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Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020), Nature Communications
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
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.<br />It is unclear how microbial-induced inflammation promotes neoplastic transformation in colitis-associated cancer (CAC). Here, the authors use models of CAC to show that inflammation induces 8-oxoguanine lesions in DNA, and that antioxidants can reduce these DNA lesions as well as CAC.
- Subjects :
- 0301 basic medicine
Male
DNA Repair
endocrine system diseases
Colorectal cancer
Carcinogenesis
General Physics and Astronomy
medicine.disease_cause
Inflammatory bowel disease
Antioxidants
0302 clinical medicine
Medicine
lcsh:Science
Aged, 80 and over
Multidisciplinary
Guanosine
Dextran Sulfate
Middle Aged
Colitis
Lynch syndrome
Interleukin-10
Adenomatous Polyposis Coli
030220 oncology & carcinogenesis
cardiovascular system
Mucosal immunology
population characteristics
DNA mismatch repair
Female
Colorectal Neoplasms
Adult
congenital, hereditary, and neonatal diseases and abnormalities
DNA damage
Colon
Science
General Biochemistry, Genetics and Molecular Biology
Article
Helicobacter Infections
03 medical and health sciences
Gastrointestinal cancer
Escherichia coli
Animals
Humans
Neoplastic transformation
cardiovascular diseases
neoplasms
Aged
Inflammation
Helicobacter pylori
Bacteria
business.industry
Cancer
nutritional and metabolic diseases
General Chemistry
medicine.disease
Colorectal Neoplasms, Hereditary Nonpolyposis
digestive system diseases
Mice, Inbred C57BL
Disease Models, Animal
Oxidative Stress
030104 developmental biology
Mutation
Cancer research
Dysbiosis
lcsh:Q
business
DNA Damage
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....45bb3217d7e52baeb3b82087f2506526