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.
Highlights
Ulcerative colitis (UC) is associated with substantially increased risk of colorectal cancer (CRC) [1], but not all UC patients will develop cancer [2]
Our results indicate that the colonic epithelium of Mbd4–/– mice is more vulnerable to DSS-induced injury, which exacerbates inflammationdriven tissue injury and cancer
Typical colon tumors induced by azoxymethane/ dextran sodium sulfate (AOM/DSS) in WT and Mbd4–/– mice are shown in Figure 1B; tumors were found almost exclusively in the distal half of the colon for both genotypes
Summary
Ulcerative colitis (UC) is associated with substantially increased risk of colorectal cancer (CRC) [1], but not all UC patients will develop cancer [2]. It is known that particular mutations arise during the progression of cancer in UC patients [3], and recent genome wide association studies (GWAS) identified numerous polymorphisms that predispose a colitis patient to CRC [4]. Regardless of these advances, it remains difficult to predict whether an UC patient will develop colitis-associated CRC. We recently reported that three DNA repair enzymes, namely, alkyladenine DNA glycosylase (Aag), Alkbh, and Alkbh, protect against tissue injury and tumorigenesis using this mouse www.impactjournals.com/oncotarget model of inflammation-driven colon cancer [11, 16]. We ask if Mbd, a DNA glycosylase involved in repair of deaminated cytosines, is important for suppression of inflammation-mediated tumorigenesis
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