**4. Metabolic pathway**

38 Hepatocellular Carcinoma – Basic Research

HCC cell lines have high expression level of GPC3 (Midorikawa et al., 2003). In addition, GPC3 expression is correlated with the prognosis of HCC, where GPC3-positive HCC patients have a significantly lower 5-year survival rate than patients who are GPC3-negative

One of the GPC3 tumorigenic roles is the activation of Wnt/β-catenin signaling. It is shown that GPC3 is able to interact with Wnt ligands, and induces canonical Wnt-signaling to trigger the stabilization of β-catenin and induction of cyclin D1 (Capurro et al., 2005). The heparin sulfate chain of GPC3 is reported to bind with basic growth factors such as FGF-2. The interaction between GPC3 and FGF-2 is frequently observed in HCC cells, and is responsible for phosphorylation of ERK and AKT (Midorikawa et al., 2003). This interaction plays a role in the increase of HCC cell proliferation, and growth of tumor in nude mouse model. Additionally, GPC3 interplays with hedgehog signaling in regulating developmental growth (Capurro et al., 2008). Though yet to be elucidated, the GPC3-hedgehog signaling is

Targeting GPC3 and its related growth signaling is a relevant approach to inhibit HCC growth. Inhibition of the interaction between GPC3 and Wnt or FGF-2 should theoretically reduce HCC growth (Capurro et al., 2005; Midorikawa et al., 2003). GPC3 is also a useful target in immunotherapy against HCC. The therapeutic monoclonal antibody against GPC3 has been developed which could induce antibody-dependent HCC cytotoxicity. Targeting GPC3 is able to inhibit tumor growth of HCC cell line xenograft (Ishiguro et al., 2008). Study also showed the concomitant treatment with GPC3 monoclonal antibody and sorafenib was more potent in preventing tumor growth than sorafenib alone in the HepG2 xenograft model (Ishiguro et al., 2008). It is likely that targeting GPC3 could provide great clinical

Cadherins are important cell adhesion molecules strongly associated with cancer progression. Downregulation of E-cadherin (Du et al., 2009) and overexpression of Pcadherin are often observed in advanced tumor which processes crucial cellular event like epithelial-mesenchymal transition (Sun et al., 2011). Cadherin 17 (CDH17) is another adhesion molecule upregulated in HCC, and it is linked to the tumorigenesis in various gastrointestinal regions (Wang et al., 2005). The upregulation of CDH17 is capable of transforming premalignant liver progenitor cells into liver carcinomas in mice. While forced expression of CDH17 promoted tumor growth from hepatic progenitor cells, silencing of CDH17 reduced the aggressiveness of metastatic HCC cells (Liu et al., 2009). Knockdown of CDH17 by RNA-interference decreased the proliferation rate of HCC cell lines despite their metastatic potential in vitro and in vivo. It is shown that targeting CDH17 can concurrently inactivate Wnt/β-catenin signaling and reduce cyclin D1 level, leading to both growth inhibition and cell death. Inhibition of CDH17 results in the re-localization of nuclear βcatenin to the cytoplasm so as to attenuate the Wnt/β-catentin signaling (Liu et al., 2009).

Multiple isoforms of CDH17 protein are present in the HCC samples, and it is found that the isoform lacking exon 7 is the most abundant in HCC samples (Wang et al., 2005). CDH17 isoform lacking exon 7 cannot be found in normal liver tissue whereas it is present in about 50% of human HCC and 30% of premalignant tissues. Detection of this CDH17 isoform was

(Shirakawa et al., 2009).

suggested to contribute to HCC development.

benefit during HCC management.

**3.2 Cadherin 17** 
