Reference

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

Authors

Judit López-Luque, Daniel Caballero-Díaz, Adoración Martinez-Palacián, César Roncero, Joaquim Moreno-Càceres, María García-Bravo, Esther Grueso, Almudena Fernández, Eva Crosas-Molist, María García-Álvaro, Annalisa Addante, Esther Bertran, Angela M. Valverde, Águeda González-Rodríguez, Blanca Herrera, Lluis Montoliu, Teresa Serrano, Jose-Carlos Segovia, Margarita Fernández, Emilio Ramos, Aránzazu Sánchez, Isabel Fabregat.

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.

Description

Los grupos de investigación liderados por las doctoras Isabel Fabregat (IDIBELL), y Aránzazu Sánchez (UCM), en colaboración con el CIEMAT y el CSIC, han desarrollado un modelo de ratón modificado genéticamente que permite, por primera vez, estudiar de forma específica en los hepatocitos el papel de la actividad catalítica del receptor del factor de crecimiento epidérmico (EGFR). El trabajo, publicado en la revista Hepatology, demuestra, por un lado, que la activación de la vía del EGFR es crucial durante los primeros estadios de la regeneración hepática tras una hepatectomía parcial, viéndose esta retrasada, con baja activación de señales proliferativas y predominio de los mecanismos citostáticos. Por otro lado, la vía del EGFR juega un papel muy relevante en los estadios primarios de aparición de tumores en el hígado, presentando los ratones transgénicos un retraso en la aparición de prenódulos tras la inyección del carcinógeno dietil-nitrosamina (DEN). Este efecto se correlaciona con una menor inflamación, motor de la aparición de la hepatocarcinogenesis.

 

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REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de la doctora Isabel Fabregat, actualmente ubicado en el IDIBELL, empezó en la Universidad Complutense de Madrid, estudiando los mecanismos que controlan la proliferación, diferenciación y muerte de las células del hígado durante el desarrollo y la regeneración hepática. De éste surgió el grupo de la doctora Aránzazu Sánchez, que sigue ubicado en la UCM, manteniendo ambos grupos una estrecha colaboración. Una de sus líneas de investigación se ha enfocado al estudio del papel que juega la vía del receptor del EGF (EGFR) en las células hepáticas, sobretodo en relación a la resistencia a la muerte causada por el factor de crecimiento transformante beta (TGF-β). En este contexto, se diseñó este nuevo modelo animal, que puede contribuir al esclarecimiento de la función de la vía del EGFR en la fisiología y patología del hígado.

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