Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes: implications for carcinogenesis

Gastroenterology. 2005 May;128(5):1354-68. doi: 10.1053/j.gastro.2005.01.055.


Background & aims: Inflammatory mediators and cell fate genes, such as the Notch gene family, both have been implicated in cancer biology. Because cholangiocarcinomas arise in a background of inflammation and express the inflammatory mediator inducible nitric oxide synthase (iNOS), we aimed to determine whether iNOS expression alters Notch expression and signaling.

Methods: Notch receptor and ligand expression in human liver was evaluated by immunohistochemistry. The effect of iNOS and NO on Notch-1 expression was examined in cell lines.

Results: Notch-1, but not other Notch receptors, were up-regulated by cholangiocytes in primary sclerosing cholangitis and cholangiocarcinoma. The colocalization of Notch-1 and iNOS also was observed in large bile ducts from the hilar region of primary sclerosing cholangitis patients. Notch-1 expression in murine cholangiocytes was iNOS dependent. iNOS expression also facilitated Notch signaling by inducing the nuclear translocation of its intracellular domain and the expression of a transcriptional target, hairy and enhancer of split (Hes)-1. The gamma-secretase inhibitor N-[N-(3,5-Difluorophenacetyl-L-alanyl)-S-phenylglycine]-t-butyl ester, which blocks Notch signaling, enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cholangiocarcinoma cells.

Conclusions: These data implicate a direct link between the inflammatory mediator iNOS and Notch signaling, and have implications for the development and progression of cholangiocarcinoma.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / physiopathology
  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Bile Duct Neoplasms / metabolism*
  • Bile Duct Neoplasms / physiopathology
  • Bile Ducts / cytology
  • Cell Line, Transformed
  • Cholangitis, Sclerosing / metabolism
  • Cholangitis, Sclerosing / physiopathology
  • Endopeptidases / metabolism
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Phenotype
  • Receptor, Notch1
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • S-Nitrosoglutathione / pharmacology
  • Signal Transduction / physiology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Up-Regulation


  • NOTCH1 protein, human
  • Nitric Oxide Donors
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Transcription Factors
  • S-Nitrosoglutathione
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinase 8
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse