Oncotarget

Research Papers:

The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury

Amy Marie Yu, Jennifer A. Calvo, Suresh Muthupalani and Leona D. Samson _

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Oncotarget. 2016; 7:28624-28636. https://doi.org/10.18632/oncotarget.8721

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Abstract

Amy Marie Yu1, Jennifer A. Calvo1,2, Suresh Muthupalani3, Leona D. Samson1,2,4,5

1Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

2Biology Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

3Department of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

4Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

5Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

Correspondence to:

Leona D. Samson, email: [email protected]

Keywords: Mbd4, colon cancer, inflammation, ulcerative colitis, AOM/DSS

Received: February 17, 2016     Accepted: March 28, 2016     Published: April 13, 2016

ABSTRACT

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–/– mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4–/– mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4–/– mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4–/– immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4–/– mice transplanted with WT bone marrow. Mbd4–/– mice with WT bone marrow behaved similarly to Mbd4–/– mice. Together, our results indicate that the colonic epithelium of Mbd4–/– mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer.


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