Cargando…
Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer
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 D...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156452/ https://www.ncbi.nlm.nih.gov/pubmed/32286276 http://dx.doi.org/10.1038/s41467-020-15549-6 |
_version_ | 1783522209769193472 |
---|---|
author | Irrazabal, Thergiory Thakur, Bhupesh K. Kang, Mingsong Malaise, Yann Streutker, Catherine Wong, Erin O. Y. Copeland, Julia Gryfe, Robert Guttman, David S. Navarre, William W. Martin, Alberto |
author_facet | Irrazabal, Thergiory Thakur, Bhupesh K. Kang, Mingsong Malaise, Yann Streutker, Catherine Wong, Erin O. Y. Copeland, Julia Gryfe, Robert Guttman, David S. Navarre, William W. Martin, Alberto |
author_sort | Irrazabal, Thergiory |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7156452 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-71564522020-04-22 Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer Irrazabal, Thergiory Thakur, Bhupesh K. Kang, Mingsong Malaise, Yann Streutker, Catherine Wong, Erin O. Y. Copeland, Julia Gryfe, Robert Guttman, David S. Navarre, William W. Martin, Alberto Nat Commun Article 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. Nature Publishing Group UK 2020-04-14 /pmc/articles/PMC7156452/ /pubmed/32286276 http://dx.doi.org/10.1038/s41467-020-15549-6 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Irrazabal, Thergiory Thakur, Bhupesh K. Kang, Mingsong Malaise, Yann Streutker, Catherine Wong, Erin O. Y. Copeland, Julia Gryfe, Robert Guttman, David S. Navarre, William W. Martin, Alberto Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer |
title | Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer |
title_full | Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer |
title_fullStr | Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer |
title_full_unstemmed | Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer |
title_short | Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer |
title_sort | limiting oxidative dna damage reduces microbe-induced colitis-associated colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156452/ https://www.ncbi.nlm.nih.gov/pubmed/32286276 http://dx.doi.org/10.1038/s41467-020-15549-6 |
work_keys_str_mv | AT irrazabalthergiory limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT thakurbhupeshk limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT kangmingsong limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT malaiseyann limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT streutkercatherine limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT wongerinoy limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT copelandjulia limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT gryferobert limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT guttmandavids limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT navarrewilliamw limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer AT martinalberto limitingoxidativednadamagereducesmicrobeinducedcolitisassociatedcolorectalcancer |