title: Epidermal growth factor receptor signaling in hepatocellular carcinoma: inflammatory activation and a new intracellular regulatory mechanism.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is a chemoresistant tumor strongly associated with chronic hepatitis. Identification of molecular links connecting inflammation with cell growth/survival, and characterization of pro-tumorigenic intracellular pathways is therefore of therapeutic interest. The epidermal growth factor receptor (EGFR) signaling system stands at a crossroad between inflammatory signals and intracellular pathways associated with hepatocarcinogenesis. We investigated the regulation and activity of different components of the EGFR system, including the EGFR ligand amphiregulin (AR) and its sheddase ADAM17, and the modulation of intracellular EGFR signaling by a novel mechanism involving protein methylation.
  
  
  METHODS
  ADAM17 protein expression was examined in models of liver injury and carcinogenesis. Crosstalk between tumor necrosis factor (TNF)-α, AR and EGFR signaling was evaluated in human HCC cells and mouse hepatocytes. Modulation of EGFR signaling and biological responses by methylation reactions was evaluated in AML12 mouse hepatocytes.
  
  
  RESULTS
  ADAM17 was upregulated in liver injury and hepatocarcinogenesis. TNF-α triggered AR shedding and EGFR transactivation in HCC cells. AR was necessary for TNF-α activation of ERK1/2 and Akt signaling in hepatocytes. Inhibition of methylation reactions increased the ERK1/2 signal amplitude triggered by AR/EGFR and reduced DNA synthesis in AML12 cells.
  
  
  CONCLUSIONS
  Increased ADAM17 in pre-neoplastic liver injury further supports its implication in hepatocarcinogenesis. AR release and EGFR transactivation by TNF-α constitutes a novel link between inflammatory signals and pro-tumorigenic mechanisms in liver cells. Finally, the identification of a new mechanism controlling growth factor signaling, and biological responses, involving methylation reactions within the RAS/RAF/MEK/ERK pathway, exposes a new target for antineoplastic intervention.
authors.affiliation: Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nicou
authors.forename: Oihane
authors.initials: O
authors.lastname: Garcia-Irigoyen
authors.forename: M Ujue
authors.initials: MU
authors.lastname: Latasa
authors.forename: Raquel
authors.initials: R
authors.lastname: Urtasun
authors.forename: Maria
authors.initials: M
authors.lastname: Elizalde
authors.forename: Fabiana
authors.initials: F
authors.lastname: Salis
authors.forename: María J
authors.initials: MJ
authors.lastname: Perugorría
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Juan A
authors.initials: JA
authors.lastname: Recio
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D066258:Amphiregulin; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008745:Methylation; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse