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Tumor Biology |
Center for Basic Research in Digestive Diseases [M. J., N. F. L., G. J. G], Division of Gastroenterology and Hepatology, Department of Laboratory Medicine and Pathology [L. J. B.], Mayo Clinic/Foundation/Medical School, Rochester, Minnesota 55905
Chronic infection and inflammation are risk factors for the development
of cholangiocarcinoma, a highly malignant, generally fatal
adenocarcinoma originating from biliary epithelia. However, the link
between inflammation and carcinogenesis in these disorders is obscure.
Because nitric oxide (NO) is generated in inflamed tissues by inducible
nitric oxide synthase (iNOS) and because DNA repair proteins are
potentially susceptible to NO-mediated nitrosylation, we formulated the
hypothesis that inflammatory cytokines induce iNOS and sufficient NO to
inhibit DNA repair enzymes leading to the development and progression
of cholangiocarcinoma. iNOS and nitrotyrosine were demonstrated in
18/18 cholangiocarcinoma specimens. Furthermore, iNOS and NO generation
could be induced in vitro by inflammatory cytokines
(mixture of interleukin-1ß, IFN-
, and tumor necrosis factor
) in three human cholangiocarcinoma cell lines. NO-dependent
DNA damage as assessed by the comet assay was demonstrated during
exposure of the three cholangiocarcinoma cell lines to cytokines.
Moreover, global DNA repair activity was inhibited by 70% by a
NO-dependent process after exposure of cells to cytokines. Our data
indicate that activation of iNOS and excess production of NO in
response to inflammatory cytokines cause DNA damage and inhibit DNA
repair proteins. NO inactivation of DNA repair enzymes may provide a
link between inflammation and the initiation, promotion, and/or
progression of cholangiocarcinoma.
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