Abstract A006: miR-195 Re-expression Reverses Chemoresistance in Ovarian Cancer by Suppressing WNT7A/β-Catenin Signaling

Abstract Background: Ovarian cancer is the most lethal gynecologic malignancy, primarily due to late diagnosis, rapid metastasis, and chemoresistance. Cancer stem-like cells (CSCs) contribute significantly to drug resistance and tumor relapse. WNT7A, a key activator of β-catenin signaling, is specifically overexpressed in ovarian cancer and plays a critical role in maintaining CSC phenotypes and epithelial–mesenchymal transition (EMT) and drug resistance. miR-195, a member of the tumor-suppressive miR-15/107 family, is frequently downregulated in ovarian tumors and has been shown to inhibit multiple oncogenic pathways. We investigated whether miR-195 could restore drug sensitivity by targeting WNT7A and developed a novel Auro-Liposome (AuLPS) delivery system to enhance its therapeutic potential. Methods: Ovarian CSCs were enriched using anchorage-independent spheroid culture and validated by CSC marker expression using immunoblotting. miR-195 expression was assessed by qRT-PCR. Functional assays (gain/loss-of-function) were used to evaluate the impact of miR-195 on CSC markers, EMT, and drug response. A luciferase reporter assay confirmed direct binding of miR-195 to the WNT7A 3′UTR. β-catenin activation and nuclear localization were analyzed by Western blot and immunofluorescence. A custom Auro-Liposome (AuLPS) formulation was designed for miR-195 delivery and compared to commercial transfection reagents in vitro. Additionally, an in vivo adhesion assay assessed the impact of miR-195 re-expression on ovarian cancer cell attachment to the omentum. Results: Spheroid-derived CSCs showed elevated expression of stemness markers (NANOG, OCT4, SOX2, ALDH1A) and suppressed miR-195 levels. miR-195 overexpression reduced NANOG expression, impaired spheroid growth, and enhanced chemosensitivity. miR-195 directly targeted WNT7A, leading to downregulation of active β-catenin (Ser45 and Ser33/37/Thr41) and inhibition of WNT/β-catenin signaling. Notably, the Auro-Liposome (AuLPS) system outperformed commercial reagents, achieving superior intracellular delivery of miR-195 and more potent inhibition of oncogenic pathways in ovarian cancer cells. Furthermore, in vivo adhesion assays demonstrated that miR-195 re-expression significantly reduced ovarian cancer cell adhesion to the omentum, underscoring its potential to inhibit metastatic colonization. Conclusions: Our findings identify miR-195 as a key regulator of drug resistance via WNT7A/β-catenin suppression. The development of an Auro-Liposome (AuLPS) delivery platform offers a promising strategy for miRNA-based therapy in ovarian cancer. This combined approach targets CSC-driven resistance and metastatic mechanisms, potentially improving therapeutic outcomes. Citation Format: Arpan Dey Bhowmik, Pallab Shaw, Prasanta Panja, Geeta Rao, Mohanshankar Gopinathapillai, Resham Bhattacharya, Priyabrata Mukherjee, Shailendra Kumar Dhar Dwivedi. miR-195 Re-expression Reverses Chemoresistance in Ovarian Cancer by Suppressing WNT7A/β-Catenin Signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A006.