DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice.
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.
Department of Biological Engineering and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Lisiane B
LB
Meira
James M
JM
Bugni
Stephanie L
SL
Green
Chung-Wei
CW
Lee
Bo
B
Pang
Diana
D
Borenshtein
Barry H
BH
Rickman
Arlin B
AB
Rogers
Catherine A
CA
Moroski-Erkul
Jose L
JL
McFaline
David B
DB
Schauer
Peter C
PC
Dedon
James G
JG
Fox
Leona D
LD
Samson
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics*; D004260:DNA Repair; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000633:toxicity; D016481:Helicobacter Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000254:growth & development; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011687:Purines / Q000032:analysis / Q000378:metabolism; D011743:Pyrimidines / Q000032:analysis / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013270:Stomach / Q000382:microbiology / Q000473:pathology; D051176:beta Catenin / Q000235:genetics
C495267:CTNNB1 protein, mouse; D011687:Purines; D011743:Pyrimidines; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D051176:beta Catenin; D016264:Dextran Sulfate; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)