Network-based analysis reveals microRNA regulation of oncogenic pathways in SOX10-depleted uveal melanoma

Abstract SOX10 is essential for melanocyte development and maintenance and plays a critical role in uveal melanoma (UM) initiation and progression. While SOX10’s transcriptional regulation of protein-coding genes is well characterized, its role on microRNA (miRNA) regulatory landscape in UM remains unexplored. Here, we employed network-based modeling to systematically characterize miRNA regulatory functions following SOX10 depletion in UM. First, we profiled mRNA and miRNA expression levels in SOX10 wild-type and knockdown UM cells. Then, we integrated the transcriptomic data, a UM network, and a Bayesian model to quantify miRNAs’ regulatory activities and identify key miRNAs. Subsequently, we employed pathway enrichment analysis combined with literature mining to elucidate the functional roles of identified miRNAs through their target genes and associated signaling pathways in UM. We identified 17 miRNAs that show significant changes in regulatory activities following SOX10 knockdown in UM cells. These miRNAs regulate the expression of genes involved in cancer hallmark pathways, including cell cycle progression, mTORC1 signaling, and fatty acid metabolism. Notably, miR-34a, miR-25, miR-186, and miR-211 have tumor-suppressive potential by targeting genes involved in UM progression and metastasis. Our results suggested that SOX10 depletion in UM can activate tumor-suppressive mechanisms through regulating miRNAs. Competing Interest Statement C.B. reports consulting fees from BMS, Almirall Hermal, Immunocore MSD, Novartis, Regeneron, Sanofi, Pierre Fabre, Honoraria for lectures from Bristol Myers Squibb (BMS), Merck Sharpe and Dohme (MSD), Almirall Hermal, Immunocore, Novartis, Sanofi, Pierre Fabre, Leo Pharm, support for attending meetings from Pierre Fabre, and participation on advisory boards outside the submitted work of InflaRx, Miltenyi, BMS, Almirall Hermal, Immunocore, MSD, Novartis, Regeneron, Sanofi, Pierre Fabre. C.B. is a board member of the Dermatologic Cooperative Oncology group (DeCOG) M.V.H. received honoraria for lectures and presentations from Novartis BMS, MSD, Immunocore. He participated on data safety monitoring boards or advisory boards of Novartis, BMS, MSD, Immunocore. All other authors declare no conflicts of interests Footnotes One of the co-author's name has been mis spelled and the correction was made.