Combinatorial control of transgene expression by hypoxia-responsive promoter and microrna regulation for neural stem cell-based cancer therapy.
Combinatorial control of transgene expression by hypoxia-responsive promoter and microrna regulation for neural stem cell-based cancer therapy.
复制标题
DOI：
10.1155/2014/751397
复制
发表时间：
2014
影响因子：
--
通讯作者：
Zhu D
中科院分区：
文献类型：
--
作者：
Luo Y;Zhu D
神经干细胞（NSC）因其强大的迁移能力、肿瘤嗜性和肿瘤抑制作用，最近成为癌症治疗中最有吸引力的基因递送载体之一。然而，进一步的动物研究发现，成比例的NSC载体在静脉注射后分布到非靶器官，并且非特异性转基因表达在这些器官中导致显著的细胞毒性作用。因此，需要以肿瘤位点特异性方式控制NSC载体内的转基因表达的表达盒。考虑到缺氧是肿瘤微环境的标志，我们开发了一种新的NSC载体平台，将转录靶向与microRNA（miRNA）调控偶联用于肿瘤缺氧靶向。该组合载体采用低氧应答启动子和miRNA的重复靶向序列，所述miRNA在NSC中富集但在低氧诱导后下调以控制转基因表达。这导致相对于使用没有miRNA调节的对照载体显著改善的低氧选择性。因此，将miRNA调节并入转录靶向载体中增加了额外的安全层以防止脱靶转基因表达，并且应该可用于开发具有高靶向特异性的NSC载体用于癌症治疗。
Owing to their strong migratory capacity, tumor tropism, and tumor inhibitory effect, neural stem cells (NSCs) have recently emerged as one of the most attractive gene delivery vectors for cancer therapy. However, further animal studies found that proportional NSC vectors were distributed to nontarget organs after intravenous injection and the nonspecific transgene expression led to significant cytotoxic effects in these organs. Hence, an expression cassette that controls the transgene expression within NSC vectors in a tumor site-specific manner is desired. Considering hypoxia as a hallmark of tumor microenvironment, we have developed a novel NSC vector platform coupling transcriptional targeting with microRNA (miRNA) regulation for tumor hypoxia targeting. This combinatorial vector employed a hypoxia-responsive promoter and repeated targeting sequences of an miRNA that is enriched in NSCs but downregulated upon hypoxia induction to control the transgene expression. This resulted in significantly improved hypoxic selectivity over the use of a control vector without miRNA regulation. Thus, incorporating miRNA regulation into a transcriptional targeting vector adds an extra layer of security to prevent off-target transgene expression and should be useful for the development of NSC vectors with high targeting specifcity for cancer therapy.
登录
查看更多内容
影响因子：
20.1
作者：
Rane S;He M;Sayed D;Vashistha H;Malhotra A;Sadoshima J;Vatner DE;Vatner SF;Abdellatif M
通讯作者：
Abdellatif M
影响因子：
2.5
作者：
Kim Y;Lin Q;Glazer PM;Yun Z
通讯作者：
Yun Z
DOI：
10.4161/cc.8.20.9701
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
影响因子：
5.1
作者：
Shibata, T;Giaccia, AJ;Brown, JM
通讯作者：
Brown, JM
影响因子：
5.2
作者：
Zhao, Donghong;Najbauer, Joseph;Aboody, Karen S.
通讯作者：
Aboody, Karen S.