Abstract
Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli / complications
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Adenomatous Polyposis Coli / pathology
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Adult
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Aged
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Aged, 80 and over
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Animals
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Antioxidants / pharmacology
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Carcinogenesis / drug effects
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Carcinogenesis / pathology
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Colitis / chemically induced
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Colitis / complications*
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Colitis / microbiology
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Colitis / pathology*
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Colon / drug effects
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Colon / pathology
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Colorectal Neoplasms / complications*
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Colorectal Neoplasms / microbiology
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Colorectal Neoplasms / pathology*
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Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
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DNA Damage*
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DNA Repair / drug effects
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Dextran Sulfate
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Disease Models, Animal
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Dysbiosis / complications
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Dysbiosis / pathology
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Escherichia coli / metabolism
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Female
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Guanosine / analogs & derivatives
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Guanosine / metabolism
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Helicobacter Infections / complications
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Helicobacter pylori / drug effects
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Helicobacter pylori / physiology*
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Humans
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Inflammation / complications
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Inflammation / pathology
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Interleukin-10 / deficiency
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Interleukin-10 / metabolism
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Male
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Mice, Inbred C57BL
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Middle Aged
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Mutation / genetics
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Oxidative Stress* / drug effects
Substances
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Antioxidants
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Guanosine
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Interleukin-10
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8-hydroxyguanosine
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Dextran Sulfate