The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury
Much of the global cancer burden is associated with longstanding inflammation accompanied by release of DNA-damaging reactive oxygen and nitrogen species. Here, we report that the Mbd4 DNA glycosylase is protective in the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model of inflammation-driv...
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| Format: | Article |
| Language: | en_US |
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Impact Journals/National Center for Biotechnology Information (U.S.)
2016
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| Online Access: | http://hdl.handle.net/1721.1/102633 https://orcid.org/0000-0002-7112-1454 |
| _version_ | 1811092489628549120 |
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| author | Yu, Amy Marie Calvo, Jennifer A. Muthupalani, Sureshkumar Samson, Leona D |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Yu, Amy Marie Calvo, Jennifer A. Muthupalani, Sureshkumar Samson, Leona D |
| author_sort | Yu, Amy Marie |
| collection | MIT |
| description | Much of the global cancer burden is associated with longstanding inflammation accompanied by release of DNA-damaging reactive oxygen and nitrogen species. Here, we report that the Mbd4 DNA glycosylase is protective in the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model of inflammation-driven colon cancer. Mbd4 excises T and U from T:G and U:G mismatches caused by deamination of 5-methylcytosine and cytosine. Since the rate of deamination is higher in inflamed tissues, we investigated the role of Mbd4 in inflammation-driven tumorigenesis. In the AOM/DSS assay, Mbd4[superscript –/–] mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4[superscript –/–] mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4[superscript –/–] mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4[superscript –/–] immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4[superscript –/–] mice transplanted with WT bone marrow. Mbd4[superscript –/–] mice with WT bone marrow behaved similarly to Mbd4[superscript –/–] mice. Together, our results indicate that the colonic epithelium of Mbd4[superscript –/–] mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer. |
| first_indexed | 2024-09-23T15:18:59Z |
| format | Article |
| id | mit-1721.1/102633 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:18:59Z |
| publishDate | 2016 |
| publisher | Impact Journals/National Center for Biotechnology Information (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1026332022-10-02T02:07:22Z The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury Yu, Amy Marie Calvo, Jennifer A. Muthupalani, Sureshkumar Samson, Leona D Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Division of Comparative Medicine Koch Institute for Integrative Cancer Research at MIT Yu, Amy Marie Calvo, Jennifer A. Muthupalani, Sureshkumar Samson, Leona D. Much of the global cancer burden is associated with longstanding inflammation accompanied by release of DNA-damaging reactive oxygen and nitrogen species. Here, we report that the Mbd4 DNA glycosylase is protective in the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model of inflammation-driven colon cancer. Mbd4 excises T and U from T:G and U:G mismatches caused by deamination of 5-methylcytosine and cytosine. Since the rate of deamination is higher in inflamed tissues, we investigated the role of Mbd4 in inflammation-driven tumorigenesis. In the AOM/DSS assay, Mbd4[superscript –/–] mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4[superscript –/–] mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4[superscript –/–] mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4[superscript –/–] immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4[superscript –/–] mice transplanted with WT bone marrow. Mbd4[superscript –/–] mice with WT bone marrow behaved similarly to Mbd4[superscript –/–] mice. Together, our results indicate that the colonic epithelium of Mbd4[superscript –/–] mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer. National Institutes of Health (U.S.) (Grant R01-CA075576) National Institutes of Health (U.S.) (Grant R01-CA055042) National Institutes of Health (U.S.) (Grant R01-CA149261) National Institutes of Health (U.S.) (Grant P30-ES000002) National Institutes of Health (U.S.) (Grant P30-ES02109) National Institutes of Health (U.S.) (Training Grant in Environamental Toxicology T32-ES007020MIT) American Cancer Society (Postdoctoral Fellowship PF-13-204-01) 2016-05-23T21:19:28Z 2016-05-23T21:19:28Z 2016-04 2016-02 Article http://purl.org/eprint/type/JournalArticle 1949-2553 http://hdl.handle.net/1721.1/102633 Yu, Amy Marie, Jennifer A. Calvo, Suresh Muthupalani, and Leona D. Samson. “The Mbd4 DNA Glycosylase Protects Mice from Inflammation-Driven Colon Cancer and Tissue Injury.” Oncotarget (May 9, 2016). © 2016 Impact Journals, LLC https://orcid.org/0000-0002-7112-1454 en_US http://dx.doi.org/10.18632/oncotarget.8721 Oncotarget Creative Commons Attribution http://creativecommons.org/licenses/by/3.0/ application/pdf Impact Journals/National Center for Biotechnology Information (U.S.) Impact Journals/National Center for Biotechnology Information (U.S.) |
| spellingShingle | Yu, Amy Marie Calvo, Jennifer A. Muthupalani, Sureshkumar Samson, Leona D The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury |
| title | The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury |
| title_full | The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury |
| title_fullStr | The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury |
| title_full_unstemmed | The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury |
| title_short | The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury |
| title_sort | mbd4 dna glycosylase protects mice from inflammation driven colon cancer and tissue injury |
| url | http://hdl.handle.net/1721.1/102633 https://orcid.org/0000-0002-7112-1454 |
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