Approximately half of all microRNA reside within intronic regions and are often co-transcribed with their host genes. However, most studies of intronic microRNA focus on individual microRNA, while conversely most studies of protein-coding and non-coding genes frequently ignore any intron-derived microRNA. We hypothesize that the individual components of such multi-genic 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 microRNA:host loci in colon cancer. The FTX locus, comprising of a long non-coding RNA FTX and multiple intronic microRNA, was highly upregulated in cancer, and cooperativity within this multi-component locus promoted cancer growth. FTX interacted with DHX9 and DICER and regulated A-to-I RNA editing and microRNA expression. These results show for the first time that a long non-coding RNA can regulate A-to-I RNA editing, further expanding the functional repertoire of long non-coding RNA. Intronic miR-374b and -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 -545. Taken together, our data unveil the intricate interplay between intronic microRNA and their host transcripts in the modulation of key signaling pathways and disease progression, adding new perspectives to the functional landscape of multi-genic loci.