ArticleHepatology (Baltimore, Md.)2019
A Frizzled-Like Cysteine-Rich Domain in Glypican-3 Mediates Wnt Binding and Regulates Hepatocellular Carcinoma Tumor Growth in Mice.
Article in Hepatology (Baltimore, Md.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 122 citations in OpenAlex.
- A novel predictive model of microvascular invasion in hepatocellular carcinoma based on differential protein expression.BMC gastroenterology · 2023Trial
- CSTF2-mediated 3'UTR shortening drives oncogenic activation of GPC3 in hepatocellular carcinoma.Oncogene · 2026Article
- Longitudinal Multifrequency MR Elastography Reveals Biomechanical Signatures of Progression in a Translational Liver Tumor Model.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Heparan Sulfate Controls Nanoscale Assembly of GPC3-Wnt Receptor Complexes.bioRxiv : the preprint server for biology · 2026Article
- Ablation of glypican-3 enhances radiosensitivity in liver cancer by prolonging G2/M arrest and activating the ATM/CHK2 pathway.bioRxiv : the preprint server for biology · 2026Article
- Oncolytic virus-mediated GPC3 delivery overcomes antigen heterogeneity in hepatocellular carcinoma and enhances GPC3-directed immunotherapy.Frontiers in immunology · 2026Article
- Clinicopathologic and prognostic significance of TIAM2 overexpression in resected hepatocellular carcinoma.Future science OA · 2025Article
- Effect of AFP and PIVKA-II secretion status on prognosis of advanced hepatocellular carcinoma patients receiving TACE combined with systemic therapy.BMC cancer · 2025Article
- Targeting glypican-3 as a new frontier in liver cancer therapy.World journal of hepatology · 2025Review
- Secreted lumican from the tumor microenvironment potentiates HCC stemness and progression.Hepatology communications · 2025Article
- Targeting Glypican-3 for Liver Cancer Therapy: Clinical Applications and Detection Methods.Journal of clinical and translational hepatology · 2025Review
- Review
- Structural Features of Glypicans and their Impact on Wnt Signaling in Cancer.Proteoglycan research · 2025Article
- The co-receptor Tetraspanin12 directly captures Norrin to promote ligand-specific β-catenin signaling.eLife · 2025Article
- Frizzled receptors: gatekeepers of Wnt signaling in development and disease.Frontiers in cell and developmental biology · 2025Review
- The co-receptor Tetraspanin12 directly captures Norrin to promote ligand-specific β-catenin signaling.bioRxiv : the preprint server for biology · 2024Article
- The role of glypican-3 in hepatocellular carcinoma: Insights into diagnosis and therapeutic potential.European journal of medical research · 2024Review
- Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy.Journal of hematology & oncology · 2024Review
- Early monitoring values of oncogenic signalling molecules for hepatocellular carcinoma.World journal of gastrointestinal oncology · 2024Article
- Review
17 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
Wnt signaling is one of the key regulators of hepatocellular carcinoma (HCC) tumor progression. In addition to the classical receptor frizzled (FZD), various coreceptors including heparan sulfate proteoglycans (HSPGs) are involved in Wnt activation. Glypican-3 (GPC3) is an HSPG that is overexpressed in HCC and functions as a Wnt coreceptor that modulates HCC cell proliferation. These features make GPC3 an attractive target for liver cancer therapy. However, the precise interaction of GPC3 and Wnt and how GPC3, Wnt, and FZD cooperate with each other are poorly understood. In this study, we established a structural model of GPC3 containing a putative FZD-like cysteine-rich domain at its N-terminal lobe. We found that F41 and its surrounding residues in GPC3 formed a Wnt-binding groove that interacted with the middle region located between the lipid thumb domain and the index finger domain of Wnt3a. Mutating residues in this groove significantly inhibited Wnt3a binding, β-catenin activation, and the transcriptional activation of Wnt-dependent genes. In contrast with the heparan sulfate chains, the Wnt-binding groove that we identified in the protein core of GPC3 seemed to promote Wnt signaling in conditions when FZD was not abundant. Specifically, blocking this domain using an antibody inhibited Wnt activation. In HCC cells, mutating residue F41 on GPC3 inhibited activation of β-catenin in vitro and reduced xenograft tumor growth in nude mice compared with cells expressing wild-type GPC3. Conclusion: Our investigation demonstrates a detailed interaction of GPC3 and Wnt3a, reveals the precise mechanism of GPC3 acting as a Wnt coreceptor, and provides a potential target site on GPC3 for Wnt blocking and HCC therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.