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

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.
Cancer research: Tracking microRNA molecules A new method for monitoring microRNAs (miRNAs), very short RNA molecules that regulate gene expression, shows promise for developing and testing new cancer therapies. These miRNAs are strongly implicated in cancer, and are used for diagnosis and as therapeutic targets. However, currently available systems for monitoring them are inefficient and lack capacity for scaling up. Jong Heon Kim and co-workers at the National Cancer Center in Goyang, South Korea, have developed a new miRNA monitoring method that can be used in multiple disease models, including long-term experiments in small animals. They used the method to clarify how the cancer drug ivermectin acts, to identify a molecule similar to ivermectin but that may be more effective, and to identify novel molecules that interact with cancer-related miRNAs. This method shows promise for both clinical and basic research applications.