Glypican-3 Promotes the Growth of Hepatocellular Carcinoma by Stimulating Canonical Wnt Signaling

Capurro, Mariana; Yun, Xiang; Lobe, Corrinne G.; Filmus, Jorge

doi:10.1158/0008-5472.can-04-4244

Cited by 424 publications

(458 citation statements)

References 73 publications

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“…GPC3 regulates availability of Wnt proteins. 12 We also show in this study that there is an apparent increase in gene dosage for GPC3, suggesting that this gene is amplified in some HCC (Fig. 3).…”

Section: Biologic Significance Of Differentially Expressed Genes Betwsupporting

confidence: 68%

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

et al. 2006

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H epatocellular carcinomas (HCC) and hepatoblastomas of childhood (HPBL) are two types of liver cancer with high mortality and morbidity and international prevalence. There have been several recent studies of patterns of gene expression and molecular classification of HCC. [1][2][3][4] The studies demonstrated that HCC can be clustered in subgroups of gene expression patterns that have different prognostic and clinical behavior. Other recent studies also examined similarities between HCC precursor lesions (low and high grade liver nodules) and demonstrated significant similarities but also differences between HCC and precursor lesions. 5 In this study, we also focused on gene expression of HCC and HPBL, but from a different perspective than previous studies. We utilized a set of tissues from normal liver (NL), HCC, HPBL and tumor adjacent (AT) tissues and determined gene expression patterns not as a ratio of tumor vs. normal, but rather as absolute separate values for each unique tissue. This allowed standard but stringent statistical analysis not feasible when gene expression is only viewed as a fold change over normal tissues. Identification of gene expression patterns of liver tumors from this perspective allows identification of the main differences between the tumor subtypes and the adjacent nontumor (but often cirrhotic) liver; it also offers the potential of defining new therapeutic and diagnostic modalities. Our findings include some genes already shown to increase in HCC, thus validating our overall approach. Our results also revealed many other genes, not so far involved with biology of liver tumors. In addition, we carried a whole genome analysis of 27 HCC and determined chromosomal loci with genetic abnormalities common to most of the HCC. Materials and MethodsSee Supplemental information at the HEPATOLOGY

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Section: Biologic Significance Of Differentially Expressed Genes Betwsupporting

confidence: 68%

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

et al. 2006

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“…Interestingly, Wnt ligands are lipid-modified (34,41,42), and a lipid raft localization has been reported for Wnt1 (34). Additionally, glypicans, which are established HSPG partners for Wnt signaling (43,44), also localize to lipid rafts (45,46), as does the Wnt co-receptor LRP6 (47). Therefore, for optimal signaling it would seem most favorable if the Sulfs are concentrated in the same membrane microdomain as these other elements of Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

Functional Consequences of the Subdomain Organization of the Sulfs

Tang

Rosen

2009

Journal of Biological Chemistry

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Sulf-1 and Sulf-2 are novel extracellular sulfatases that act on internal glucosamine 6-O-sulfate modifications within heparan sulfate proteoglycans and regulate their interactions with various signaling molecules, including Wnt ligands. Although the Sulfs are multidomain proteins, there is limited information available about how the subdomains contribute to their enzymatic and signaling activities. In this study, we found that both human Sulfs were synthesized as prepro-enzymes and cleaved by a furin-type proteinase to form disulfide-bond linked heterodimers of 75-and 50-kDa subunits. The mature Sulfs were secreted into conditioned medium, as well as retained on the cell membrane. Although the catalytic center resides in the N-terminal 75-kDa subunit, the C-terminal 50-kDa subunit was indispensable for both arylsufatase and glucosamine 6-O-sulfate-endosulfatase activity. We found that the hydrophilic regions of the Sulfs were essential for endosulfatase activity but not for arylsulfatase activity. Using Edman sequencing, we identified furin-type proteinase cleavage sites in Sulf-1 and Sulf-2. Deletion of these sequences resulted in uncleavable forms of Sulfs. The uncleavable Sulfs retained enzymatic activity. However, they were unable to potentiate Wnt signaling, which may be due to their defective localization into lipid rafts on the plasma membrane.Heparan sulfate proteoglycans (HSPGs) 2 are major components of the extracellular matrix/cell surface and regulate a variety of biological phenomena, including cell proliferation, cell migration, and differentiation (1). These effects are mediated through the ability of HSPGs to bind to a diverse repertoire of protein ligands. Among these are morphogens, growth factors, chemokines, and other classes of molecules (2, 3).HSPGs consist of multiple heparan sulfate (HS) chains covalently linked to a limited set of core proteins. The HS chains contain repeating uronic acid and glucosamine disaccharide units. The binding functions of HSPGs depend on the fine structure of the attached heparan sulfate chains where sulfation modifications occur in four positions (N-, 3-O, and 6-O of glucosamine and 2-O of uronic acid) in highly variegated, yet highly regulated patterns (3, 4). 6-O-Sulfation of glucosamine is established to be critical for certain HSPG functions in organisms from Drosophila through mammals (5, 6).Several years ago, we cloned cDNAs encoding two novel extracellular sulfatases (Sulf-1 and Sulf-2) in human and mouse (7), initiated by the identification of the Sulf-1 ortholog in the quail embryo (QSulf-1) (8). We and others showed that both Sulfs are neutral pH endosulfatases, which remove glucosamine-6-O-sulfate from internal glucosamine residues of highly sulfated subregions within heparin/HSPGs (7, 9, 10). The ability of these enzymes to modulate the heparin/HSPG interactions of a number of growth factors, morphogens, and chemokines has been confirmed in direct binding assays (9, 11-13). In some cellular contexts, the Sulfs act to promote signaling pathways (...

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“…Glypicans play an important role in developmental morphogenesis and are known to be modulators for the Wnt signaling pathway (14)(15)(16)(17). It has been shown that GPC3, another member of the glypican family, may function as a coreceptor for Wnt and facilitate the Wnt/Frizzled binding in hepatocellular carcinoma cells (18,19).…”

mentioning

confidence: 99%

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

Hewitt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

126

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Neuroblastoma is a childhood cancer that is fatal in almost half of patients despite intense multimodality treatment. This cancer is derived from neuroendocrine tissue located in the sympathetic nervous system. Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan that is important for neuronal cell adhesion and neurite outgrowth. In this study, we find that GPC2 protein is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival compared with patients with low GPC2 expression. We demonstrate that silencing of GPC2 by CRISPR-Cas9 or siRNA results in the inhibition of neuroblastoma tumor cell growth. GPC2 silencing inactivates Wnt/ β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. We have isolated human single-domain antibodies specific for GPC2 by phage display technology and found that the single-domain antibodies can inhibit active β-catenin signaling by disrupting the interaction of GPC2 and Wnt3a. To explore GPC2 as a potential target in neuroblastoma, we have developed two forms of antibody therapeutics, immunotoxins and chimeric antigen receptor (CAR) T cells. Immunotoxin treatment was demonstrated to inhibit neuroblastoma growth in mice. CAR T cells targeting GPC2 eliminated tumors in a disseminated neuroblastoma mouse model where tumor metastasis had spread to multiple clinically relevant sites, including spine, skull, legs, and pelvis. This study suggests GPC2 as a promising therapeutic target in neuroblastoma.glypican | neuroblastoma | single-domain antibody | chimeric antigen receptor T-cell therapy | immunotoxin

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Glypican-3 Promotes the Growth of Hepatocellular Carcinoma by Stimulating Canonical Wnt Signaling

Cited by 424 publications

References 73 publications

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

Functional Consequences of the Subdomain Organization of the Sulfs

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

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