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...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
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 |
| Summary: | 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. |
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