title: Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis.
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.
  
  
  CONCLUSIONS
  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).
authors: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Judit
authors: J
authors: López-Luque
authors: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Daniel
authors: D
authors: Caballero-Díaz
authors: 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.
authors: Adoración
authors: A
authors: Martinez-Palacián
authors: 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.
authors: César
authors: C
authors: Roncero
authors: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Joaquim
authors: J
authors: Moreno-Càceres
authors: Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, , Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Advanced Therapies Mixed Unit, CIEMAT/IIS Fundación Jiménez Díaz, Madrid, Spain.
authors: María
authors: M
authors: García-Bravo
authors: Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, , Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors: Esther
authors: E
authors: Grueso
authors: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain.
authors: Almudena
authors: A
authors: Fernández
authors: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Eva
authors: E
authors: Crosas-Molist
authors: 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.
authors: María
authors: M
authors: García-Álvaro
authors: 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.
authors: Annalisa
authors: A
authors: Addante
authors: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Esther
authors: E
authors: Bertran
authors: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC/UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
authors: Angela M
authors: AM
authors: Valverde
authors: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC/UAM), Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain.
authors: Águeda
authors: Á
authors: González-Rodríguez
authors: 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.
authors: Blanca
authors: B
authors: Herrera
authors: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain.
authors: Lluis
authors: L
authors: Montoliu
authors: Pathological Anatomy Service, University Hospital of Bellvitge, Barcelona, Spain.
authors: Teresa
authors: T
authors: Serrano
authors: Cell Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, , Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Advanced Therapies Mixed Unit, CIEMAT/IIS Fundación Jiménez Díaz, Madrid, Spain.
authors: Jose-Carlos
authors: JC
authors: Segovia
authors: 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.
authors: Margarita
authors: M
authors: Fernández
authors: Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain.
authors: Emilio
authors: E
authors: Ramos
authors: 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.
authors: Aránzazu
authors: A
authors: Sánchez
authors: Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Spain.
authors: Isabel
authors: I
authors: Fabregat
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002384:Catalysis; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice
chemical_list: D066246:ErbB Receptors