OCI-5/GPC3, a Glypican Encoded by a Gene That Is Mutated in the Simpson-Golabi-Behmel Overgrowth Syndrome, Induces Apoptosis in a Cell Line–specific Manner

González, Alfonso Dueñas; Kaya, Mitsunori; Shi, Wen; Song, Hui‐Fang; Testa, Joseph R.; Penn, Linda Z.; Filmus, Jorge

doi:10.1083/jcb.141.6.1407

Cited by 170 publications

(129 citation statements)

References 41 publications

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“…Further investigation may reveal the relationship of this regenerative phenomenon to the molecular biology of hepatocellular carcinoma. Although GPC3 was originally identified as a suppressor of cell proliferation, 21,22 it also acts as a negative regulator of inhibitory growth factors such as BMP-7. 20,23 Intracellular distribution of GPC3 might be related to such an altered function.…”

Section: Discussionmentioning

confidence: 99%

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

et al. 2005

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Expression profiling of hepatocellular carcinoma has demonstrated that glypican 3 (GPC3), a heparan sulfate proteoglycan anchored to the membrane, is expressed at a markedly elevated level in hepatocellular carcinoma. In this paper, two monoclonal antibodies against GPC3, GPC3-C02 and A1836A, were confirmed to specifically recognize GPC3 molecule in cells from hepatocellular carcinoma and hepatoblastoma cell lines by immunoblotting, and both were confirmed to recognize different epitopes of the GPC3 molecule by epitope mapping. Then, we evaluated the feasibility of GPC3-immunohistochemistry in the pathological diagnosis of benign and malignant hepatocellular lesions by applying these monoclonal antibodies to formalin-fixed and paraffin-embedded specimens. The immunoreactivity turned out to be identical in the two monoclonal antibodies and was thus confirmed to represent the actual expression of the GPC3 molecule. The expression was observed in the fetal liver, but not in normal adult liver, liver cirrhosis or hepatitis except for a tiny focus of a regenerative nodule of fulminant hepatitis. Diffusely positive staining of GPC3 was observed in malignant hepatocytes in hepatoblastomas and in hepatocellular carcinomas (47/56, 84%). GPC3 expression was independent of the differentiation and size of the hepatocellular carcinoma. On the other hand, there was only weak and focal staining in low-grade (2/8) and high-grade dysplastic nodules (6/8). GPC3 immunoreactivity was detected in only one of 23 metastatic lesions of colorectal carcinoma, and its expression was entirely absent in the liver cell adenoma (0/7), carcinoid tumor (0/1), and cholangiocellular carcinoma (0/16). When compared with immunohistochemistry of hepatocyte antigen and alpha-fetoprotein, GPC3-immunohistochemistry was siginificantly much more specific and sensitive for hepatocellular carcinomas. Thus, GPC3 was confirmed to be one of the oncofetal proteins now attracting attention for their promise both as markers of hepatocellular carcinoma in routine histological examination and as targets in monoclonal antibody-based hepatocellular carcinoma therapy. Modern Pathology (2005) 18, 1591-1598.

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Section: Discussionmentioning

confidence: 99%

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

et al. 2005

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“…We previously showed that membranebound GPC3 induces programmed cell death in cell lines derived from a rat MM and a human breast cancer (Gonzalez et al, 1998). Induction of apoptosis is cell line-speci®c, because such a response was not elicited in human HT-29 colorectal tumor cells or NIH3T3 ®broblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Hemagglutinin (HA) epitope-tagged human GPC3 cDNA was cloned into pEF-BOS vector (Gonzalez et al, 1998). Vector alone was used as a control.…”

Section: Ectopic Expression Of Gpc3 In Human MM Cellsmentioning

confidence: 99%

“…Ectopic expression of GPC3 in HMESO and Meso-17 was demonstrated by Northern and Western blot analyses. Total cell lysates were prepared as previously described (Gonzalez et al, 1998) and quantitated using the Bradford colorimetric assay. Equal amounts of denatured protein were separated electrophoretically in a 7.5% SDS ± PAGE gel, transferred to PVDF membrane (Dupont NEN), and the resulting Western blot was blocked with 5% non-fat milk in phosphate bu ered saline.…”

Section: Ectopic Expression Of Gpc3 In Human MM Cellsmentioning

confidence: 99%

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Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma

et al. 2000

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Gene expression changes in rat asbestos-induced malignant mesothelioma (MM) cells were investigated by di erential mRNA display. A mRNA transcript identi®ed by this approach was abundant in normal rat mesothelial cells but not expressed in rat MM cell lines. Northern blot analysis con®rmed that this transcript is uniformly silenced in rat MM cell lines and primary tumors. Nucleotide sequence analysis revealed that this transcript is encoded by the rat glypican 3 gene (GPC3), whose human homolog is mutated in the SimpsonGolabi-Behmel overgrowth syndrome. Allelic loss at the GPC3 locus was infrequent (6.9%) in MM cell lines, and no mutations were found. GPC3 transcript levels were markedly decreased in 16 of 18 primary tumors and 17 of 22 human MM cell lines. Most of the cell lines were shown to have aberrant methylation of the GPC3 promoter region. In two of four human MM cell lines tested, GPC3 expression was restored after 2-deoxy 5-azacytidine (DAC)-mediated demethylation of its promoter region. Ectopic expression of GPC3 inhibited in vitro colony formation of human MM cells. Collectively, these data suggest that down-regulation of GPC3 is a common occurrence in MM and that GPC3, an X-linked recessive overgrowth gene, may encode a negative regulator of mesothelial cell growth. Oncogene (2000) 19, 410 ± 416.

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“…6 ± 8 The exaggerated growth is probably due to an imbalance between growth-promoting and growth-inhibitory factors at speci®c early developmental stages, resulting in defective growth inhibition or apoptosis in certain cell types. 23,24 Recently, a mutation in the gene encoding for glypican 3 was detected in a minority of patients with SGBS. 10 Glypican-3 is a cell-surface proteoglycan which is involved in the control of organ growth.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation

et al. 2001

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OBJECTIVE:To develop and to characterize a human preadipocyte cell strain with high capacity for adipose differentiation serving as a model for studying human adipocyte development and metabolism in vitro. METHODS: Cells were derived from the stromal cells fraction of subcutaneous adipose tissue of an infant with Simpson ± Golabi ± Behmel syndrome (SGBS). Adipose differentiation was induced under serum-free culture conditions by exposure to 10 nM insulin, 200 pM triiodothyronine, 1 mM cortisol and 2 mM BRL 49653, a PPARg agonist. RESULTS: During the differentiation process SGBS cells developed a gene expression pattern similar to that found in differentiating human preadipocytes with a characteristic increase in fat cell-speci®c mRNAs encoding lipoprotein lipase (LPL), glycero-3-phosphate dehydrogenase (GPDH), GLUT4, leptin and others. Differentiated SGBS cells exhibited an increase in glucose uptake upon insulin stimulation and in glycerol release upon catecholamine exposure. SGBS adipocytes were morphologically, biochemically and functionally identical to in vitro differentiated adipocytes from healthy subjects. However, while preadipocytes from healthy control infants rapidly lost their capacity to differentiate after a few cell divisions in culture, SGBS cells maintained their differentiation capacity over many generations: upon appropriate stimulation 95% of SGBS cells of generation 30 developed into adipocytes. A mutation in the glypican 3 gene was not detected in the patient. Thus, it remains unclear whether the molecular alteration in SGBS cells is also responsible for the high differentiation capacity and further investigations are required. CONCLUSION: The human cell strain described here provides an almost unlimited source of human preadipocytes with high capacity for adipose differentiation and may, therefore, represent a unique tool for studying human fat cell development and metabolism. International Journal of Obesity (2001) 25, 8 ± 15

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OCI-5/GPC3, a Glypican Encoded by a Gene That Is Mutated in the Simpson-Golabi-Behmel Overgrowth Syndrome, Induces Apoptosis in a Cell Line–specific Manner

Cited by 170 publications

References 41 publications

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma

Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma

Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation

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