Increased oxidative DNA damage, inducible nitric oxide synthase, nuclear factor кB expression and enhanced antiapoptosis-related proteins in Helicobacter pylori-infected non-cardiac gastric adenocarcinoma

AIM:Several epidemiological studies have demonstrateda close association between Helicobacter pylori(H Pylori)infection and non-cardiac carcinoma of the stomach.Hpyloriinfection induces active inflammation with neutrophilicinfiltrations as well as production of oxygen free radicalsthat can cause DNA damage.The DNA damage induced byoxygen free radicals could have very harmful consequences,leading to gene modifications that are potentially mutagenicand/or carcinogenic.The aims of the present study wereto assess the effect of Hpyloriinfection on the expressionof inducible nitric oxidative synthase(iNOS)and theproduction of 8-hydroxy-deoxyguanosine(8-OHdG),asensitive marker of oxidative DNA injury in human gastricmucosa with and without tumor lesions,and to assess thepossible factors affecting cell death signaling due tooxidative DNA damage.METHODS:In this study,40 gastric carcinoma specimensand adjacent specimens were obtained from surgicalresection.We determined the level of 8-OHdG formationby HPLC-ECD,and the expression of iNOS and mechanismof cell death signaling [including nuclear factor-κB(NFκB),MEKK-1,Caspase 3,B Cell lyrnphomal leukemia-2(Bcl-2),inhibitor of apoptosis protein(IAP)and myeloid cellleukemia-1(Mcl-1)] by Western-blot assay.RESULTS:The concentrations of 8-OHdG,iNOS,NFκB,Mcl-1and IAP were significantly higher in cancer tissues than inadjacent non-cancer tissues.In addition,significantly higherconcentrations of 8-OHdG,iNOS,NFκB,Mcl-1 and IAP weredetected in patients infected with H pylori compared withpatients who were not infected with H pylori Furthermore,8-OHdG,iNOS,NFκB,Mcl-1 and IAP concentrations weresignificantly higher in stage 3 and 4 patients than in stage1 and 2 patients. CONCLUSION:Chronic H pylori infection induces iNOSexpression and subsequent DNA damage as well as enhancesanti-apoptosis signal transduction.This sequence of eventssupports the hypothesis that oxygen-free radical-mediateddamage due to H pylori plays a pivotal role in the developmentof gastric carcinoma in patients with chronic gastritis.