Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis
Open accessAbstract
Different data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte‐specific truncated form of human EGFR, which acts as negative dominant mutant (ΔEGFR) and allows definition of its tyrosine kinase–dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two‐thirds partial hepatectomy, ΔEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor‐β pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor‐β through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in ΔEGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, ΔEGFR livers were able to recover liver mass by overactivating compensatory signals, such as c‐Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because ΔEGFR mice showed a delay in the appearance of diethyl‐nitrosamine‐induced tumors, which correlated with decreased proliferation and delay in the diethyl‐nitrosamine‐induced inflammatory process. Conclusion : These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology. (H epatology 2016;63:604–619)
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MET or EGFR signalling alone can compensate for one another, but blocking both results in deficient liver regeneration and animal death after partial hepatectomy.
“While MET or EGFR signalling alone can compensate for one another, blocking both signalling pathways results in deficient liver regeneration, with respect to original liver mass, and animal death after partial hepatectomy.[127], [128], [129]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [128]
The Discussion (page not provided) reports that mice with impaired EGFR signaling recovered liver mass after partial hepatectomy and had increased c-Met activation, suggesting partial compensation. It does not report the reverse compensation or test whether blocking both pathways causes deficient regeneration and death; it also says some EGFR functions are not compensated by c-Met. (LLM, conf=0.86)
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- Authors
- López‐Luque, J., Caballero‐Díaz, D., Martinez‐Palacián, A., Roncero, C., Moreno‐Càceres, J., García‐Bravo, M., Grueso, E., Fernández, A., Crosas‐Molist, E., García‐Álvaro, M., Addante, A., Bertran, E., Valverde, A. M., González‐Rodríguez, Á., Herrera, B., Montoliu, L., Serrano, T., Segovia, J., Fernández, M., Ramos, E., Sánchez, A., & Fabregat, I.
- Affiliations
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Department of Biochemistry and Molecular Biology II,School of Pharmacy, Complutense University of Madrid, and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC,Madrid,Spain
- Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division,, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT),Madrid,Spain
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Universidad Complutense de Madrid (ES)
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat,Barcelona,Spain
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC/UAM),Madrid,Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER),Madrid,Spain
- Bellvitge University Hospital (ES)
- Corresponding author
- Fabregat, Isabel
- ORCID
- Venue
- Hepatology
- Published
- 2015-10-10
- Volume
- 63
- Issue
- 2
- Pages
- 604-619
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W2129924635
- Cited by
- 68
- References
- 1
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 7 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 3
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Fundación Eugenio Rodríguez Pascual
- Comunidad de Madrid (S2010/BMD-2402)
- European Commission (316549)
- Generalitat de Catalunya (2009SGR, S2010/BMD-2402)
- Ministerio de Economía y Competitividad (BES-2013, SAF2012-33283, BFU2012-35538, SAF2012)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III (RD12/0019/0023, RETICS-RD12/0019/0023)
- European Regional Development Fund
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- epidermal growth factor receptor, liver regeneration, hepatocarcinogenesis, partial hepatectomy, hepatocyte proliferation, TGF-beta, c-Met, lipid metabolism, diethylnitrosamine, liver inflammation, transgenic mouse model, tyrosine kinase
- MeSH terms
- Animals, Catalysis, Humans, Liver Neoplasms, Liver Regeneration, Male, Mice, Carcinogenesis, ErbB Receptors
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