Aquaporin 3 Promotes Invasion and Migration of Hepatocellular Carcinoma Cells via Glycerol-Dependent Remodeling of Phospholipid Homeostasis and Energy Metabolism.
Abstract
PURPOSE: Hepatocellular carcinoma (HCC) remains a clinically challenging malignancy due to its high metastatic potential and frequent postoperative recurrence. Aquaporin 3 (AQP3) was previously identified by our group as being upregulated in HCC and promoting tumor metastasis; however, the underlying molecular mechanisms remain incompletely understood. This study investigated whether AQP3 promotes HCC cell invasion and migration through its glycerol transport function by regulating membrane lipid homeostasis and energy metabolism. METHODS: Using PLC/PRF/5 cells as an HCC model, we evaluated cell invasion and migration by transwell and wound-healing assays. Lipid metabolism, energy status, membrane fluidity, and cell-matrix adhesion were assessed using biochemical, metabolomic, and FRAP-based approaches. Exogenous glycerol supplementation was used for functional rescue experiments. RESULTS: AQP3 knockdown reduced intracellular lipid droplet accumulation and glycerol levels. Reduced glycerol availability led to two parallel consequences: disrupted membrane lipid synthesis and impaired energy metabolism. Disrupted membrane lipid synthesis was associated with decreased membrane fluidity and weakened cell-matrix adhesion, while impaired energy metabolism contributed to insufficient energy supply. Together, these defects in membrane integrity and energy metabolism suppressed HCC cell invasion and migration. Notably, exogenous glycerol supplementation partially reversed the defects in energy metabolism, membrane properties, and cell motility. CONCLUSION: This study demonstrates that AQP3 acts as a metabolic regulator through its glycerol transport activity, coordinating membrane lipid homeostasis and energy supply in HCC cells. Our findings provide evidence for a mechanistic axis that links AQP3-mediated glycerol transport to metabolic remodeling, membrane structural changes, and cell motility, and suggest that the AQP3-glycerol metabolic axis may serve as a potential therapeutic target for HCC.
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