Expression of Apurinic/Apyrimidinic Endonuclease-1 (APE-1) in H. pylori-Associated Gastritis, Gastric Adenoma, and Gastric Cancer

• Published in: Helicobacter (Cambridge, Mass.) Mass.), 2008-06, Vol.13 (3), p.209-218
• Main Authors: Futagami, Seiji, Hiratsuka, Tetsuro, Shindo, Tomotaka, Horie, Akane, Hamamoto, Tatsuhiko, Suzuki, Kenji, Kusunoki, Masafumi, Miyake, Kazumasa, Gudis, Katya, Crowe, Sheila E., Tsukui, Taku, Sakamoto, Choitsu
• Format: Article
• Language: English
• Subjects: 8-OHdG; Adenoma - enzymology; Adenoma - genetics; Adenoma - microbiology; Adult; Aged; APE-1; Cells, Cultured; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Female; gastric adenoma; gastric cancer; Gastric Mucosa - metabolism; Gastric Mucosa - microbiology; Gastritis - enzymology; Gastritis - genetics; Gastritis - microbiology; H. pylori infection; Helicobacter; Helicobacter Infections - enzymology; Helicobacter Infections - genetics; Helicobacter Infections - metabolism; Helicobacter pylori; Humans; Male; Middle Aged; RNA, Messenger - metabolism; Stomach Neoplasms - enzymology; Stomach Neoplasms - genetics; Stomach Neoplasms - microbiology
• ISSN: 1083-4389; 1523-5378
• DOI: 10.1111/j.1523-5378.2008.00605.x

Background and Aim:  Apurinic/apyrimidinic endonuclease‐1 (APE‐1) is a key enzyme in DNA base excision repair (BER), linked to cancer chemosensitivity. However, little is known about the localization of APE‐1 in Helicobacter pylori‐infected gastric mucosa or its role in the development of gastric cancer. To investigate the role of APE‐1 in the development of gastric cancer, we examined APE‐1 expression and localization in cultured cells and gastric biopsies from patients with H. pylori‐infected gastritis or gastric adenoma, and from surgically resected gastric cancer. Methods:  APE‐1 mRNA and protein expression were determined in H. pylori (CagA+) water‐extract protein (HPWEP)‐stimulated MKN‐28 cells, gastric adenocarcinoma cell‐line (AGS) cells, and human peripheral macrophages by real‐time polymerase chain reaction and Western blot analysis. APE‐1 expression and 8‐OHdG as a measure of oxidative DNA damage were evaluated by immunostaining. Localization of APE‐1 and IκBα phosphorylation in gastric adenoma and gastric cancer tissues were evaluated by single‐ and double‐label immunohistochemistry. Results:  In studies in vitro, HPWEP‐stimulation significantly increased APE‐1 mRNA expression levels in both MKN‐28 cells and human peripheral macrophages. Hypo/reoxygenation treatment significantly increased APE‐1 protein expression in HPWEP‐stimulated MKN‐28 cells. HPWEP stimulation significantly increased both APE‐1 expression and IκBα phosphorylation levels in MKN‐28 and AGS cells. In human tissues, APE‐1 expression in H. pylori‐infected gastritis without goblet cell metaplasia was significantly increased as compared to that in tissues from uninfected subjects. Eradication therapy significantly reduced both APE‐1 and 8‐OHdG expression levels in the gastric mucosa. APE‐1 expression was mainly localized in epithelial cells within gastric adenoma and in mesenchymal cells of gastric cancer tissues. APE‐1 expression in gastric cancer tissues was significantly reduced compared to that in H. pylori‐infected gastric adenoma, while 8‐OHdG index and IκBα phosphorylation levels did not differ between these two neoplastic tissue types. Co‐localization of APE‐1 and IκBα phosphorylation was observed not in gastric cancer cells but in gastric adenoma cells. Conclusion:  H. pylori infection is associated with increased APE‐1 expression in human cell lines and in gastric tissues from subjects with gastritis and gastric adenomas. The observed distinct expression patterns of APE