Clinical and Functional Characterization of PDE1A as a Wnt/β-Catenin-Linked Biomarker of Progression and Platinum Resistance in Epithelial Ovarian Cancer

Abstract

Objectives: Phosphodiesterase 1A (PDE1A) regulates intracellular cyclic nucleotide signaling and has been implicated in tumor progression, but its clinical relevance and functional role in epithelial ovarian cancer (EOC), particularly in relation to the response to platinum remain unclear. This study aimed to evaluate the clinical significance of PDE1A in EOG and to clarify its functional role in tumor progression and response to platinum-based chemotherapy. Methods: PDE1A mRNA and protein levels were analyzed using public databases, RNA sequencing, and immunohistochemistry. Correlations between PDE1A expression, clinicopathological features, and prognosis were assessed. Functional roles were investigated in ovarian cancer cell lines. Results: PDE1A was significantly overexpressed in EOC tissues compared with that in normal ovarian epithelial tissues. Overexpression correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, poor tumor grade, and reduced response to platinum-based chemotherapy. High PDE1A levels were linked to worse disease-free survival and overall survival, and multivariate analysis confirmed PDE1A as an independent prognostic factor. To elucidate its functional role, we performed in vitro experiments showing that PDE1A knockdown suppressed cell proliferation and colony formation, induced G1 arrest, and downregulated beta-catenin signaling with reduced cyclin D1 and c-Myc expression. Notably, these inhibitory effects were partially rescued by lithium chloride (LiCl), a Wingless-related integration site (Wnt)/beta catenin activator. Conclusions: In conclusion, our findings identify PDE1A as a Wnt/beta-catenin-linked biomarker of tumor progression and platinum resistance in EOC and provide a biological rationale for further investigation of PDE1A-targeted strategies in preclinical models.