期刊
NUCLEIC ACIDS RESEARCH
卷 46, 期 15, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky447
关键词
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资金
- Veterans General Hospitals
- University System of Taiwan Joint Research Program [VGHUST 105-G7-2-2, 106-G7-2-2, 107-G1-2-3, 105-G7-2-1, 106-G7-2-1]
- Ministry of Science and Technology [MOST 106-2622-E-007-014-CC1, 106-2221-E-007-085-MY3, 107-3017-F-007-002]
- Frontier Research Center on Fundamental and Applied Sciences of Matters, from the Featured Areas Research Center Program [MOE 107QR001, 107Q2529E1]
- [VGHUST107-G1-2-3]
Baculovirus (BV) holds promise as a vector for anticancer gene delivery to combat the most common liver cancer-hepatocellular carcinoma (HCC). However, in vivo BV administration inevitably results in BV entry into non-HCC normal cells, leaky anticancer gene expression and possible toxicity. To improve the safety, we employed synthetic biology to engineer BV for transgene expression regulation. We first uncovered that miR-196a and miR-126 are exclusively expressed in HCC and normal cells, respectively, which allowed us to engineer a sensor based on distinct miRNA expression signature. We next assembled a synthetic switch by coupling the miRNA sensor and RNA binding protein L7Ae for translational repression, and incorporated the entire device into a single BV. The recombinant BV efficiently entered HCC and normal cells and enabled cis-acting transgene expression control, by turning OFF transgene expression in normal cells while switching ON transgene expression in HCC cells. Using proapoptotic hBax as the transgene, the switch-based BV selectively killed HCC cells in separate culture and mixed culture of HCC and normal cells. These data demonstrate the potential of synthetic switch-based BV to distinguish HCC and non-HCC normal cells for selective transgene expression control and killing of HCC cells.
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