Basic-liver, pancreas, and biliary tractInducible Nitric Oxide Synthase Up-Regulates Notch-1 in Mouse Cholangiocytes: Implications for Carcinogenesis
Section snippets
Human Liver Tissue
This minimal-risk study was approved by the institutional review board. Archival liver specimens were obtained from patients who had undergone liver transplantation for PSC (N = 16) and surgical resection for cholangiocarcinoma (CCA) (N = 12). Normal liver specimens were obtained from 15 liver biopsy samples of 7 living and 8 deceased liver transplant donors. Patients with other potential causes for their liver disease were excluded from the study by examination of the medical record and
Notch-1 Protein Expression Is Enhanced in PSC and CCA
We assessed the expression of Notch-1 protein by immunohistochemistry in PSC, CCA, and normal human liver. In either normal or diseased liver tissue, Notch-1 immunoreactivity was localized exclusively to cholangiocytes and never was observed in hepatocytes (Figure 1A). In normal liver specimens, moderate- to high-level expression (defined as a score of 2 on a scale of 0–2) was observed only in 27% (4 of 15) of the normal liver specimens. In contrast, Notch-1 expression was observed in the
Discussion
The principal findings of this study relate to the cellular mechanisms by which iNOS alters cell-fate decisions, promoting malignant transformation in biliary epithelia. The observations show the following: (1) Notch-1, but not other Notch receptors, were up-regulated by cholangiocytes in PSC, a preneoplastic biliary tract disease, and this expression pattern was retained by human cholangiocarcinoma; (2) Notch-1 and iNOS also were colocalized in large bile duct obtained from the hilar region of
References (52)
- et al.
The pathobiology of biliary epithelia
Gastroenterology
(1997) - et al.
Hepatic and malignancies in primary sclerosing cholangitis
J Hepatol
(2002) - et al.
Role of nitric oxide in carcinogenesis and tumour progression
Lancet Oncol
(2001) - et al.
Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells
Biochem Biophys Res Commun
(2002) - et al.
The Notch pathwaydemocracy and aristocracy in the selection of cell fate
Curr Opin Neurobiol
(1996) The ins and outs of notch signaling
Mol Cell Neurosci
(1997)- et al.
TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms
Cell
(1991) - et al.
Cloning, characterization, and the complete 56.8-kilobase DNA sequence of the human NOTCH4 gene
Genomics
(1998) - et al.
Homologs of vertebrate growth factors in Drosophila melanogaster and other invertebrates
Curr Top Dev Biol
(1990) - et al.
Human ligands of the Notch receptor
Am J Pathol
(1999)