Glypican-3 knockdown inhibits the cell growth, stemness, and glycolysis development of hepatocellular carcinoma cells under hypoxic microenvironment through lactylation.

Context: Hepatocellular carcinoma (HCC) is a common malignant tumour in China. Glypican-3 (GPC3) is reported to be closely related to the occurrence and development of various tumours.

Objective: This study aimed to explore the role of GPC3 in HCC.

Materials And Methods: The cell behaviours were investigated using Cell Counting Kit-8 (CCK-8), Traswell, and sphere formation assays. The protein and mRNA expression levels were detected using western blot and Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) assays.

Results: The results showed that GPC3 knockdown decreased the cell viability and stemness, glucose uptake, lactate production, and extracellular acidification rate (ECAR), while increased the oxygen consumption rate (OCR) in hypoxia-treated HCC cells. Additionally, GPC3 knockdown decreased the global lactylation and c-myc lactylation, which further decreased the protein stability and expressions of c-myc.

Discussion And Conclusion: GPC3-mediated lactylation modification may be a new direction in HCC treatment in the future.