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Journal of Zhejiang University SCIENCE B

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Optimized TTF-1 core promoter-driven miRNA-7 expression effectively inhibits the growth of human NSCLC cells


Author(s):  Shipeng CHEN, Lian GUAN, Xu ZHAO, Jing YANG, Longqing CHEN, Mengmeng GUO, Juanjuan ZHAO, Chao CHEN, Ya ZHOU, Yong HAN, Lin XU

Affiliation(s):  Special Key Laboratory of Gene Detection and Therapy & more

Corresponding email(s):  xulinzhouya@163.com, Chinahotfog@126.com, zhouyazmc@163.com

Key Words:  Lung cancer; TTF-1; Promoter; miR-7; NF-1


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Shipeng CHEN, Lian GUAN, Xu ZHAO, Jing YANG, Longqing CHEN, Mengmeng GUO, Juanjuan ZHAO, Chao CHEN, Ya ZHOU, Yong HAN, Lin XU. Optimized TTF-1 core promoter-driven miRNA-7 expression effectively inhibits the growth of human NSCLC cells[J]. Journal of Zhejiang University Science B, 1998, -1(3): .

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author="Shipeng CHEN, Lian GUAN, Xu ZHAO, Jing YANG, Longqing CHEN, Mengmeng GUO, Juanjuan ZHAO, Chao CHEN, Ya ZHOU, Yong HAN, Lin XU",
journal="Journal of Zhejiang University Science B",
volume="-1",
number="-1",
pages="",
year="1998",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200116"
}

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%A Shipeng CHEN
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%A Xu ZHAO
%A Jing YANG
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%A Mengmeng GUO
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%A Chao CHEN
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A1 - Xu ZHAO
A1 - Jing YANG
A1 - Longqing CHEN
A1 - Mengmeng GUO
A1 - Juanjuan ZHAO
A1 - Chao CHEN
A1 - Ya ZHOU
A1 - Yong HAN
A1 - Lin XU
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Abstract: 
Targeted gene therapy has become a promising approach for lung cancer treatment. In our previous work, we reported that the targeted expression of miRNA-7 (miR-7) operated by TTF-1 promoter inhibited the growth of human lung cancer cells in vitro and in vivo; however, the intervention efficiency needed to be further improved. In this study, we identified the core promoter of TTF-1 (from -1299 bp to -871 bp) by 5’ deletion assay and screened out the putative binding transcription factors (TFs) NF-1 and AP-1. Further analysis revealed that the expression level of NF-1, but not AP-1, was positively connected with the activation of TTF-1 core promoter in human NSCLC cells. Moreover, the silencing of NF-1 could reduce the expression level of miR-7 operated by TTF-1 core promoter. Of note, we optimized four distinct sequences to form additional NF-1 binding sites (TGGCA) in the sequence of TTF-1 core promoter (termed as optTTF-1 promoter), and verified the binding efficiency of NF-1 on the optTTF-1 promoter by EMSA assay. As expected, the optTTF-1 promoter could more effectively drive miR-7 expression and inhibit the growth of human NSCLC cells in vitro, accompanied by a reduced transduction of NDUFA4/Akt pathway. Consistently, optTTF-1 promoter-driven miR-7 expression could also effectively abrogate the growth and metastasis of tumor cells in a murine xenograft model of human NSCLC. Finally, no significant changes were detected in the biological indicators and the histology of some important tissues and organs, including heart, liver and spleen. On the whole, our study revealed that the optimized TTF-1 promoter could more effectively operate miR-7 to influence the growth of human NSCLC cells, providing a new basis for the development of miRNA-based targeting gene therapy against clinical lung cancer.

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