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

Abstract

Transcription factor and microRNA (miRNA) can mutually regulate each other and jointly regulate their shared target genes to form feed-forward loops (FFLs). While there are many 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 and miRNAs 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 and miRNAs also tended to be hubs and bottlenecks. Finally, we identified potential anticancer indications for existing drugs with novel mechanism of action. Collectively, this study highlights the potential of pan-cancer FFLs as a novel paradigm in elucidating pathogenesis of cancer and developing anticancer drugs.

Bta‐miR‐149‐5p inhibits proliferation and differentiation of bovine adipocytes through targeting CRTCs at both transcriptional and posttranscriptional levels

“…Previous literature has explored the prevalence of coregulation of common target genes by miRNAs and transcription factors in mammalian genomes (Shalgi, Lieber, Oren, & Pilpel, 2007). Particularly, the structures known as the feed forward loops (FFL) motif through which a TF regulates a miRNA (TF‐FFL) or a miRNA regulates a transcription factor (miRNA‐FFL) and both of them regulate common target genes has been identified as recurring patterns of association between miRNAs and TFs, and performs essential roles in regulating biological events (Jiang et al, 2016). In addition, the actions of miRNAs and transcription factors are tightly linked through the events of signaling cascade, in which they interact by triggering or intermediating each other's activity sequentially (Li et al, 2013; Recamonde‐Mendoza, Werhli, & Biolo, 2019).…”

A review of computational approaches detecting microRNAs involved in cancer

“…Jiang at al. (111) and Yan et al (112) studied the FFLs active in multiple cancer types. In (111) network motifs were reconstructed in 13 tumor types using predicted interactions.…”

Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression

“…We investigated the co-regulatory network to examine whether such co-regulations have important roles in HF. As a result, we identified several feed-forward loops (FFLs) potentially associated with HF [39]. For example, two genes ABAT and PTGDS, which were associated with multiple HF-related pathways such as regulation of blood pressure and positive regulation of muscle contraction [40], were jointly regulated by miR-129-5p and LOC101927179 as shown in Fig.…”