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Hepatology. 2016 Feb;63(2):604-19. doi: 10.1002/hep.28134. Epub 2015 Oct 10.

Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis.

Author information

1
Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
2
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.
3
Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, , Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
4
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
5
Advanced Therapies Mixed Unit, CIEMAT/IIS Fundación Jiménez Díaz, Madrid, Spain.
6
Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain.
7
Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC/UAM), Madrid, Spain.
8
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
9
Pathological Anatomy Service, University Hospital of Bellvitge, Barcelona, Spain.
10
Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain.
11
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Spain.

Abstract

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. (Hepatology 2016;63:604-619).

PMID:
26313466
DOI:
10.1002/hep.28134
[Indexed for MEDLINE]

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