Micro-editing mistake translates into a devastating brain tumor

Abstract

RNA modifications are increasingly being recognized as critical players in cancer. While adenosine-to-inosine RNA editing is consistently deregulated in cancer, we are still unable to draw a straight line connecting transcript-specific editing and carcinogenesis. The findings by Choudhury et al. in this issue of the JCI bridge this gap by mechanistically implicating underediting of miR-376a* in promoting glioma invasiveness through redirection of its mRNA targets. Moreover, RAP2A and AMFR convincingly emerge as key regulators of glioma migration and invasion affected by deregulated microRNA editing. Being inherently malleable, epigenetic mechanisms may provide feasible targets for therapeutic benefit.

Figure 1. Mature miRNA-376a* seed sequence is unedited in high-grade gliomas, consequently promoting glioma cell migration and invasion through altered target specificity.

RNA editing of miRNA seed sequences can potentially redirect their target specificity. While it is normally present in both edited an unedited forms in whole brain, dysregulated editing in high-grade gliomas results in accumulation of unedited miRNA-376a*. The capacity of unedited miRNA-376a* to repress RAP2A, a member of the Ras family of GTP-binding proteins, and its inability to target AMFR, a receptor for a tumor motility–stimulating secreted protein, promotes migration and invasion of glioma cells in vitro, and clinically correlates with the extent of invasive tumor spread.