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.

 

FotoGrupos

 

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.

Descárgate este artículo aquí.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

01-11-2019

Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper...

Read more

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

01-10-2019

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create...

Read more

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Read more

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Read more

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Read more

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Read more

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Read more

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Read more

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Read more

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Read more

Protector Members