miRNAs (microRNAs) are short non-coding RNAs that can regulate gene expression in cancer development, which makes them valuable targets for therapeutic intervention. In the present study we report on an approach that can not only arrest the functions of mature miRNAs by binding to them, but it can also induce the ‘mis-processing’ of the target miRNA, producing a non-functional truncated miRNA. This approach involves generating an expression construct that produces an RNA fragment with 16 repeat sequences. The construct is named miR-Pirate (miRNA-interacting RNA-producing imperfect RNA and tangling endogenous miRNA). The transcript of the construct contained mismatches to the seed region, and thus it would not target the potential targets of the miRNA under study. The homology of the construct is sufficiently high, allowing the transcript to block miRNA functions. The functions of the construct were validated in cell cultures, in tumour formation assays and in transgenic mice stably expressing this construct. To explore the possibility of adopting this approach in gene therapy, we transfected cells with synthetic miR-Pirate and obtained the results we expected. The miR-Pirate, expressed by the construct or synthesized chemically, was found to be able to specifically pirate and silence a mature miRNA through its dual roles and thus could be clinically applied for miRNA intervention.
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Research Article|
February 15 2013
Misprocessing and functional arrest of microRNAs by miR-Pirate: roles of miR-378 and miR-17
Zhaoqun Deng;
Zhaoqun Deng
1
1Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, M4N 3M5, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, M4N 3M5
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Xiangling Yang;
Xiangling Yang
1
1Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, M4N 3M5, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, M4N 3M5
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Ling Fang;
Ling Fang
1Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, M4N 3M5, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, M4N 3M5
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Zina J. Rutnam;
Zina J. Rutnam
1Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, M4N 3M5, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, M4N 3M5
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Burton B. Yang
Burton B. Yang
2
1Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, M4N 3M5, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, M4N 3M5
2To whom correspondence should be addressed (email byang@sri.utoronto.ca).
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Publisher: Portland Press Ltd
Received:
May 01 2012
Revision Received:
October 30 2012
Accepted:
December 05 2012
Accepted Manuscript online:
December 05 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 450 (2): 375–386.
Article history
Received:
May 01 2012
Revision Received:
October 30 2012
Accepted:
December 05 2012
Accepted Manuscript online:
December 05 2012
Citation
Zhaoqun Deng, Xiangling Yang, Ling Fang, Zina J. Rutnam, Burton B. Yang; Misprocessing and functional arrest of microRNAs by miR-Pirate: roles of miR-378 and miR-17. Biochem J 1 March 2013; 450 (2): 375–386. doi: https://doi.org/10.1042/BJ20120722
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