title: Activation of signal transduction pathways during hepatic oncogenesis.
abstract: OBJECTIVE
  Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) is essential to identify therapeutic targets. A hepatitis B virus (HBV) related double transgenic murine model was developed.
  
  
  METHODS
  Liver specific expression of HBV X protein (HBx) and insulin receptor substrate 1 (IRS1) was achieved and transgenic mice were followed from birth to age 21 months. Liver and tumor tissue were assessed for histologic changes as well as activation of signal transduction pathways by qRT-PCR and multiplex ELISA protein assays.
  
  
  RESULTS
  Overexpression of HBx and IRS1 stimulates liver cell proliferation in the double transgenic mice. Only the male mice developed HCC starting at age 15-18 months. The IN/IGF1/IRS1/MAPK/ERK and IN/IGF1/IRS1/PI3K/AKT/GSK3β cascades were activated early (6-9 months) in the liver followed by WNT/β-catenin and Notch signaling. Aspartate β-hydroxylase (ASPH) was found to link these upstream growth factor signaling pathways to downstream Notch activation in tumor tissues.
  
  
  CONCLUSIONS
  Sustained overexpression of HBx and IRS1 led to constitutive activation of a tripartite growth factor signal transduction cascade in the liver and was necessary and sufficient to promote HCC development and progression.
authors.affiliation: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, 4th Fl., Providence, RI 02903, USA.
authors.forename: Waihong
authors.initials: W
authors.lastname: Chung
authors.affiliation: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, 4th Fl., Providence, RI 02903, USA.
authors.forename: Miran
authors.initials: M
authors.lastname: Kim
authors.affiliation: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, 4th Fl., Providence, RI 02903, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: de la Monte
authors.affiliation: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, 4th Fl., Providence, RI 02903, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Longato
authors.affiliation: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, 4th Fl., Providence, RI 02903, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Carlson
authors.affiliation: Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Betty L
authors.initials: BL
authors.lastname: Slagle
authors.affiliation: Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, 975 NE 10th St., Oklahoma City, OK 73104, USA.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Dong
authors.affiliation: Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, 4th Fl., Providence, RI 02903, USA. Electronic address: jack_wands_md@brown.edu.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D055504:Insulin Receptor Substrate Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000502:physiology
chemical_list: C495267:CTNNB1 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Growth factor signaling pathways; Hepatocellular carcinoma; Transgenic mice