Mircoop-V2: Detecting Synergistic Mirna Interactions In Cancer

Official URL: https://risc01.sabanciuniv.edu/record=b3205817

RNAs bind to their target messenger RNA (mRNA) to post-transcriptionally repress the target gene’s expression through mRNA degradation and/or translational inhibition. As they are important regulators of gene expression, they take roles in dierent biological processes and are associated with pathologies such as cancer. While most miRNAs can repress their target only minimally, some miRNAs are known to act synergistically to strongly modulate the expression level of a common mRNA target. Harnessing this synergism in miRNA therapeutics oers the potential to enhance potency and ecacy while minimizing toxicity compared to single miRNA therapies. Previously, a method called miRCoop was developed to identify potential synergistic miRNA pairs and their shared target mRNAs using kernel interaction tests on matched patient gene expression data of miRNAs and mRNAs. In this thesis, we present an improved version of this tool, called miRCoop-v2, which enhances several aspects of the original method. miRCoop-v2 can identify synergistic miRNA interactions involving transcription factors, explicitly incorporates miRNA arm information, utilizes a larger miRNA-mRNA target interaction dataset, and runs 30 times faster than its predecessor. This speed-up allows us to apply miRCoop-v2 to 31 dierent cancers to predict synergistic miRNA pairs and their shared targets. Results of the miRCoop v2 prove that it can be a valuable tool in the detection of cancer-related interactions between miRNA, TF (transcription factors), and target mRNA. Some significant examples include MYC, STAT3, MKI67, miR-19a-3p, and miR-424-5p. Even in situations where direct literature evidence for specific cancer may be lacking, the importance of these miRNAs and mRNAs in other cancer types suggests their potential relevance and therapeutic value across various cancer contexts. We also have developed a web application to present the results, allowing users to access cancer-specific triplet and synergy module results, pan-cancer analyses of selected cancers, and interactive visualizations of the findings. We hope miRCoopv2 will facilitate experimental eorts in detecting synergistic miRNA interactions. The application is accessible at http://mircoop.sabanciuniv.edu