However, many biochemical and genetic studies,2,5,1315except one,16showing that GPC3 does not regulate IGF signaling. heparan sulfate glycan chains. GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC. An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanized IgG molecule is currently undergoing clinical evaluation in patients with HCC. There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC. Keywords:glypicans, immunotherapy, biological markers, liver neoplasms, melanoma, ovarian neoplasms, endodermal sinus tumor, neuroblastoma, Wilms tumor == 1. Introduction == Liver cancer is the fifth Rofecoxib (Vioxx) most common malignant cancer worldwide. According to the American Cancer Society (www.cancer.org), hepatocellular carcinoma (HCC) accounts for about 75 percent of liver cancer cases. Cholangiocarcinoma (CCA) is the second most common primary liver malignant tumor arising from cholangiocytes and CCA accounts for about 10% of primary liver Rofecoxib (Vioxx) cancer cases. In 2009 2009, 22,620 new cases of primary liver cancer were found and 18,160 of these patients died in the United States. There are often no symptoms of liver cancer until the later stages. Currently, surgery is the standard treatment for liver cancer. Liver cancer does not respond to most chemotherapy drugs. There is an urgent need to develop new drugs with different mechanisms of action. Immunotherapy represents one new approach, but it remains a challenge mainly due to a lack of good tumor-specific targets. Glypican-3 (GPC3, also called DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB, SGBS, and SGBS1) is a cell surface protein that is highly expressed in HCC and some other human cancers including melanoma. TheGPC3gene 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 sulfate (HS) glycan chains. The GPC3 protein is attached to the cell membrane by a glycosyl-phosphatidylinositol (GPI) anchor (Fig. 1). The C terminal membrane-bound protein is recognized by the monoclonal antibody (mAb) 1G12. Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS), a rare X chromosome-linked overgrowth disorder typically associated with coarse faces with protruding jaw and tongue, widened nasal bridge, and upturned nasal tip.1The patients are usually quite tall. The mice with GPC3 knockout show similar symptoms as seen in SGBS.2GPC3 binds Wnt and Hedgehog (Hh) proteins.3,4GPC3 is also able to bind fibroblast growth factor 2 (FGF-2) through its HS chains.5Since it shows high expression in HCC, GPC3 has a potential as a promising target for tumor-specific therapy. Also, because small amounts of GPC3 can be detected in the blood of some patients with GPC3-positive cancers,6,7measurement of GPC3 in the blood may be a useful diagnostic to follow the course of these patients. This review will give a brief overview of the structure, function and biology of GPC3 and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy. == Fig. 1. == Schematic of the GPC3 protein. The human GPC3 gene encodes a 70 kDa Rofecoxib (Vioxx) precursor protein of 580 amino acids. Upon translocation into the endoplasmic reticulum, the N-terminal signal peptide (SS; residues 124) and the C-terminal GPI anchor addition Rofecoxib (Vioxx) signal (a predicted cleavage site: S560) are removed and the latter is replaced with a GPI anchor. The GPC3 precursor is cleaved into two subunits, NH2terminus (residues Q25 R358) and the GPI-anchored membrane-bound COOH terminus starting from S359. The three N-linked glycans (black lollipops; N124, N241 and N418) are indicated. == 2. GPC3 structure == In 1988, Filmus and colleagues identified the Rofecoxib (Vioxx) gene calledOCI-5in a rat undifferentiated epithelial cell line.8TheOCI-5gene was later namedGPC3based on its homology with other known members of the glypican family.1TheGPC3gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.:NP_004475) encodes Rabbit polyclonal to MDM4 a 70-kDa core protein with 580 amino acids. Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091). The distribution and functional significance of GPC3 isoforms are unknown. The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40.