Network-Based Integration of Multi-Omics Data Identifies the Determinants of miR-491-5p Effects

SIMPLE SUMMARY: The re-introduction of miRNAs with tumor-suppressor activity in cancer cells has not yet been implemented in clinical practice yet. However, the identification of miRNAs’ targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA’s effects. We devised a multi-omics approach to precisely characterize the effects of miR-491-5p, a cytotoxic miRNA in ovarian cancer cells, and performed an integrated network analysis. We identified the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases—either direct or indirect targets of miR-491-5p—as regulatory hubs for miR-491-5p-mediated effects. Targeting different combinations of these hubs with specific inhibitors mimic miR-491-5p-induced cytotoxicity. Pharmacological inhibitors of these targets are available for clinical use or in clinical trials; thus, this study might enable innovative therapeutic options for ovarian cancer, the leading cause of death from gynecological malignancies in developed countries. ABSTRACT: The identification of miRNAs’ targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA’s effects. Based on this assumption we devised a multi-omics approach to precisely characterize miRNAs’ effects. We combined miR-491-5p target affinity purification, RNA microarray, and mass spectrometry to perform an integrated analysis in ovarian cancer cell lines. We thus constructed an interaction network that highlighted highly connected hubs being either direct or indirect targets of miR-491-5p effects: the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases. By using different combinations of specific inhibitors of these hubs, we could greatly enhance their respective cytotoxicity and mimic the miR-491-5p-induced phenotype. Our methodology thus constitutes an interesting strategy to comprehensively study the effects of a given miRNA. Moreover, we identified targets for which pharmacological inhibitors are already available for a clinical use or in clinical trials. This study might thus enable innovative therapeutic options for ovarian cancer, which remains the leading cause of death from gynecological malignancies in developed countries.