When GPC3 is upregulated in malignant liver cells (HCC), possibly by chronic inflammation due to hepatitis viral infection or other etiological factors (Figure 1B) (45), GPC3 serves as a Wnt co-receptor to attract Wnt to the cell surface via the newly identified cysteine-rich hydrophobic groove in the N-lobe of GPC3 containing F41. This evidence concerns the gene GPC3 and hepatocellular carcinoma.