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

Norihisa Ishimura, Steven F. Bronk, Gregory James Gores

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Abstract

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 γ-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.

Original languageEnglish (US)
Pages (from-to)1354-1368
Number of pages15
JournalGastroenterology
Volume128
Issue number5
DOIs
StatePublished - May 2005

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Nitric Oxide Synthase Type II
Carcinogenesis
Up-Regulation
Cholangiocarcinoma
Notch Receptors
Sclerosing Cholangitis
Apoptosis
Ligands
Amyloid Precursor Protein Secretases
Bile Ducts
Genes
Tumor Necrosis Factor-alpha
Immunohistochemistry
Inflammation
Cell Line
Liver
Neoplasms

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes : Implications for carcinogenesis. / Ishimura, Norihisa; Bronk, Steven F.; Gores, Gregory James.

In: Gastroenterology, Vol. 128, No. 5, 05.2005, p. 1354-1368.

Research output: Contribution to journalArticle

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