The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma
Open accessAbstract
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 significantly 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.
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GPC3 is highly expressed in HCC relative to other cancer types.
“Importantly, GPC3 is highly expressed in HCC relative to other cancer types (Fig. 3a)40,61.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [40]
The Hepatocyte lineage section reports diffuse GPC3 staining in 47 of 56 HCC cases (84%), while Other cell lineages reports little or no staining in the colorectal metastases, cholangiocellular carcinomas, and carcinoid tumor examined. The comparison does not establish higher expression than other cancer types generally: the paper also reports diffuse GPC3 staining in hepatoblastoma. (LLM, conf=0.84)
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Cheng, C. C. Y., Cheung, M. F., Lee, A. Y., Wu, Q., Chow, S. H.-C., Ang, J. Y. J., Riquelme Medina, I., Lo, G., Wu, H., Yang, W., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-09154-w · Cited by 3 · see citing works
- Authors
- Yamauchi, N., Watanabe, A., Hishinuma, M., Ohashi, K.-I., Midorikawa, Y., Morishita, Y., Niki, T., Shibahara, J., Mori, M., Makuuchi, M., Hippo, Y., Kodama, T., Iwanari, H., Aburatani, H., & Fukayama, M.
- Affiliations
- The University of Tokyo (JP)
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Mitsui Memorial Hospital (JP)
- Corresponding author
- Yamauchi, Naoko
- ORCID
- Venue
- Modern Pathology
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 18
- Issue
- 12
- Pages
- 1591-1598
- ISSN
- 0893-3952 (ISSN-L)
- OpenAlex
- W1976801200
- Cited by
- 338
- References
- 0
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 7 · 2023: 10 · 2022: 15 · 2021: 12 · 2020: 17 · 2019: 14 · 2018: 14 · 2017: 14 · 2016: 16 · 2015: 20 · 2014: 20 · 2013: 23 · 2012: 9
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Modern Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- glypican-3, hepatocellular carcinoma, oncofetal protein, diagnostic biomarkers, monoclonal antibodies, immunohistochemistry, hepatoblastoma, dysplastic nodules, heparan sulfate proteoglycans, alpha-fetoprotein, colorectal cancer metastasis
- MeSH terms
- Antibodies, Monoclonal, Antigens, Neoplasm, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Lung Neoplasms, Biomarkers, Tumor, Hepatoblastoma, Heparan Sulfate Proteoglycans, Hepatocytes, Cell Line, Tumor, Glypicans
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