GPC3 protein: a core oncofetal antigen for hepatocellular carcinoma diagnosis and targeted therapy

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This article focuses on the molecular characteristics and biological functions of glypican-3 (GPC3), systematically elaborating its structural composition as an oncofetal proteoglycan anchored to the cell membrane via GPI, as well as the regulatory mechanisms of furin cleavage and Notum-mediated release, analyzing the expression characteristics and diagnostic value of GPC3 in hepatocellular carcinoma and liposarcoma, squamous lung cancer, and Merkel cell carcinoma, and exploring the molecular mechanisms by which GPC3 participates in tumor growth, differentiation, and metastasis through regulating the Wnt, Hedgehog, FGF-2, and BMP signaling pathways.

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GPC3 Protein: A Core Oncofetal Antigen for Diagnosis and Targeted Therapy of Hepatocellular Carcinoma

Brief summary: This article focuses on the molecular characteristics and biological functions of glypican-3 (GPC3), systematically describing its structural composition as an oncofetal proteoglycan anchored to the cell membrane via GPI, as well as the regulatory mechanisms of furin cleavage and Notum-mediated release. It analyzes the expression characteristics and diagnostic value of GPC3 in hepatocellular carcinoma as well as in liposarcoma, squamous lung cancer, and Merkel cell carcinoma, and discusses the molecular mechanisms by which GPC3 participates in tumor growth, differentiation, and metastasis by regulating the Wnt, Hedgehog, FGF-2, and BMP signaling pathways.

I. The therapeutic dilemma of hepatocellular carcinoma and the background of GPC3 discovery.

Liver cancer ranks fifth in incidence and second in mortality among tumors in China. Hepatocellular carcinoma is the most common type of primary liver cancer, and for many years there has been no relevant therapeutic breakthrough, creating an urgent need to develop novel liver cancer treatments. Glypican-3 (GPC3) is an oncofetal proteoglycan anchored to the cell membrane. It is typically detected in the fetal liver but is undetectable in healthy adult liver. This expression pattern—high in the fetal period, silent in adulthood, and reactivated in tumors—is a typical feature of oncofetal antigens and makes GPC3 one of the most specific molecular markers for hepatocellular carcinoma.

II. The clinical value of GPC3 as a diagnostic marker for hepatocellular carcinoma.

As a potential early marker of hepatocellular carcinoma, GPC3 is highly expressed in 74.8% of hepatocellular carcinoma tissues and is closely associated with elevated serum alpha-fetoprotein levels (88% vs. 55%). GPC3 is not only expressed on the surface of tumor cells but is also released into the periphery in soluble form; combined with alpha-fetoprotein, it can further improve the sensitivity of non-invasive diagnosis of liver tumors. Therefore, GPC3 has become a new diagnostic and therapeutic target for hepatocellular carcinoma. In terms of diagnostic performance, the combined detection of GPC3 and alpha-fetoprotein can compensate for the limitation of insufficient sensitivity of a single marker, and is particularly valuable as a supplement for the detection of alpha-fetoprotein-negative hepatocellular carcinoma patients. In addition, through immunohistochemical staining, GPC3 has been found to be expressed on the surface of other tumors as well; cell-surface expression of the tumor antigen GPC3 has been observed in tumor biopsies from patients with liposarcoma, squamous lung cancer, and Merkel cell carcinoma. The prevalence of GPC3-positive tumors in squamous cell carcinoma, myxoid liposarcoma, and Merkel cell carcinoma is 33%, 33%, and 70%, respectively, suggesting that GPC3 may also hold promise as a therapeutic target for other tumors.

III. The molecular structure of GPC3 and the regulatory mechanism of its membrane binding.

GPC3 consists of a core protein and heparan sulfate chains and binds to the cell membrane via a glycosylphosphatidylinositol anchor. GPC3 has a furin cleavage site between Arg358 and Ser359. Furin cleavage produces a 40 kDa N-terminal subunit and a 30 kDa C-terminal subunit, which can be linked by disulfide bonds. Two heparan sulfate side chains are present near the C-terminus of GPC3 (Ser495 and Ser509). Ser560 of GPC3 is inserted into the lipid bilayer and anchors the protein to the bilayer via phosphatidylinositol. GPC3 can be released from the cell surface into the extracellular environment after cleavage by Notum, an extracellular lipase that releases GPC3 by cleaving the GPI anchor. This multi-level regulatory mechanism of "furin cleavage–disulfide bond linkage–Notum release" determines the abundance of GPC3 on the cell surface and the circulating level of its soluble form, and also provides a molecular basis for soluble GPC3 as a liquid biopsy marker.

IV. The signaling pathway mechanisms by which GPC3 regulates cell growth and differentiation.

Mechanistic studies have shown that GPC3 plays an important role in cell growth and differentiation by regulating the activities of Wnts, Hedgehogs, fibroblast growth factor-2, and bone morphogenetic proteins. As a heparan sulfate proteoglycan, the glycosaminoglycan chains of GPC3 can serve as co-receptors or reservoirs for a variety of growth factors, regulating the effective binding of these factors to signaling receptors. In the Wnt signaling pathway, GPC3 can promote the binding of Wnt to Frizzled receptors and enhance canonical Wnt signaling; in the Hedgehog signaling pathway, GPC3 participates in the presentation and signal amplification of Hedgehog ligands; in the FGF-2 and BMP signaling pathways, the heparan sulfate chains of GPC3 likewise exert regulatory effects. The coordinated activation of these signaling pathways collectively drives the imbalance of proliferation and differentiation in hepatocellular carcinoma cells.

V. Applications of GPC3 in tumor molecular imaging, immunotherapy, and metastasis regulation.

GPC3 has been used as a target for molecular imaging and therapeutic intervention in hepatocellular carcinoma. To date, magnetic resonance imaging, positron emission tomography, and near-infrared imaging targeting GPC3 have been investigated for early detection of hepatocellular carcinoma, and various GPC3-targeted immunotherapeutic strategies have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, peptide/DNA vaccines, immunotoxin therapy, and gene therapy. GPC3 also plays an important regulatory role in tumor metastasis. In synergy with the HGF/c-Met signaling pathway, the heparan sulfate side chains of GPC3 can function in hepatocellular carcinoma cell migration. Studies have shown that the anti-heparan sulfate antibody HS20 inhibits c-Met activation when treating hepatocellular carcinoma cells, thereby inhibiting HGF-mediated migration and metastasis. Knockout of GPC3 reduces the migration and motility of hepatocellular carcinoma cells, further confirming the functional contribution of GPC3 to tumor metastasis.

VI. Conclusion.

In GPC3-related basic research and drug development, high-quality recombinant GPC3 protein is a core tool for elucidating its binding mechanisms with ligands such as Wnt, Hedgehog, FGF-2, and BMP and for evaluating the activity of targeted drugs. Fc-chimeric GPC3 protein forms dimers through the Fc fragment, more closely resembling the multivalent binding state of natural GPC3 on the cell surface, and can be used for high-affinity ligand binding assays and antibody screening. To meet the needs of GPC3 functional research and hepatocellular carcinoma targeted therapy development, Ulab provides GPC3/Glypican 3 Fc Chimera Protein, Human. This product is suitable for applications such as binding activity analysis of GPC3 with ligands including Wnt, Hedgehog, FGF-2, and BMP; in vitro screening and evaluation of GPC3-targeted antibody drugs and antibody-drug conjugates; mechanistic research on GPC3-mediated signaling pathways; and the development of molecular imaging and immunotherapeutic strategies for hepatocellular carcinoma.

This article is reviewed and published by the technical expert team of UA

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