Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer
| Autor: | Catherine J. Streutker, Julia K. Copeland, Alberto Martin, Thergiory Irrazabal, David S. Guttman, Yann Malaise, Robert Gryfe, Erin O. Y. Wong, Mingsong Kang, Bhupesh Kumar Thakur, William Wiley Navarre |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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