title: Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice.
abstract: OBJECTIVE
  The Notch signaling pathway is activated in leukemia and solid tumors (such as lung cancer), but little is known about its role in liver cancer.
  
  
  METHODS
  The intracellular domain of Notch was conditionally expressed in hepatoblasts and their progeny (hepatocytes and cholangiocytes) in mice. This was achieved through Cre expression under the control of an albumin and α-fetoprotein (AFP) enhancer and promoter (AFP-Notch intracellular domain [NICD]). We used comparative functional genomics to integrate transcriptome data from AFP-NICD mice and human hepatocellular carcinoma (HCC) samples (n = 683). A Notch gene signature was generated using the nearest template prediction method.
  
  
  RESULTS
  AFP-NICD mice developed HCC with 100% penetrance when they were 12 months old. Activation of Notch signaling correlated with activation of 3 promoters of insulin-like growth factor 2; these processes appeared to contribute to hepatocarcinogenesis. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. These samples had altered expression in Notch pathway genes and activation of insulin-like growth factor signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer. Blocking Notch signaling in liver cancer cells with the Notch activation signature using γ-secretase inhibitors or by expressing a dominant negative form of mastermind-like 1 reduced their proliferation in vitro.
  
  
  CONCLUSIONS
  Notch signaling is activated in human HCC samples and promotes formation of liver tumors in mice. The Notch signature is a biomarker of response to Notch inhibition in vitro.
authors.affiliation: HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain.
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Clara
authors.initials: C
authors.lastname: Alsinet
authors.forename: Kilangsungla
authors.initials: K
authors.lastname: Yanger
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zong
authors.forename: Sara
authors.initials: S
authors.lastname: Toffanin
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rodriguez-Carunchio
authors.forename: Manel
authors.initials: M
authors.lastname: Solé
authors.forename: Swan
authors.initials: S
authors.lastname: Thung
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007335:Insulin-Like Growth Factor II / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051880:Receptors, Notch; D007335:Insulin-Like Growth Factor II