Work

WWOX attenuates the progression of gallbladder cancer by suppressing cellular glycolysis through the modulation of the P73/HIF-1α signaling pathway

Year: 2025

Type: article

Abstract: OBJECTIVE: To investigate the biological role and underlying molecular mechanisms of WWOX in the development of gallbladder cancer (GBC) under conditions of elevated glucose levels. METHODS: Tumor and adjacent tissues from GBC patients were procured. GBC-SD cells were exposed to varying glucose concentrations to create a high-glucose cell model, and a high-glucose mouse model was established through dietary glucose supplementation. The expression levels of WWOX in clinical samples and cells were quantified and validated using Western blot (WB) and immunohistochemistry. The impact of the WWOX/P73/HIF-1α axis on cellular glycolysis and GBC progression under high-glucose conditions was assessed through a series of experiments, including CCK-8 assays, colony formation, scratch tests, Transwell migration assays, and WB. RESULTS: WWOX expression was observed to be significantly downregulated in GBC. Enhanced WWOX expression in GBC-SD cells under high-glucose conditions suppressed cell survival and glycolytic activity. Co-immunoprecipitation experiments confirmed the interaction between WWOX and p73. WWOX was found to facilitate the degradation of HIF-1α by modulating P73, thereby inhibiting cell proliferation, migration, and invasion, reducing glycolytic activity, and consequently impeding GBC progression. In vivo studies further demonstrated that WWOX can inhibit GBC proliferation and epithelial-mesenchymal transition (EMT), with this regulatory effect being linked to the P73/HIF-1α molecular axis. CONCLUSION: WWOX interacts with the downstream protein p73, promoting the degradation of HIF-1α, which in turn reduces cellular glycolysis in a high-glucose environment and slows the progression of GBC.

Source: Tissue and Cell

DOI: 10.1016/j.tice.2025.102885