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Updated: Jul 6, 2026

Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes: implications for carcinogenesis
Norihisa Ishimura1, Steven F Bronk, Gregory J Gores
1Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota 55905, USA.
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.
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