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

Murthy, Siva S.; Shen, Tong; Rienzo, Assunta De; Lee, W C; Ferriola, Patrice C.; Jhanwar, Suresh C.; Mossman, Brooke T.; Filmus, Jorge; Testa, Joseph R.

doi:10.1038/sj.onc.1203322

Cited by 139 publications

(100 citation statements)

References 21 publications

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“…6 Heparan sulfate proteoglycans are well known to interact with growth factors through heparan sulfate chains and thereby to serve as coreceptors for heparin-binding growth factors. [7][8][9] While studies on ovarian cancer cell lines, mesotheliomas, and breast tumors have demonstrated the downregulation of GPC3, [10][11][12] other investigations on hepatocellular carcinoma have shown a marked elevation of GPC3 mRNA over the level observed in corresponding normal tissues. [13][14][15][16] In the present study, we report the generation of GPC3-C02 and A1836A, a pair of anti-human GPC3 mouse monoclonal antibodies that can detect GPC3 in paraffinembedded tissues by an immunohistochemical technique.…”

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

et al. 2005

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“…The role of this protein is not yet exactly known. Many studies suggest that GPC3 is a negative cellular growth regulator (Pilia et al, 1996;Weksberg et al, 1996;Cano-Gauci et al, 1999;Lin et al, 1999;Murthy et al, 2000;Xiang et al, 2001), one of the most compelling evidence being that a germline mutation of the gene causes the Simpson -Golabi -Behmel overgrowth syndrome (Pilia et al, 1996) and that Gpc3 knockout mice partly recapitulate the syndrome (Cano-Gauci et al, 1999). On the other hand, GPC3 has been shown to be overexpressed in hepatocellular carcinomas (Hsu et al, 1997;Toretsky et al, 2001;Zhu et al, 2001;Midorikawa et al, 2003) and to be associated with advanced stages as well as with the invasive potential of this cancer (Hsu et al, 1997).…”

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“…As the gene is located on the X chromosome and DNA methylation is implicated in chromosome X inactivation (Monk, 1986), this observation raises the possibility that a loss of methylation could be implicated in the overexpression of GPC3 in some cancer forms. Hypermethylation of the GPC3 promoter associated with gene silencing has been observed in certain adult cancers Lin et al, 1999;Murthy et al, 2000;Xiang et al, 2001). Owing to the potential involvement of GPC3 expression in the aetiology of embryonal tumours, we tested the methylation status of the GPC3 promoter in DNA samples derived from both normal and embryonal tumour cells.…”

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Methylation analysis of the glypican 3 gene in embryonal tumours

Boily¹,

Saikali²,

Sinnett³

2004

Br J Cancer

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We have previously shown that the glypican 3 (GPC3) gene was expressed in neuroblastoma (NB) and Wilms' tumour (WT), two embryonal tumours. GPC3 is an X-linked gene that has its peak expression during development and that is downregulated in all investigated tissues after birth. GPC3 expression could be involved in the aetiology of embryonal tumours such as NB and WT. Methylation is known to play a role in gene silencing, notably in chromosome X inactivation. Southern blot-and PCR-based methylation assays were used to assess the methylation status of the GPC3 promoter on genomic DNA from both normal and embryonal tumour cells. In normal cells, the promoter was not methylated in males and partially methylated in females. Our results suggest that DNA methylation of the promoter region is not essential for the transcriptional repression of the GPC3 gene and that the methylation observed in females is probably linked to the inactive X chromosome. In tumour samples, methylation abnormalities have been found exclusively in female NB samples (loss of methylation) and mainly in male WT samples (gain of methylation). Overall, methylation did not significantly correlate with the expression status of GPC3. Although promoter methylation is likely to affect the expression status of the gene, our results suggest that the deregulation of GPC3 transcriptional expression seen in NB and WT involves other regulatory levels.

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“…11 It has been suggested GPC3 plays a negative role in cell proliferation and an apoptosis-inducing role in specific tissues. 12 The gene is frequently methylated in various tumors and cell lines, [13][14][15] suggesting a tumor-suppressive role in tumorigenesis. However, it is also overexpressed in HCC; 16 recently, both Sung et al 17 and Capurro et al 5 reported GPC3 overexpression in HCC both at messenger and protein level.…”

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Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis

et al. 2007

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Hepatocellular nodules in cirrhosis include regenerative (large regenerative, LRN) and dysplastic (low and high grade, LGDN and HGDN) nodules, early and grade 1 HCC (eHCC-G1), and overt HCC. The differential diagnosis may be particularly difficult when lesions such as HGDN and eHCC-G1 are involved. We investigated the diagnostic yield of a panel of 3 putative markers of hepatocellular malignancy such as HSP70, glypican 3 (GPC3), and glutamine synthetase (GS). We selected 52 surgically removed nonmalignant nodules (15 LRNs, 15 LGDNs, 22 HGDNs) and 53 HCCs (10 early, 22 grade 1, and 21 grade 2-3) and immunostained them for HSP70, GPC3, and GS. The sensitivity and specificity of the individual markers for the detection of eHCC-G1 were 59% and 86% for GS, 69% and 91% for GPC3, and 78% and 95% for HSP70. We identified 2 main phenotypes: (1) all negative, seen in 100% LRN and LGDN, 73% HGDN and 3% eHCC-G1; (2) all positive, a feature detected in less than half the eHCC-G1. Using a 3-marker panel, when at least 2 of them, regardless which, were positive, the sensitivity and specificity for the detection of eHCC-G1 were respectively 72% and 100%; the most sensitive combination was HSP70؉/GPC3؉ (59%) when a 2-marker panel was used. Conclusion: The adopted panel of 3 markers is very helpful in distinguishing eHCC-G1 from dysplastic nodules arising in cirrhosis. (HEPATOLOGY 2007;45:725-734.)

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

Cited by 139 publications

References 21 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

Methylation analysis of the glypican 3 gene in embryonal tumours

Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis

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