PDE1A in epithelial ovarian cancer: Oncogenic role, metastatic association, and potential as a prognostic biomarker and therapeutic target

초록

Objectives Phosphodiesterase 1A (PDE1A), which belongs to a class of phosphohydrolytic enzymes, modulates the intensity of intracellular second messenger signaling and integration of Ca2+ and cyclic nucleotide in various diseases such as cancers. However, its role in epithelial ovarian cancer (EOC) has not been clarified yet. Therefore, in this study, we aimed to evaluate the function, molecular mechanism, and clinical-pathologic significance of PDE1A in EOC. Methods The expression level of PDE1A was screened by RNA sequencing of 10 EOCs and normal epithelial ovarian tissues. Expression levels and the functional role of PDE1A were evaluated by Immunohistochemistry staining of EOC, borderline, benign, and normal epithelial tissues, qPCR, western blotting, and public data sets, respectively. Our recruited cohort and Gene Expression Omnibus (GEO) dataset were used to analyze clinical-pathologic characteristics and prognosis of PDE1A among EOC patients. Also, the functional roles and associated signaling pathways of PDE1A were investigated in EOC cell lines. Results PDE1A protein was elevated in EOCs according to GEO and The Cancer Genome Atlas (TCGA) datasets. High mRNA and protein levels of PDE1A were observed in EOCs compared to borderline, benign, and normal non-adjacent ovarian epithelial tissues (P < 0.001). Also, high expression of PDE1A was significantly associated with serous (P = 0.001), high grade (P = 0.009), and advanced-stage FIGO stage (P = 0.025) EOCs. Importantly, a high expression level of PDE1A was associated with poor overall survival (OS) and disease-free survival (DFS) compared with low expression of PDE1A in EOCs (both P < 0.001). Also, a significant association with platinum-based chemotherapy resistance was observed in the high expression of the PDE1A group of EOC patients (P < 0.014). Importantly, multivariate analysis revealed the significance of PDE1A as a prognostic biomarker for both DFS and OS in EOC. In vitro results also demonstrated the knockdown of PDE1A was associated with decreased cell invasion (P < 0.001), migration (P < 0.001), proliferation (P < 0.001), and colony-forming abilities (P < 0.001), supporting the oncogenic role in EOC. We further investigated the underlying mechanism by which PDE1A affects the migration and invasion function of ovarian cancer cells. Furthermore, we found that the β-catenin protein level was dramatically decreased in PDE1A-silenced cells. Also, the effect of PDE1A knockdown on the reduction of β-catenin was remarkably reversed by MG132, leading to activation of Wnt signaling responsive genes and facilitating metastasis. Conclusions Our study is the first work to identify an oncogenic role of PDE1A and its association with metastasis in EOC tissues and cell lines, which may provide insights into the application of PDE1A as a novel predictor of clinical outcome and a potential therapeutic target in EOC patients.