Systematic Analysis of Intronic miRNAs Reveals Cooperativity within the Multicomponent FTX Locus to Promote Colon Cancer Development.

Abstract

Approximately half of all miRNA reside within intronic regions and are often cotranscribed with their host genes. However, most studies of intronic miRNA focus on individual miRNA, while conversely most studies of protein-coding and noncoding genes frequently ignore any intron-derived miRNA. We hypothesize that the individual components of such multigenic loci may play cooperative or competing roles in driving disease progression and that examining the combinatorial effect of these components would uncover deeper insights into their functional importance. To address this, we performed systematic analyses of intronic miRNA:host loci in colon cancer. The FTX locus, comprising of a long noncoding RNA FTX and multiple intronic miRNA, was highly upregulated in cancer, and cooperativity within this multicomponent locus promoted cancer growth. FTX interacted with DHX9 and DICER and regulated A-to-I RNA editing and miRNA expression. These results show for the first time that a long noncoding RNA can regulate A-to-I RNA editing, further expanding the functional repertoire of long noncoding RNA. Intronic miR-374b and miR-545 inhibited tumor suppressors PTEN and RIG-I to enhance proto-oncogenic PI3K-AKT signaling. Furthermore, intronic miR-421 may exert an autoregulatory effect on miR-374b and miR-545. Taken together, our data unveil the intricate interplay between intronic miRNA and their host transcripts in the modulation of key signaling pathways and disease progression, adding new perspectives to the functional landscape of multigenic loci. SIGNIFICANCE: This study illustrates the functional relationships between individual components of multigenic loci in regulating cancer progression.See related commentary by Calin, p. 1212.