Abstract
A-to-I RNA modifications performed by the adenosine deaminase acting on RNA (ADAR) protein family are gaining traction as important mechanisms in cancer biology. A-to-I RNA editing changes adenosine to inosine on double stranded RNA, which co-transcriptionally alters transcript sequence and structure. A number of microRNA (miRNA) precursors are known to be edited by the ADARs, which alters the expression and/or function of the mature miRNA. A-to-I editing levels are high in thyroid tumors, but the ADAR-editase mechanisms governing thyroid cancer progression are unexplored. We recently demonstrated a functional role for ADAR1 and RNA editing in thyroid cancer, as shown by the suppression of tumorigenesis in vitro and in vivo following ADAR1 gene silencing. We also dissected the mechanism of action underlying this process in thyroid tumorigenesis and found that editing of the miRNA miR-200b is responsible, at least in part, for the aggressive features induced by ADAR1. Importantly, this editing event is overrepresented in thyroid tumors, and correlates with a worse progression-free survival and disease stage. Lastly, our results underscore the potential benefits of inhibiting RNA editing as a future treatment for advanced thyroid cancer, as pharmacological inhibition of ADAR1 editase activity with 8-azaadenosine reduced cancer cell aggressiveness in a heterotopic xenograft model. Overall, our study highlights the importance of miRNA editing in gene regulation and suggests its potential as a biomarker for thyroid cancer prognosis and therapy.