Definition

In 1988, the existence of GPC3 gene was first discovered by Filmus et al. in rat undifferentiated epithelial cell lines, and in 1996, Piria et al. cloned GPC3 complementary DNA (cDNA) in a case of aberration syndrome patients, and after analysis, it was found that it was identical or highly homologous to other phosphatidylinositol families, so it was named GPC3 gene. Glypican-3 is a protein encoded by the GPC3 gene in humans. The GPC3 gene is located on the human X chromosome (Xq26), where the most common gene (Isoform 2, GenBank: NP-004475) encodes the 70 kDa core protein with 580 amino acids.

Fig.1 Schematic of The Glypican-3 Protein

The protein core of GPC3 consists of two subunits, where the size of the N-terminal subunit is about 40 kDa and the size of the C-terminal subunit is about 30 kDa. Six phosphatidylinositol proteoglycans (GPC1-6) have been identified in mammals. Cell surface heparan sulfate proteoglycans consist of membrane-associated protein cores replaced by varying numbers of heparan sulfate chains. Members of the membrane by glycosylated phosphatidylinositol bonds. These proteins may play a role in controlling cell division and growth regulation. GPC3 mutated amino acids cause Simpson Golabi Behmel syndrome (SGBS), a phenomenon that may be related to the interaction between GPC3-FGFR2.

Fig. 2 Schematic Diagram of GPC3 on The Cell Membrane

Function

GPC3 can regulate Wnt/β-catenin and Yap signaling pathways. GPC3 interacts with Wnt and frizzled (FZD) to form complexes and trigger downstream signaling. The core protein of GPC3 can act as a co-acceptor or acceptor for Wnt. The cysteine-rich domain on the GPC3N leaf has been identified as a hydrophobic groove that interacts with Wnt3a. Blocking the Wnt-binding domain on GPC3 with HN3 single-domain antibodies inhibits Wnt activation. Wnt also identified heparan sulfate structures on GPC3, which contain IdoA2S and GlcNS6S, and 3-O-sulfation in GlcNS6S3S significantly enhanced Wnt's binding to heparan sulfate.

Fig. 3 Regulatory Effect of GPC3 on The WNT Signaling Pathway

GPC3 also regulates Yap signaling. It may interact with FAT1 on the cell surface.

GPC3 plays a role in HCC progression by binding to molecules such as Wnt-signaling proteins and growth factors. In addition, GPC3 has been used as a target for HCC molecular imaging and therapeutic interventions. To date, GPC3-targeted magnetic resonance imaging, positron emission tomography, and near-infrared imaging have been studied for early HCC detection, and various immunotherapy regimens targeting GPC3 have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, peptide/DNA vaccine therapy, immunotoxin therapy, and gene therapy.

GPC3 is a good prognostic indicator of HCC. Studies have shown that the expression level of GPC3 increases with the increase of HCC malignancy. Studies have typed the different expressions of GPC3 protein in HCC, and it can be seen that the prognosis of GPC3-positive HCC is much lower than that of GPC3-negative HCC.

GPC3 Activates the HCC Carcinogenic Pathway

Carcinogenic signaling pathways identified to be involved in the development of HCC include growth factor-related pathways such as insulin-like growth factor (IGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF); and cell differentiation-related pathways such as Wnt, Hedgehog, and Notch signaling. Among these signaling pathways, activation of the classical Wnt signaling pathway is a common feature of HCC, although the genetic pathogenesis of HCC is highly heterogeneous. Wnt signaling leads to β-caten β in translocation into the nucleus, forms complexes with T cytokines/lymphatic enhancement factor (TCF/LEF) transcription factors, and activates Wnt target gene expression.

Clinical Application

GPC3 plays an important role in regulating cell growth and differentiation and is closely related to the occurrence and development of primary liver cancer. GPC3 is highly expressed in HCC, but not expressed in normal tissues in adults or at low levels, indicating that GPC3 has obvious sensitivity and specificity for the diagnosis of liver cancer, and can be used as a tumor marker for HCC-specific identification. GPC3 is specifically overexpressed in HCC, making it an ideal target for HCC-targeted therapy. At present, HCC treatment methods for GPC3 include GPC3 antibody therapy, GPC3-derived peptide DNA vaccine therapy, immunotoxin therapy and gene therapy.

Alpha Lifetech Inc. is dedicated to developing Glypican-3 diagnostic regents. Alpha Lifetech Inc. is a reputable supplier focusing on research, manufacture and sales of In Vitro Diagnostic (IVD) regents. All the IVD regents offered by Alpha Lifetech Inc. have undergone strict QC validation and are certified by the COA (certificate of analysis). Meanwhile, we can provide customized services according to customers' requirements. Alpha Lifetech Inc. is committed to supplying high-quality, high-sensitivity antigen and antibody products for scientific research and industrial customers. In addition to regular small packages, Alpha Lifetech Inc.'s large-scale fermentation platform also allows us to provide raw material-grade IVD regents for the majority of industrial customers.

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