Journal
CANCER GENE THERAPY
Volume 27, Issue 6, Pages 424-437Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41417-019-0113-y
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Funding
- NATIONAL CANCER INSTITUTE [P30CA014599, R21CA226303] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000430] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007281] Funding Source: NIH RePORTER
- NCATS NIH HHS [UL1 TR000430] Funding Source: Medline
- NCI NIH HHS [R21 CA226303, P30 CA014599] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007281] Funding Source: Medline
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MicroRNAs (miRNAs) are ~22 nucleotide noncoding RNAs that are involved in virtually all aspects of cellular process as their deregulations are associated with many pathological conditions. Mature miRNAs (mMIRs) are generated through a series of tightly-regulated nuclear and cytoplasmic processing events of the transcribed primary, precursor and mMIRs. Effective manipulations of miRNA expression enable us to gain insights into miRNA functions and to explore potential therapeutic applications. Currently, overexpression of miRNAs is achieved by using chemically-synthesized miRNA mimics, or shRNA-like stem-loop vectors to express primary or precursor miRNAs, which are limited by low transfection efficacy or rate-limiting miRNA processing. To overcome rate-limiting miRNA processing, we developed a novel strategy to express mMIRs which are driven by converging U6/H1 dual promoters. As a proof-of-concept study, we constructed mMIR expression vectors for hsa-miR-223 and hsa-Let-7a-1, and demonstrated that the expressed mMIRs effectively silenced target gene expression, specifically suppressed miRNA reporter activity, and significantly affected cell proliferation, similar to respective primary and precursor miRNAs. Furthermore, these mMIR expression vectors can be easily converted into retroviral and adenoviral vectors. Collectively, our simplified mMIR expression system should be a valuable tool to study miRNA functions and/or to deliver miRNA-based therapeutics.
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