title: Combinatorial control of transgene expression by hypoxia-responsive promoter and microrna regulation for neural stem cell-based cancer therapy.
abstract: 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.
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Liwan District, Guangzhou City, Guangdong Province 510150, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Liwan District, Guangzhou City, Guangdong Province 510150, China.
authors.forename: Detu
authors.identifier: 0000-0002-9268-1012
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D058953:Neural Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D019076:Transgenes / Q000235:genetics*
chemical_list: D035683:MicroRNAs