GPC3

Official Full Name

glypican 3

Organism

Homo sapiens

GeneID

2719

Background

Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

Synonyms

SGB; DGSX; MXR7; SDYS; SGBS; OCI-5; SGBS1; GTR2-2;

Protein Sequence

MAGTVRTACLVVAMLLSLDFPGQAQPPPPPPDATCHQVRSFFQRLQPGLKWVPETPVPGSDLQVCLPKGPTCCSRKMEEKYQLTARLNMEQLLQSASMELKFLIIQNAAVFQEAFEIVVRHAKNYTNAMFKNNYPSLTPQAFEFVGEFFTDVSLYILGSDINVDDMVNELFDSLFPVIYTQLMNPGLPDSALDINECLRGARRDLKVFGNFPKLIMTQVSKSLQVTRIFLQALNLGIEVINTTDHLKFSKDCGRMLTRMWYCSYCQGLMMVKPCGGYCNVVMQGCMAGVVEIDKYWREYILSLEELVNGMYRIYDMENVLLGLFSTIHDSIQYVQKNAGKLTTTIGKLCAHSQQRQYRSAYYPEDLFIDKKVLKVAHVEHEETLSSRRRELIQKLKSFISFYSALPGYICSHSPVAENDTLCWNGQELVERYSQKAARNGMKNQFNLHELKMKGPEPVVSQIIDKLKHINQLLRTMSMPKGRVLDKNLDEEGFESGDCGDDEDECIGGSGDGMIKVKNQLRFLAELAYDLDVDDAPGNSQQATPKDNEISTFHNLGNVHSPLKLLTSMAISVVCFFFLVH

Open

Disease

Liver cancer, Lung cancer, Metastatic liver/bile duct neoplasm, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

19 +

Discontinued Drug

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Detailed Information

Glypican-3 (GPC3, also called DGSX, MXR7, GTR2-2, OCI-5, SDYS, SGB, SGBS, and SGBS1) is a cell surface protein which is highly expressed in hepatocellular carcinoma (HCC) and some other human cancers. The GPC3 gene encodes a 70-kDa precursor core protein, which can be cleaved by furin to generate a 40-kDa amino (N) terminal protein and a 30-kDa membrane-bound carboxyl (C) terminal protein, which has two heparan sulphate (HS) glycan chains. The GPC3 protein is attached to the cell membrane through a glycosyl-phosphatidylinositol (GPI) anchor. The C terminal membrane-bound protein is recognized by the monoclonal antibody (mAb) 1G12. Loss-of-function mutations of GPC3 lead to Simpson-Golabi-Behmel syndrome (SGBS), a rare X chromosome-linked overgrowth disorder typically associated with coarse faces with protruding jaw and tongue, upturned nasal tip and widened nasal bridge. The patients are usually quite tall. The mice with GPC3 knockout show similar symptoms as seen in SGBS. GPC3 binds Wnt and Hedgehog (Hh) proteins. GPC3 is also able to bind fibroblast growth factor-2 (FGF-2) through its HS chains. Because it shows high expression in HCC, GPC3 has the potential as a promising target for tumor-specific therapy.

GPC3 expression in HCC

Several studies have confirmed that GPC3 is a potential liver cancer therapeutic target because it is over-expressed in HCC but not expressed or expressed at low levels in normal adult tissue. Hsu et al. identified GPC3 as a potential biomarker for HCC. By using an mRNA differential display method with paired HCC and non-tumor liver samples, Hsu et al. found GPC3 mRNA highly expressed in 9 out of 14 HCC samples, whereas none were detected in eight non-tumor liver samples. This HCC specificity was further confirmed by Northern blot analysis in an expanded number of HCC samples, fetal and adult normal tissues, as well as other adult tumor types. From 154 patients, 143 out of 191 (74.8%) primary and recurrent HCC samples were GPC3 positive, but only 5 out of 154 (3.2%) nontumor liver samples had detectable GPC3 mRNA.

GPC3 may also be used as an ancillary tool in the histopathologic diagnostic process to distinguish HCC from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Libbrecht et al. found that GPC3 expression was higher in small HCCs than in cirrhosis and other types of small focal lesions, indicating that the transition from premalignant lesions to small HCC is associated with a sharp increase of GPC3 expression in a majority of cases.

GPC3-mediated signaling pathway in HCC progression

In addition to being a reliable indicator for the diagnosis and prognosis of HCC, GPC3 has an important role in the progression of HCC (Figure1). GPC3 functions as a coreceptor/storage site for some ligands, e.g. Wnt and FGF, via its HS side chains, and facilitates ligand and/or its receptors to stimulate the signaling pathways involved in HCC growth and invasion. Several studies showed that GPC3 could promote the growth of hepatoma cells in vivo and in vitro. Capurro et al suggested that GPC3 promoted the growth of hepatoma cells by stimulating canonical Wnt/b-catenin signaling pathway activity in vivo and in vitro. Recently, this GPC3-mediated activation of Wnt signaling pathway in HCC cells has been confirmed by other reports. Li et al showed that ectopic GPC3 could increase the c-Myc expression, a typical target of the canonical Wnt signaling pathway; c-Myc can also transcriptionally activate GPC3 directly in HCC cells. Zittermann et al reported that soluble GPC3, which is cleaved off the cell membrane at the GPI anchor domain, could inhibit the in vivo growth of HCC cells by blocking the canonical Wnt signaling pathway in tumors generated by Huh6 and Huh7, and Akt and ERK signaling activation in HepG2- and Huh7-derived tumors, respectively.

Figure 1. The diagram of possible GPC3-mediated signaling pathway in HCC progression.

GPC-3 is a new target for HCC therapy

GPC-3 overexpression plays an important role in HCC transformation, proliferation and metastasis. Thus, GPC-3 is a molecular target for HCC therapy. Silencing GPC-3 gene transcription by specific shRNA inhibits HCC cell proliferation. GPC-3 as a target for HCC therapy has been investigated with GPC-3 vaccine and anti-GPC-3 antibodies. Among them, antibody-based therapy is the most outstanding clinically. Given that GPC-3 is increased in early, high-grade dysplastic macronodules, plus that the significant proportion of overt HCC are immunoreactive with anti-GPC-3, a therapeutic mAb in the C-terminal portion of GPC-3 is generated in MRL/lpr mice against a GST-fusion. The antibody causes cytotoxicity; however it is effective in the xenograft model.

HCC is a highly chemoresistant cancer with no effective medication. Molecular targeted therapy provides an optimal option for HCC patient who cannot be treated by surgery. However, molecular therapy remains a challenge mainly owing to lack of specific targets. Oncofetal GPC-3 promotes HCC development through up-regulation of the Wnt/β-catenin pathway that provides a novel therapy for HCC. GPC-3 is not only a promising biomarker but also a therapeutic target for HCC. Further study should be conducted in combination of specific siRNA and multi-targets for HCC therapy.

References:

Ho M, Kim H. Glypican-3: A new target for cancer immunotherapy. European Journal of Cancer, 2011, 47(3):333-338.
Wang L, et al. Glypican-3 is a biomarker and a therapeutic target of hepatocellular carcinoma. Hepatobiliary & Pancreatic Diseases International, 2015, 14(4):361-366.
Filmus J, Capurro M. Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. Febs Journal, 2013, 280(10).
Feng M, Ho M. Glypican-3 antibodies: A new therapeutic target for liver cancer. FEBS Letters, 2014, 588(2):377-382.
Yongle W, et al. GPC-3 in hepatocellular carcinoma: current perspectives. Journal of Hepatocellular Carcinoma, 2016, Volume 3:63-67.

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