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

Abstract

AIM:Several epidemiological studies have demonstrated a close association between Helicobacter pylori (H Pylori) infection and non-cardiac carcinoma of the stomach. H pylori infection induces active inflammation with neutrophilic infiltrations as well as production of oxygen free radicals that can cause DNA damage. The DNA damage induced by oxygen free radicals could have very harmful consequences, leading to gene modifications that are potentially mutagenic and/or carcinogenic. The aims of the present study were to assess the effect of H pylori infection on the expression of inducible nitric oxidative synthase (iNOS) and the production of 8-hydroxy-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA injury in human gastric mucosa with and without tumor lesions, and to assess the possible factors affecting cell death signaling due to oxidative DNA damage. METHODS:In this study, 40 gastric carcinoma specimens and adjacent specimens were obtained from surgical resection. We determined the level of 8-OHdG formation by HPLC-ECD, and the expression of iNOS and mechanism of cell death signaling [including nuclear factor-κB(NFκB), MEKK-1, Caspase 3, B Cell lymphomal leukemia-2 (Bcl-2), inhibitor of apoptosis protein (IAP ) and myeloid cell leukemia-1 (Mcl-1)] by Western-blot assay. RESULTS:The concentrations of 8-OHdG, iNOS, NFκB, Mcl-1 and IAP were significantly higher in cancer tissues than in adjacent non-cancer tissues. In addition, significantly higher concentrations of 8-OHdG, iNOS, NFκB, Mcl-1 and IAP were detected in patients infected with H pylori compared with patients who were not infected with H pylori. Furthermore, 8-OHdG, iNOS, NFκB, Mcl-1 and IAP concentrations were significantly higher in stage 3 and 4 patients than in stage 1 and 2 patients. CONCLUSION:Chronic H pylori infection induces iNOS expression and subsequent DNA damage as well as enhances anti-apoptosis signal transduction. This sequence of events supports the hypothesis that oxygen-free radical-mediated damage due to H pylori plays a pivotal role in the development of gastric carcinoma in patients with chronic gastritis.Chang CS, Chen WN, Lin HH, Wu CC, Wang CJ. Increased oxidative DNA damage, inducible nitric oxide synthase, nuclear factor κB expression and enhanced antiapoptosisrelated proteins in Helicobacter pylori-infected non-cardiac gastric adenocarcinoma. World J Gastroenterol 2004; 10 (15): 2232-2240

Mcl-1 is a relevant molecular target for antisense oligonucleotide strategies in gastric cancer cells

“…26 Interestingly, in gastric cancer patient biopsies the incidence of the well known gastric cancer risk factor H. pylorii correlates with both, increased levels of Mcl-1 and IL-6 expression. 23,27 Moreover, Mcl-1 protein and IL-6 are associated with high grade gastric cancer. 26,40 This apparent link between IL-6 and Mcl-1 prompted us to study the influence of IL-6 on Mcl-1 expression in our gastric cancer cell lines.…”

“…Notably, Mcl-1 is overexpressed in about 75% of gastric cancer specimens [25][26][27] and its expression correlates with tumor progression and postoperative recurrence in gastric carcinoma patients. 26 Interestingly, in gastric cancer patient biopsies the incidence of the well known gastric cancer risk factor H. pylorii correlates with both, increased levels of Mcl-1 and IL-6 expression.…”

“…25,26 Compared to adjacent noncancer tissues, Mcl-1 was significantly overexpressed in cancer tissues and in patients infected with Helicobacter pylorii. 27 Even more important, the expression of Mcl-1 was found to be an indicator of tumor progression and postoperative recurrence in patients with gastric carcinoma. 26 From this background Mcl-1 appears to be an attractive molecular target to overcome the chemoresistance phenotype of gastric cancer.…”

Serum oxidative stress status in CagA positive Helicobacter pylori infection

“…Oksidatif stresin yaşlanma, Alzheimer ve diğer nörodejenaratif hastalıklar, ateroskleroz, hipertansiyon ve mide kanseri patogenezinde önemli bir mekanizma olduğu ortaya çıkmıştır. 7,10 H.pilori enfeksiyonu oksidatif stresi artırdığı bilinmektedir.6,11 Çalışma, "CagA pozitif suşlar, daha virulan olduğundan CagA negatif suşlar göre oksidatif stresi daha fazla artırmalıdır" hipotezini test etme amaçlı tasarlanmıştır.…”

Overcoming Fas-Mediated Apoptosis Accelerates Helicobacter-Induced Gastric Cancer in Mice

“…These strategies seem to be distinct to specific cancer types such that within cancers of a given organ, there tends to be a preferred or at least predominant mechanism of apoptosis avoidance (2)(3)(4)(5)(6)(7)(8)(9). Additionally, there may be more than one antiapoptotic pathway present.…”