TY - JOUR
T1 - Expression and clinicopathological significance of notch signaling and cell-fate genes in biliary tract cancer
AU - Mazur, Pawel K.
AU - Riener, Marc Oliver
AU - Jochum, Wolfram
AU - Kristiansen, Glen
AU - Weber, Achim
AU - Schmid, Roland M.
AU - Siveke, Jens T.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/1
Y1 - 2012/1
N2 - Objectives: 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.
AB - Objectives: 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.
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U2 - 10.1038/ajg.2011.305
DO - 10.1038/ajg.2011.305
M3 - Article
C2 - 21931375
AN - SCOPUS:84855456052
SN - 0002-9270
VL - 107
SP - 126
EP - 132
JO - American Journal of Gastroenterology
JF - American Journal of Gastroenterology
IS - 1
ER -