AIM:NitrativeandoxidativeDNAdamagesuchas8-nitroguanineand8-oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodG)formationhasbeenimplicatedininitiationand/orpromotionofinflammation-mediatedcarcinogenesis.TheaimofthisstudyistoclarifywhethertheseDNAlesionsparticipateintheprogressionofintrahepaticcholangiocarcinoma.METHODS:Weinvestigatedtherelationoftheformationof8-nitroguanineand8-oxodGandtheexpressionofhypoxia-induciblefactor-1α(HIF-1α)withtumorinvasionin37patientswithintra-hepaticcholangiocarcinoma.RESULTS:Immunohistochemicalanalysesrevealedthat8-nitroguanineand8-oxodGformationoccurredtoamuchgreaterextentincanceroustissuesthaninnon-canceroustissues.HIF-1αcouldbedetectedincanceroustissuesinallpatients,suggestinglowoxygentensioninthetumors.HIF-1αexpressionwascorrelatedwithinduciblenitricoxidesynthase(iNOS)expression(r=0.369andP=0.025)and8-oxodGformation(r=0.398andP=0.015).DoubleimmunofluorescencestudyrevealedthatiNOSandHIF-1αco-localizedincanceroustissues.Notably,theformationof8-oxodGwascorrelatedsignificantlywithlymphaticinvasion(r=0.386andP=0.018).Moreover,8-nitroguanineand8-oxodGinnon-canceroustissueswereassociatedsignificantlywithneuralinvasion(P=0.042andP=0.026,respectively).TheseresultssuggestthatreciprocalactivationbetweenHIF-1αandiNOSmediatespersistentDNAdamage,whichinducestumorinvasivenessviamutations,resultinginpoorprognosis.CONCLUSION:Theformationof8-nitroguanineand8-oxodGplaysanimportantroleinmultiplestepsofgeneticchangesleadingtotumorprogression,includinginvasiveness.
