Table 3.

Influence of GPC-3 on key signaling pathways in HCC

Signaling pathway	Role of GPC-3	Mechanism	Impact on HCC	Key findings	References
Wnt signaling	↑ autocrine/paracrine canonical Wnt signaling	↑ Wnt concentration at receptor sites, facilitating Wnt-receptor interaction and stabilizing the Wnt-FZD complex	↑HCC cell proliferation; associated with dysregulation in 95% of HCC cases	GPC-3 acts as a bridge to stabilize Wnt and FZD through its HS chains; mutation in the Wnt-binding groove of GPC-3 reduces Wnt activation	[15, 48, 52–57]
YAP signaling	Target gene of YAP; positive correlation with YAP activation	Downregulation of GPC-3 reduces YAP signaling; HN3 antibody targeting GPC-3 blocks YAP signaling	Promotes liver tumorigenesis and HCC progression	↑YAP which plays a role in the recruitment of M2 macrophages	[58–62]
Growth factor signaling	Interacts with growth factors via HS chains	Facilitates signaling cascades by acting as a co-receptor; binds to growth factors, enhancing oncogenicity and cell migration	Stimulates cell growth, survival, and metastasis in HCC	GPC-3 interaction with FGF, IGF, and HGF enhances signaling pathways like RAS-MAPK, PI3K-AKT ↑Cell migration ↑Invasion	[63–71]

GPC-3 Glypican 3, HCC hepatocellular carcinoma, Wnt wingless/Int-1, YAP Yes-associated protein, FGF fibroblast growth factor, IGF insulin-like growth factor, HGF hepatocyte growth factor, TGF-β2 transforming growth factor beta 2, HS heparan sulfate, FZD frizzled. Symbol: ↑increase