miR-6850 drives phenotypic changes and signaling in high grade serous ovarian cancer.

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression, and their dysregulation is closely linked to cancer development. Ovarian cancer (OC), particularly the high-grade serous ovarian carcinoma (HGSOC) subtype, is the most lethal gynecological malignancy, primarily due to late-stage diagnosis and limited treatment options. Among the miRNAs encoded at the often amplified 8q24.3 region, miR-6850 has emerged as a potential candidate target owing to its genomic positioning inside this hotspot and its unexpectedly low expression in HGSOC tissues and cell lines. In silico investigations indicated that, despite the gain in MIR6850 copy number, its mature products, miR-6850-5p and miR-6850-3p, were expressed at low levels; notably, MIR6850 gene amplification was associated with enhanced disease-specific survival. Functional studies revealed that ectopic production of both isoforms in SKOV-3 and NIH:OVCAR3 cells inhibited proliferation, compromised clonogenic capacity, and disturbed cell cycle progression. Moreover, miR-6850 altered cell phenotype by facilitating mesenchymal-to-epithelial transition (MET), as shown by the overexpression of E-cadherin and β-catenin and the downregulation of Slug and Vimentin. It also regulated cell adhesion and migration while reducing global protein synthesis via the downregulation of the PI3K/Akt/mTOR pathway. Our results together identify miR-6850 as a tumor-suppressive miRNA in HGSOC, demonstrating its diverse anti-oncogenic actions and underscoring its potential as a prognostic biomarker and therapeutic target in ovarian cancer.