Mild Inflammation Accelerates Colon Carcinogenesis in Mlh1-Deficient Mice

Abstract

Objective: Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice. Method: Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1^–/–), Mlh1 heterozygous (Mlh1^+/–) and wild-type (Mlh1^+/+) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, β-catenin and p53. Results: Male and female Mlh1^–/– mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1^+/– and Mlh1^+/+ mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of β-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis. Conclusion: Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.