PDE4B/β-Catenin/FoxM1 Axis is Involved in CagA-Induced Gastric Carcinogenesis and Progression

Abstract

Background: Gastric cancer (GC) is a common malignant tumor associated with high mortality rates. Phosphodiesterase 4B (PDE4B) has been identified as a key participator in the progression of some malignancies by facilitating tumorigenesis. The Wnt/β-Catenin pathway has been established as a critical pathway in the progression of cancers, including GC. However, the effects of the PDE4B/Wnt/β-catenin/Forkhead box M1 (FoxM1) axis on GC progression are yet to be investigated. Methods: The protein expressions of PDE4B, BCL-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved-caspase3, β-catenin and FoxM1 were examined through western blot. The AGS-cytotoxin-associated gene A (CagA) and MKN45-CagA cell lines were used to assess cell proliferation ability via cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EDU) assays, cell migration and invasion via wound healing and Transwell assays, and cell apoptosis via flow cytometry. Results: Analysis of the Ualcan and Gene Expression Profiling Interactive Analysis (GEPIA) databases revealed that PDE4B exhibited higher expression in GC tissues. The PDE4B protein expression was significantly enhanced after CagA induction in gastric epithelial cell line (GES-1), AGS and MKN45 cells. In addition, PDE4B overexpression facilitated, while PDE4B knockdown suppressed, CagA-induced cell proliferation, migration and invasion in GC. However, PDE4B overexpression was suppressed, while PDE4B knockdown accelerated CagA-induced GC cell apoptosis. Additionally, the enhanced β-catenin and FoxM1 expressions mediated by PDE4B up-regulation were reversed after XAV-939 (Wnt inhibitor) treatment, suggesting that PDE4B can regulate FoxM1 through β-catenin. Additionally, the aggravated GC progression mediated by PDE4B overexpression was rescued after FoxM1 knockdown, indicating that PDE4B can aggravate the CagA-induced malignant progression of GC through FoxM1. Conclusions: The PDE4B/β-catenin/FoxM1 axis might be involved in CagA-induced gastric carcinogenesis and progression, suggesting PDE4B is a promising biomarker for comprehending the underlying mechanisms of GC development.