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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...

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Autores principales: 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
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
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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.
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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
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