A Comprehensive Analysis of Transcription Factor-microRNA Network in Six Different Major Cancers: Uncovering the Regulatory Backstages of Cancer

Abstract

Regulatory backstage of cancer involves complex multifactorial mechanisms. Among these, the posttranscriptional modulation between microRNA (miRNAs) and mRNAs is implicated as major regulatory mechanisms in different cancers. The tissue- and disease-specific regulation of miRNAs by transcription factors (TFs) further adds to the complexity of this system potentially impacting cancer pathogenesis. To uncover the major TFs impacting miRNA transcription in cancer, the differentially expressed miRNAs and mRNAs in six different cancer types, namely, liver hepatocellular carcinoma, lung adenocarcinoma, prostate adenocarcinoma, stomach adenocarcinoma, breast invasive carcinoma, and colon adenocarcinoma, were compiled from The Cancer Genome Atlas. Using bioinformatics approaches and the TransmiR database, we assembled the 374 TFs that transcriptionally regulate miRNAs through repression mechanisms, and the negatively correlating TF-miR pairs in each cancer type. Importantly, we found that E2F1 and EZH2, primarily linked with cell proliferation and cell cycle regulation, are potential regulators of miRNA transcription in cancers. The comprehensive TF-miR pairs in each cancer type uncovered in this study represent the unique and shared constituents that could functionally affect the cancer pathology. Understanding the mechanisms that regulate miRNA transcription in different cancers could help understand the pathology of cancer from a novel perspective with shared TFs constitutive to multiple cancers. This may also open up new avenues for cancer therapeutic innovation, in which miRNA-based interventions might be able to target and be relevant to multiple cancers at once in the future.