title: Expression and clinicopathological significance of notch signaling and cell-fate genes in biliary tract cancer.
abstract: OBJECTIVE
  Biliary tract cancer (BTC) is a fatal cancer originating from epithelial cells of the intra- and extra-hepatic biliary duct system and the gallbladder. Genes and pathways regulating stem and progenitor cells as well as cell-fate decisions are increasingly recognized in tumorigenesis. We evaluated the expression of Notch1, Notch2, and HES1 (hairy and enhancer of split 1), as well as the biliary cell-fate regulators SOX9 (SRY (sex determining region Y)-box 9) and HNF1β (hepatocyte nuclear factor 1β), in BTC for correlation with clinicopathological parameters.
  
  
  METHODS
  Tissue microarrays including normal bile ducts and 111 BTCs consisting of 17 intrahepatic cholangiocarcinomas, 58 extrahepatic cholangiocarcinomas, and 36 gallbladder carcinomas were analyzed using immunohistochemistry.
  
  
  RESULTS
  Lack of cytoplasmic SOX9 expression was associated with a higher tumor grade (P=0.010) and a significantly reduced overall survival (P=0.002; median 6 months vs. 24 months) in univariate survival analysis, whereas lack of nuclear SOX9 expression was associated with a higher tumor stage (P=0.003). Notch pathway members showed high expression in BTC. However, no correlation was found between cytoplasmic or nuclear Notch1, Notch2, and HES1, as well as HNF1β expression, and any of the clinicopathological parameters. In multivariate analysis, cytoplasmic SOX9 expression was an independent prognostic factor for overall survival (P=0.031, relative risk=0.571).
  
  
  CONCLUSIONS
  We show strong Notch pathway activation and identify SOX9 as a prognostic marker in BTC. These results substantiate diagnostic and therapeutic approaches targeting developmentally active genes and pathways.
authors.affiliation: 2nd Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Germany.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.forename: Marc-Oliver
authors.initials: MO
authors.lastname: Riener
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001661:Biliary Tract Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D051881:Receptor, Notch1 / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics; D012189:Retrospective Studies; D055758:SOX9 Transcription Factor / Q000235:genetics; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D055758:SOX9 Transcription Factor; D000072056:Transcription Factor HES-1; C496495:HNF1B protein, human; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C527932:SOX9 protein, human; C078493:HES1 protein, human