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Cited by 77Liver physiology and pathologyProteoglycans and glycosaminoglycans researchWnt/β-catenin signaling in development and cancer

Suppression of Liver Regeneration and Hepatocyte Proliferation in Hepatocyte-Targeted Glypican 3 Transgenic Mice†

Open access
Liu, Bowen, Bell, Aaron W., Paranjpe, Shirish, Bowen, William C., Khillan, Jaspal S., Luo, Jian-Hua, Mars, Wendy M., Michalopoulos, George K.·2010·Hepatology
DOI 10.1002/hep.23794PMC PMC2936713
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Abstract

Glypican 3 (GPC3) belongs to a family of glycosylphosphatidylinositol-anchored, cell-surface heparan sulfate proteoglycans. GPC3 is overexpressed in hepatocellular carcinoma. Loss-of-function mutations of GPC3 result in Simpson-Golabi-Behmel syndrome, an X-linked disorder characterized by overgrowth of multiple organs, including the liver. Our previous study showed that GPC3 plays a negative regulatory role in hepatocyte proliferation, and this effect may involve CD81, a cell membrane tetraspanin. To further investigate GPC3 in vivo , we engineered transgenic (TG) mice overexpressing GPC3 in the liver under the control of the albumin promoter. GPC3 TG mice with hepatocyte-targeted, overexpressed GPC3 developed normally in comparison with their nontransgenic littermates but had a suppressed rate of hepatocyte proliferation and liver regeneration after partial hepatectomy. Moreover, gene array analysis revealed a series of changes in the gene expression profiles in TG mice (both in normal mice and during liver regeneration). In unoperated GPC3 TG mice, there was overexpression of runt related transcription factor 3 (7.6-fold), CCAAT/enhancer binding protein alpha (2.5-fold), GABA A receptor (2.9-fold), and wingless-related MMTV integration site 7B (2.8-fold). There was down-regulation of insulin-like growth factor binding protein 1 (8.4-fold), Rab2 (5.6-fold), beta-catenin (1.7-fold), transforming growth factor beta type I (3.1-fold), nodal (1.8-fold), and yes-associated protein (1.4-fold). Changes after hepatectomy included decreased expression in several cell cycle–related genes. Conclusion: Our results indicate that in GPC3 TG mice, hepatocyte overexpression of GPC3 suppresses hepatocyte proliferation and liver regeneration and alters gene expression profiles, and potential cell cycle–related proteins and multiple other pathways are involved and affected.

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  • Some forms of liver cancer are associated with GPC3 inhibition, which leads to reactivated cell proliferation.

    “Interestingly, some forms of liver cancer are associated with GPC3 inhibition, which leads to reactivated cell proliferation.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [97]

    The Discussion (page unavailable) says GPC3 is greatly elevated in human hepatocellular carcinoma, not inhibited; it suggests these cancers may be unresponsive to GPC3’s growth-regulating effects. The paper reports that blocking GPC3 promoted growth in cultured hepatocytes, but does not present GPC3 inhibition as a feature of liver cancer. (LLM, conf=0.88)

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  • Glypican-3 stimulates Hippo signaling and blocks YAP activity; maintaining high levels of GPC3 after liver regeneration prevents uncontrolled hepatocyte proliferation.

    “Glypican-3 (GPC3) plays a key role in stopping regeneration, as it stimulates Hippo signaling and blocks YAP activity. Once LR is complete, maintaining high levels of GPC3 prevents uncontrolled hepatocyte proliferation[97].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [97]

    The Results (page unavailable) report reduced nuclear YAP, increased inactive cytoplasmic phosphorylated YAP, and suppressed hepatocyte proliferation in GPC3-overexpressing mice after partial hepatectomy. The Discussion (page unavailable) says the growth-suppressive mechanism remains elusive: the paper does not establish that GPC3 stimulates Hippo signaling or that maintaining high GPC3 after regeneration is complete prevents uncontrolled proliferation. (LLM, conf=0.88)

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5 of the 43 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. [1]Fransson LA Glypicans International Journal of Biochemistry & Cell Biology 2003 35 125 129 12479862
  2. [6]Pellegrini M Pilia G Pantano S Lucchini F Uda M Fumi M Cao A Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome Dev Dyn 1998 213 431 439 9853964
  3. [19]Nadal C Zajdela F Hepatic polyploidy in the rat. IV. Experimental changes in the nucleolar volume of liver cells and their mechanisms of regulation Exp Cell Res 1967 48 518 528 6082326

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Authors
Liu, B., Bell, A. W., Paranjpe, S., Bowen, W. C., Khillan, J. S., Luo, J.-H., Mars, W. M., & Michalopoulos, G. K.
Affiliations
University of Pittsburgh (US)
Corresponding author
Michalopoulos, George K.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2010-09
Volume
52
Issue
3
Pages
1060-1067
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.23794
PMC
PMC2936713
OpenAlex
W1964480542
Cited by
77
References
43
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 9 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 2 · 2015: 4 · 2014: 9 · 2013: 12 · 2012: 6
FWCI
5.04
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1826 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000005, CA30241)
  • National Cancer Institute (CA 35373, R01CA035373, CA30241, R37CA030241)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
glypican-3, hepatocyte proliferation, liver regeneration, partial hepatectomy, albumin promoter, CD81, tetraspanins, heparan sulfate proteoglycans, gene expression profiling, cell cycle genes, hepatocellular carcinoma, Simpson-Golabi-Behmel syndrome, transgenic mice
MeSH terms
Animals, Hepatectomy, Liver, Liver Regeneration, Male, Mice, Transgenic, Receptors, GABA-A, Receptors, Virus, Cell Cycle Proteins, Insulin-Like Growth Factor Binding Protein 1, rab2 GTP-Binding Protein, Gene Expression Profiling, CCAAT-Enhancer-Binding Protein-alpha, Hepatocytes, Models, Animal, Cell Proliferation, beta Catenin, Mice, Glypicans, Transforming Growth Factor beta1

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