DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice
Lisiane B. Meira, … , James G. Fox, Leona D. Samson
Lisiane B. Meira, … , James G. Fox, Leona D. Samson
Published June 2, 2008
Citation Information: J Clin Invest. 2008;118(7):2516-2525. https://doi.org/10.1172/JCI35073.
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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

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Figure 4

Increased severity of stomach pathology in Aag–/– versus Aag+/+ animals infected with H. pylori.

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Increased severity of stomach pathology in Aag–/– versus Aag+/+ animals ...
(A) Histopathology of gastric disease and mucosal metaplasia induced by H. pylori infection in the stomach mucosa of Aag+/+ or Aag–/– mice. Uninfected Aag+/+ mouse stomach showed normal microscopic architecture (H&E) and a thin surface lining of gastric-type neutral mucins (red; AB/PAS), and anti-TFF2 stained intermittent mucous neck cells within normal oxyntic mucosa. Uninfected Aag–/– mice were indistinguishable from the uninfected Aag+/+, so only the Aag+/+ is shown. For infected Aag–/– mice, moderate gastritis with marked mucous metaplasia, hyperplasia, and oxyntic atrophy (loss of parietal and chief cells) was observed (H&E). Hyperplastic mucous neck cell population replaced resident zymogenic cells, secreting a mixture of gastric (red) and intestinal-type (acidic, blue) mucins (AB/PAS). Mucous metaplasia associated with expanded mucous neck cell population highlighted by TFF2 immunoreactivity. For infected Aag+/+ mice, gastritis but minimal oxyntic alterations were observed (H&E). Mucous neck cells were significantly reduced in number in the Aag+/+H. pylori–infected mouse (AB/PAS). Fewer TFF2-positive mucous neck cells were observed in the infected Aag+/+ mouse. Scale bars: 160 μm. (B) Pathology scores for infected Aag+/+ (circles) and infected Aag–/– (diamonds) mice. (C) Serum IgG1 and IgG2c responses to H. pylori in Aag–/– and Aag+/+ mice 32 weeks after infection. (D) H. pylori colonization levels in the stomach. Data presented as mean ± SD of log-transformed CFU/μg of genomic DNA.