title: SOCS1 controls liver regeneration by regulating HGF signaling in hepatocytes.
abstract: OBJECTIVE
  Frequent repression of the Socs1 (suppressor of cytokine signaling 1) gene in hepatocellular carcinoma (HCC) and increased susceptibility of SOCS1-deficient mice to hepatocarcinogens suggest a tumor suppressor role for SOCS1 in the liver, but the underlying mechanisms remain unclear. Here we investigated the role of SOCS1 in regulating hepatocyte proliferation following partial hepatectomy and HGF stimulation.
  
  
  METHODS
  Because Socs1(-/-) mice die prematurely due to deregulated IFNγ signaling, we used Socs1(-/-)Ifng(-/-) mice to study the role of SOCS1 in liver regeneration following partial hepatectomy. We examined the activation of signaling molecules downstream of IL-6 and hepatocyte growth factor (HGF) receptors in the regenerating liver, primary hepatocytes, and in human hepatoma cells. We examined the interaction between SOCS1 and the HGF receptor c-Met by reciprocal immunoprecipitation.
  
  
  RESULTS
  Socs1(-/-)Ifng(-/-) mice displayed accelerated liver regeneration with increased DNA synthesis compared to Ifng(-/-) and wild type mice. The regenerating liver of Socs1(-/-)Ifng(-/-) mice did not show increased IL-6 signaling, but displayed earlier phosphorylation of Gab1, a signaling adaptor downstream of c-Met. Following HGF stimulation, hepatocytes from Socs1(-/-)Ifng(-/-) mice displayed increased phosphorylation of c-Met and Gab1, cell migration and proliferation. Accordingly, SOCS1 overexpression attenuated HGF-induced phosphorylation of c-Met, Gab1, and ERK1/2 in hepatoma cells, and decreased their proliferation and migration. SOCS1 interacted with the Tpr-Met, an oncogenic form of the Met receptor.
  
  
  CONCLUSIONS
  SOCS1 attenuates c-Met signaling and thus negative regulation of HGF signaling could be an important mechanism underlying the anti-tumor role of SOCS1 in the liver.
authors.affiliation: Immunology Division, Department of Pediatrics, Université de Sherbrooke, Centre de Recherche Clinique Etienne-Le Bel, Centre Hospitalier de l'Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
authors.forename: Yirui
authors.initials: Y
authors.lastname: Gui
authors.forename: Mehdi
authors.initials: M
authors.lastname: Yeganeh
authors.forename: Sheela
authors.initials: S
authors.lastname: Ramanathan
authors.forename: Chantal
authors.initials: C
authors.lastname: Leblanc
authors.forename: Véronique
authors.initials: V
authors.lastname: Pomerleau
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
authors.forename: Caroline
authors.initials: C
authors.lastname: Saucier
authors.forename: Subburaj
authors.initials: S
authors.lastname: Ilangumaran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050490:Oncogene Protein tpr-met / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C490897:Gab1 protein, mouse; C066855:HGF protein, human; C553307:HGF protein, mouse; D015850:Interleukin-6; D050490:Oncogene Protein tpr-met; D010750:Phosphoproteins; C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma