FOXO3a suppression predicts poor prognosis and facilitates cell migration and invasion through the WNT/β-catenin pathway in pancreatic ductal adenocarcinoma

Background: Forkhead box O3a (FOXO3a) is involved in multiple cancers, but its role and prognostic significance in pancreatic carcinoma (PC) remain unclear.Methods: FOXO3a expression in pancreatic tumor tissues was evaluated by immunohistochemistry and linked to clinicopathological features. FOXO3a-overexpressing and -silenced cell models were constructed via siRNA transfection. Proliferative capacity, as well as migratory and invasive functions of cells, were calculated by wound closure assays, Cell Counting Kit-8 (CCK-8), and Transwell chambers. Western blot analysis was employed to assess FOXO3a and WNT/β-catenin pathway proteins.Results: A significant downregulation of FOXO3a in both PC specimens and cultured cells. This downregulation was positively correlated with stage (P = 0.013), perineural invasion (P = 0.002), and distant metastasis (P <0.001). Survival data analysis further confirmed FOXO3a as a standalone indicator of prognosis in PC patients. In addition, FOXO3a exerts its function in PC via modulation of the Wnt/β-catenin signaling cascade. Experimental data showed that decreased expression of FOXO3a promoted cellular proliferation, invasive behavior, and migratory capacity; in contrast, its overexpression counteracted these effects and notably impeded the induction of the Wnt/β-catenin pathway. In vivo experiments in mouse models confirmed that upregulation of FOXO3a results in a reduction in the proliferation of PC cells.Conclusion: Decreased FOXO3a levels correlate with tumor aggressiveness and unfavorable clinical outcomes in PC. It acts as a tumor suppressor by restraining cellular proliferation, migration, and invasion via inhibition of the Wnt/β-catenin signaling pathway. FOXO3a might represent a potential biomarker for prognosis and a target for therapy in PC.