DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice.

Abstract

Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.

• Authors: Lisiane B Meira, James M Bugni, Stephanie L Green, Chung-Wei Lee, Bo Pang, Diana Borenshtein, Barry H Rickman, Arlin B Rogers, Catherine A Moroski-Erkul, Jose L McFaline, David B Schauer, Peter C Dedon, James G Fox, Leona D Samson
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 118 Issue 7 Pg. 2516-25 (Jul 2008) ISSN: 0021-9738 [Print] United States
• PMID: 18521188 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CTNNB1 protein, mouse
• Purines
• Pyrimidines
• Reactive Nitrogen Species
• Reactive Oxygen Species
• beta Catenin
• Dextran Sulfate
• 3-methyladenine-DNA glycosylase
• DNA Glycosylases
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Colon (drug effects, metabolism, pathology)
• Colonic Neoplasms (etiology, genetics, metabolism)
• DNA Damage
• DNA Glycosylases (deficiency, genetics)
• DNA Repair
• Dextran Sulfate (administration & dosage, toxicity)
• Helicobacter Infections (metabolism, microbiology, pathology)
• Helicobacter pylori (growth & development)
• Inflammatory Bowel Diseases (chemically induced, complications, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Biological
• Mutation
• Proto-Oncogene Proteins p21(ras) (genetics)
• Purines (analysis, metabolism)
• Pyrimidines (analysis, metabolism)
• Reactive Nitrogen Species (metabolism)
• Reactive Oxygen Species (metabolism)
• Spleen (drug effects, metabolism, pathology)
• Stomach (microbiology, pathology)
• beta Catenin (genetics)