Systematic dissection of dysregulated transcription factor-miRNA feed-forward loops across tumor types.

Transcription factor andmicroRNA (miRNA) canmutually regulate each other and jointly regulate their shared target genes to form feed-forward loops (FFLs). While there aremany studies of dysregulated FFLs in a specific cancer, a systematic investigation of dysregulated FFLs across multiple tumor types (pan-cancer FFLs) has not been performed yet. In this study, using The Cancer Genome Atlas data, we identified 26 pan-cancer FFLs, which were dysregulated in at least five tumor types. These pan-cancer FFLs could communicate with each other and form functionally consistent subnetworks, such as epithelial to mesenchymal transition-related subnetwork. Many proteins andmiRNAs in each subnetwork belong to the same protein and miRNA family, respectively. Importantly, cancer-associated genes and drug targets were enriched in these pan-cancer FFLs, in which the genes andmiRNAs also tended to be hubs and bottlenecks. Finally, we identified potential anticancer indications for existing drugs with novelmechanismof action. Collectively, this study highlights the potential of pan-cancer FFLs as a novel paradigmin elucidating pathogenesis of cancer and developing anticancer drugs.