Hepatocellular carcinoma (HCC) is the most common liver cancer and mostly affects people with existing liver disease (hepatitis, cirrhosis). It's formed from liver hepatocytes and is also associated with chronic liver infection by hepatitis virus (eg, HBV and HCV), alcohol consumption, non-alcoholic fatty liver disease and so on.
Glycan-3 (GPC3) structure, function and biology – human cancer and how to use it as an immunotherapy target. GPC3 is an overactive cell surface protein in HCC. GPC3 is an oncofetal glycoprotein anchored to the cell wall with a glycosylphosphatidylinositol anchor. GPC3 is over-reported in some tumours, particularly liver cancer (HCC).
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Glypican-3
GPC3 is a glycoprotein present in a lot of tissues in the human body, and it's in the glycoprotein family. GPC3 appears mostly on the cell surface. It's involved in cell growth, differentiation and signalling, and a whole series of physiological and pathological activities, including tumour growth and progression. The GPC3 gene is chromosome X, 26 on long arm, 11 exons, 2130bp long transcript coding for 580 amino acids, protein molecular weight 70kDa. This is the Furin cleavage site of the polypeptide. The peptide bond Arg358-Cys359 is cleft, GPC3 is divided into Nterminal 40kD and Cterminal 30kD; these subunits are linked by one or more disulfide bonds, and the Nterminal subunit can be further cleaved to make sGPC3, in the peripheral blood; GPC3 is heparin sulfate modified at Cys495 and Cys508; Ser560 is phosphatidyl is attached to cell membrane lipid rafts by phosphatinositol.
| Signal peptide |
In the signal transduction and transport pathway. |
| N-glycosylation Site |
Glycosylation modification stabilizes and functions it. |
| External Domain |
GPC3 is replete with cystine residues, forming characteristic disulfide bonds to hold the three-dimensional structure. |
| Molecular Weight |
70 kDa |
| Hydrophilicity/hydrophobicity |
GPC3 is a hydrophilic glycoprotein and it's soluble in the extracellular matrix when glycosylated. |
| Isoelectric Point |
GPC3 is prone to a wide range in isoelectric point that depends on phosphorylation and glycosylation but is normally between pH 5 and pH 9. |
| Function |
GPC3 has gained mass cult status in tumours, since it might be a tumour marker in cancers. Meanwhile, it also regulates the biological activities of cell growth factors like HGF and FGF. |
Fig. 1 Schematic diagram of GPC3 on the cell membrane (Guo, M., et al. 2020).
Biological Functions of GPC3
GPC3 is abundant in many membranes of different embryonic cell membranes, but nowhere on the membranes of adult liver cells, in healthy bodies. GPC3 is a membrane protein attached to the cell's membrane. There is no intracellular part that sends signals, but GPC3 is a vital part of the ECM. It can also bind to growth factors, chemokines and cytokines, create a concentration gradient at the surface of the cell membrane, and drive these ligands towards associated receptors.
WNT Signaling Pathway
WNT signalling mediates most pathological and physiological functions directly, including embryonic development, cell division, tumorigenesis, metastasis and invasion. GPC3 is a critical modulator in the beginning phase of the WNT signalling pathway. WNT signalling can be enhanced through the generation of membrane surface complexes by GPC3 in liver cancer. Both activator protein and heparan sulfate side chain can bind FZD and WNTs.
Hedgehog Signaling Pathway
The Hh signalling system is essential for morphogenesis in the embryo. This pathway can progress into different tumours when it is improperly turned on in adult humans. GPC3 is an extremely negative regulator of the Hedgehog signaling network. Some researchers proposed that the cause of SGBS in loss-of-function mutation of GPC3 was over-activation of the Hh signalling pathway.
Expression of GPC3 in Liver Cancer Tissue
GPC3 is an objective marker for HCC. GPC3 appears in the surface of most HCC cells. GPC3 is a monoclonal antibody to the carboxyl terminal part of the GPC3 molecule. GPC3 is over-expressed in many liver cancer tissues and a biomarker and target of potential therapy. GPC3 is very weak in normal liver tissue, and so has interested researchers because of its specificity for liver cancer and its potential as a marker for diagnosis and targeted therapy. For instance, high levels of GPC3 could give us novel targets for liver cancer early detection and to create new targets for targeted therapy.
Conclusion
GPC3 is a membrane-bound protein, and it doesn't have domains involved in communicating with intracellular signals. Its activity on the cell surface is probably tied to cell-cell or cell-matrix communication. GPC3 is very prevalent in HCC and is now being tested as a target for HCC antibody and cell therapy. We could in the future produce novel anti-GPC3 mAbs with different functional domains (eg, HS chains) and test if anti-GPC3 mAbs can inhibit tumour growth directly by regulating ligand-receptor interactions for Wnt and/or other signaling pathways.
References
- Guo, M., et al. Glypican-3: a new target for diagnosis and treatment of hepatocellular carcinoma. Journal of Cancer. 2020, 11(8): 2008.
- Ho, M., et al. Glypican-3: a new target for cancer immunotherapy. European journal of cancer. 2011, 47(3): 333-338.
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