;Li S;Sun X
通讯作者：
Sun X
影响因子：
6.4
作者：
Eslahi, NK;Muller, S;Pericle, F
通讯作者：
Pericle, F
影响因子：
12.4
作者：
Wu, Chunxiao;Lin, Jiakai;Wang, Shu
通讯作者：
Wang, Shu
影响因子：
82.9
作者：
Brown, Brian D.;Venneri, Mary Anna;Naldini, Luigi
通讯作者：
Naldini, Luigi
影响因子：
11.2
作者：
Ebert, O;Shinozaki, K;Woo, SLC
通讯作者：
Woo, SLC