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T.N. introduces the results of recent clinical trials targeting GPC3 in HCC and summarizes the latest knowledge regarding the role of GPC3 in HCC progression and clinical application targeting GPC3. = 0.0049). Median Cerdulatinib progression-free survival (PFS) was also improved compared to the placebo group (cabozantinib vs. placebo; 5.2 months vs. 1.9 months, respectively, with HR 0.44, 95% CI 0.36C0.52, 0.001) in the CELESTIAL study (“type”:”clinical-trial”,”attrs”:”text”:”NCT01908426″,”term_id”:”NCT01908426″NCT01908426) [7]. Ramucirumab, a VEGFR 2 antagonist, also showed a positive outcome as a second-line therapy for advanced HCC in the REACH and REACH-2 studies (“type”:”clinical-trial”,”attrs”:”text”:”NCT01140347″,”term_id”:”NCT01140347″NCT01140347 and “type”:”clinical-trial”,”attrs”:”text”:”NCT02435433″,”term_id”:”NCT02435433″NCT02435433) [8,9]. Immunotherapies may provide significant breakthroughs in cancer treatment. Immunotherapy can be divided into immune-brake molecular targeting therapy and immune-accelerator therapy. For the immune-brake molecular targeting therapies, immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (PD-1), anti-PD-1 ligand (PD-L1), and anti-cytotoxic T lymphocyte-associated protein-4 (CTLA-4) antibodies, are well established [10,11]. On the other hand, malignancy vaccine therapy and chimeric antigen receptor-T cells (CAR-T) therapy are immune-accelerator therapies in which a target molecule expressed by cancer cells is crucial [12]. As a representative molecule specifically expressed by cancer cells, glypican-3 (GPC3) in HCC has attracted attention. 2. GPC3: Structure, Expression, and Functions In 1988, Filmus et al. isolated a cDNA clone that corresponded to a developmentally regulated transcript in a Cerdulatinib cell line from rat small intestine [13]. The cDNA clone was Cerdulatinib named OCI-5. The human gene encodes a protein highly homologous to the glypican family and is now widely known as GPC3 [14]. GPC3 is an oncofetal heparan sulfate (HS) glycoprotein attached to the cell membrane by a glycophosphatidylinositol (GPI) anchor [15,16]. The GPC3 core protein consists of 580 amino acids and is 70 kDa in size. Two HS side chains are attached near the C-terminal portion. The single-chain GPC3 is usually processed by furin at the Arg358-Cys359 bond to generate the mature GPC3 consisting of a 40-kDa N-terminal subunit and a 30-kDa C-terminal subunit linked by disulfide bonds [17] (Physique 1). Various forms of GPC3 can be detected in culture supernatant of GPC3-expressing cells and in serum, indicating that proteolytic cleavages of the extracellular portion of GPC3 may occur [18,19,20]. Open in a separate window Physique 1 Structure of the glypican-3 (GPC3) molecule and possible involvement GPC3 in progression of HCC. The core protein consists of 580 amino acids. Two heparan sulfate (HS) side chains are attached near the C-terminal portion. Codrituzumab (GC33) recognizes the epitope near the Cerdulatinib glycosyl-phosphatidylinositol (GPI) anchor. Growth factors such as Wnt, fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) can be complexed with HS side chains. In Wnt signaling, GPC3 core protein functions with Frizzled receptor (FZD) as a co-receptor. Sulfatase 2 (SULF2) is known to release FGF to transduce signals through its specific receptor. MET: receptor of HGF; FGFR: fibroblast growth factor receptor; FZD: Frizzled receptor. The gene is located around the X chromosome (Xq26.2). GPC3 is usually believed to play a crucial regulatory role in cellular proliferation in embryonic mesodermal tissues since deletion of the gene leads to the development of gigantism/overgrowth syndrome known as SimpsonCGolabiCBehmel syndrome (SGBS) [21,22,23,24,25]. Mechanistically, GPC3 is likely involved in the regulations of the signaling pathways of Wnt, hedgehog, bone morphogenic protein, and FGF. In this way, it controls cell growth and apoptosis in certain cell types during development [26,27,28,29]. GPC3 is usually widely expressed in the placenta, as well as the liver, lungs, and kidneys of the embryo. In contrast, it is hardly detectable in most organs in adults [30]. This biological downregulation in adult tissues may be explained by DNA methylation within the promoter region [31,32,33]. 3. GPC3 and Tumor Progression The expression of GPC3 has been reported in various tumors, such Cerdulatinib as HCC, lung squamous cell carcinoma (SqCC), gastric carcinoma, ovarian carcinoma, melanomas, and pediatric embryonal tumors. Among them, the expression is particularly high in HCC [34,35,36,37,38,39]. In HCC cells, evidence suggests that GPC3 is usually involved in Wnt/-catenin signaling and enhances proliferation of the cells Mouse monoclonal to CD56.COC56 reacts with CD56, a 175-220 kDa Neural Cell Adhesion Molecule (NCAM), expressed on 10-25% of peripheral blood lymphocytes, including all CD16+ NK cells and approximately 5% of CD3+ lymphocytes, referred to as NKT cells. It also is present at brain and neuromuscular junctions, certain LGL leukemias, small cell lung carcinomas, neuronally derived tumors, myeloma and myeloid leukemias. CD56 (NCAM) is involved in neuronal homotypic cell adhesion which is implicated in neural development, and in cell differentiation during embryogenesis [40] (Physique 1). GPC3 core protein interacts with the Wnt receptor Frizzled (FZD) [41], and a recent study has revealed that GPC3 core protein functions as a co-receptor for Wnt to promote the Wnt/-catenin signaling in HCC cells [42]. Upregulated GPC3 accelerates the progression of lung.