Development of a miRNA-controlled dual-sensing system and its application for targeting miR-21 signaling in tumorigenesis

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Title
Development of a miRNA-controlled dual-sensing system and its application for targeting miR-21 signaling in tumorigenesis
Author(s)
Y Seo; S S Kim; N Kim; Sungchan Cho; J B Park; J H Kim
Bibliographic Citation
Experimental and Molecular Medicine, vol. 52, no. 12, pp. 1989-2004
Publication Year
2020
Abstract
MicroRNAs (miRNAs) are considered to be strong prognostic markers and key therapeutic targets in human diseases, especially cancer. A sensitive monitoring platform for cancer-associated miRNA (oncomiR) action is needed for mechanistic studies, preclinical evaluation, and inhibitor screening. In this study, we developed and systemically applied a sensitive and efficient lentivirus-based system for monitoring oncomiR actions, essentially miR-21. The specificity and sensitivity of "miRDREL" against various oncomiRs were validated by checking for tight correlations between their expression and targeting efficacy. Experiments based on the transfection of synthetic mimics and antagomir-mediated depletion of oncomiRs further confirmed the specificity of the system. Systemic application of miRDRELs to natural oncomiR targets, knockdown of key microprocessors, and physiological triggering of oncomiRs also demonstrated that the system is an effective tool for monitoring cellular oncomiR action. Importantly, molecular modeling-based screening confirmed the action of the miR-21-targeting drug ivermectin and led to the identification of a new effective derivative, GW4064, for inhibiting oncogenic DDX23-miR-21 signaling. Furthermore, proteomic-kinase inhibitor screenings identified a novel oncogenic kinome-DDX23-miR-21 axis and thus expands our understanding of miR-21 targeting therapeutics in tumorigenesis. Taken together, these data indicate that miRDREL and its versatile application have great potential in basic, preclinical studies and drug development pipelines for miRNA-related diseases, especially cancer.
ISSN
1226-3613
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s12276-020-00537-z
Type
Article
Appears in Collections:
Ochang Branch Institute > Natural Medicine Research Center > 1. Journal Articles
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