TY - JOUR
T1 - Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes
T2 - Implications for carcinogenesis
AU - Ishimura, Norihisa
AU - Bronk, Steven F.
AU - Gores, Gregory J.
PY - 2005/5
Y1 - 2005/5
N2 - 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.
AB - 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.
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U2 - 10.1053/j.gastro.2005.01.055
DO - 10.1053/j.gastro.2005.01.055
M3 - Article
C2 - 15887117
AN - SCOPUS:19044383947
SN - 0016-5085
VL - 128
SP - 1354
EP - 1368
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -