S100A4 Promotes the Proliferation and Invasion of Gastric Cancer Cells and Regulates the Reprogramming of Fatty Acid Metabolism via the Wnt/β-catenin Signaling Pathway

Background: Related studies have shown that S100A4 is dysregulated in various types of cancer and is closely associated with tumor progression. However, its specific role in gastric cancer (GC), particularly its effects on metabolic pathways, has not yet been fully elucidated. Methods: We analyzed S100A4 expression levels in gastric cancer tissues and cell lines using bioinformatics data from The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC), and western blotting (WB). We then conducted gain-of-function and loss-of-function experiments, including Cell Counting Kit-8 (CCK-8) assays, colony formation assays, scratch assays, and Transwell migration and invasion assays, to evaluate the effects of S100A4 on gastric cancer cell proliferation, invasion, and migration; Changes in lipid metabolism were assessed through lipid droplet staining (BODIPY), intracellular triglyceride quantification, and Western blotting analysis of key lipid synthesis enzymes, including ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN). The involvement of the Wnt/β-catenin pathway was investigated using Western blot analysis of relevant proteins, nuclear and cytoplasmic β-catenin expression analysis, and pharmacological inhibition with XAV939 and ICG-001. Results: S100A4 was significantly upregulated in gastric cancer tissues and cell lines and was associated with poorer overall survival. Functional experiments demonstrated that S100A4 enhanced the proliferation, migration, and invasion capabilities of gastric cancer cells. S100A4 also promoted the reprogramming of fatty acid metabolism, including increased lipid droplet formation, elevated intracellular triglyceride levels, and upregulation of lipid synthase expression. Mechanistically, these effects depended on the activation of Wnt/β-catenin signaling pathway, as pharmacological inhibition of this pathway reversed the S100A4-induced malignant phenotype and alterations in lipid metabolism. Conclusion: S100A4 may promote gastric cancer progression through regulation of fatty acid metabolism via the Wnt/β-catenin pathway and is associated with enhanced proliferation, migration, and invasion.