Integrated Multi-Omics Analysis of Colorectal Cancer Reveals Mir-20a as a Regulator of Fatty Acid Metabolism in Consensus Molecular Subtype 3

Abstract

BackgroundmicroRNAs (miRNAs) serve important roles in metabolism. The consensus molecular subtype (CMS) 3 of colorectal cancer (CRC) is characterized by activated fatty acid (FA) metabolism. We aimed to identify essential miRNAs of CMS3-CRC and analyze the regulatory role in the FA metabolism. MethodsThe RobustRankAggreg method by integrating multi-omics data including genome, epigenome, transcriptome and interactome, was applied to filter out functional genes (Fgenes). The backward derivation approach based on Fgenes and miRNA-gene interactions was further applied to identify functional miRNAs (Fmirs). Nine human CRC cell lines with different CMSs were investigated. RT-qPCR, western blotting and immunofluorescence were performed to examine the effect of miR-20a on FA synthesis and Wnt/β-catenin signaling. The effect of miR-20a on cell proliferation and metastasis were studied by clone-formation, EdU assay, wound healing and transwell assay.ResultsWe identified 12 Fmirs by integrating multi-omics features in CMS3-CRC. These Fmirs exhibited significantly enriched CRC driver miRNAs and significant impacts on CMS3-CRC cell growth. Beyond the findings, miR-20a was significantly correlated with Wnt/β-catenin signaling and participated in FA metabolism subpathway. In vitro assays combined with bioinformatics analyses demonstrated that elevated miR-20a up-regulated FA synthesis enzymes FASN, ACAC and ACLY via Wnt/β-catenin signaling, and finally promoted proliferative and migration of CMS3-CRC cells. ConclusionsOverall, our study revealed that miR-20a promoted progression of CMS3-CRC by regulating FA metabolism and served as a potential target for preventing tumor metastasis.