Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice
Open accessAbstract
The Hippo kinase cascade, a growth-suppressive pathway that ultimately antagonizes the transcriptional coactivator Yes-associated protein (YAP), has been shown in transgenic animals to orchestrate organ size regulation. The purpose of this study was to determine whether in non–genetically modified mice (1) the Hippo pathway is involved in the regulation of adaptive liver enlargement caused by the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor and (2) a dysregulation of this pathway occurs during the development of chemically induced hepatocellular carcinoma (HCC). We show that liver enlargement caused by TCPOBOP was associated with an increase of YAP protein levels that paralleled the increase in 2-bromodeoxyuridine incorporation. Interestingly, when a second dose of TCPOBOP was given to mice with enlarged livers, no further increases in liver mass or YAP protein levels were observed, suggesting that the Hippo pathway prevents further growth of the hyperplastic liver. Viral-mediated exogenous expression of active YAP in mouse livers was able to partially overcome the block of hepatocyte proliferation. We also show that HCCs developed in mice given diethylnitrosamine and then subjected to repeated treatments with TCPOBOP had increased levels of YAP that were associated with down-regulation of microRNA 375, which is known to control YAP expression, and with enhanced levels of alpha-fetoprotein and connective tissue growth factor, two target genes of YAP. Conclusion: These results suggest that the Hippo pathway regulates adaptive liver enlargement and is probably inactivated in initiated cells that escape the suppressive constrain exerted on the surrounding normal tissue, thus allowing clonal expansion to HCC (HEPATOLOGY 2011;)
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CAR's pro-proliferative role in liver is mediated through induction of c-Myc, Foxm1, and cyclin D1, and modulation of β-catenin and YAP signaling pathways.
“Prior studies have focused primarily on the pro-proliferative role of CAR in the liver, mediated through the induction of factors such as cellular-myelocytomatosis oncogene (c-Myc),15 forkhead box m1 (Foxm1),15 and cyclin D1 (Ccnd1),16 as well as modulation of β-catenin17,18 and Yes-associated protein19, 20, 21, 22 signaling pathways.”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [19]
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Self-citationThe Role of Yes‐Associated Protein in Inflammatory Diseases and Cancer
Zhong, B., Du, J., Liu, F., & Sun, S. (2025) · MedComm · doi:10.1002/mco2.70128 · Cited by 10 · see citing works
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CAR requires Gadd45β to promote phenobarbital-induced mouse liver tumors in early stage
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Fenofibrate induces liver enlargement in aging mice via activating the PPARα-YAP signaling pathway
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Endonucleosis mediates internalization of cytoplasm into the nucleus
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Yes‐Associated Protein in Hepatocytes Protects Against Early Alcohol‐Associated Liver Disease
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Research Progress of Tumor Microenvironment Involved in Tumor Development and Treatment
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Reply to: “YAP in tumorigenesis: Friend or foe?”
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Self-citationIs This the Time to Reconsider the Names for Xenobiotic Nuclear Receptors?
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TAZ AS A REGULATOR OF MESENCHYMAL TRANSFORMATION AND CLINICAL AGGRESSIVENESS IN GLIOMAS
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The Expression of YAP in Oral Squamous Cell Carcinoma Cell Line
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- Authors
- Kowalik, M. A., Saliba, C., Pibiri, M., Perra, A., Ledda-Columbano, G. M., Sarotto, I., Ghiso, E., Giordano, S., & Columbano, A.
- Affiliations
- University of Cagliari (IT)
- University of Turin (IT)
- Corresponding author
- Columbano, Amedeo
- ORCID
- Venue
- Hepatology
- Published
- 2011-06
- Volume
- 53
- Issue
- 6
- Pages
- 2086-2096
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2022551540
- Cited by
- 86
- References
- 35
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 7 · 2017: 6 · 2016: 7 · 2015: 11 · 2014: 8 · 2013: 2 · 2012: 8
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro (IG-5925, IG-5984)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- YAP, Hippo signaling pathway, hepatocellular carcinoma, TCPOBOP, constitutive androstane receptor, liver hyperplasia, hepatocyte proliferation, miR-375, alpha-fetoprotein, connective tissue growth factor, diethylnitrosamine, clonal expansion, organ size control
- MeSH terms
- YAP-Signaling Proteins, Animals, Diethylnitrosamine, Disease Models, Animal, Female, Carcinoma, Hepatocellular, Hepatomegaly, Hyperplasia, Liver, Liver Neoplasms, Mice, Inbred C3H, Mice, Inbred Strains, Phosphoproteins, Pyridines, Cell Cycle Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice
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