Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice

Cancer Sci. 2015 Mar;106(3):217-26. doi: 10.1111/cas.12591. Epub 2015 Feb 12.

Abstract

Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency.

Keywords: Colon carcinogenesis; Lynch syndrome; Mlh1; inflammation; radiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency*
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adenocarcinoma / chemically induced
  • Adenocarcinoma / genetics*
  • Adenomatous Polyposis Coli Protein / biosynthesis
  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / immunology
  • Carcinogenesis / radiation effects
  • Colitis / chemically induced
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • DNA Mismatch Repair / genetics
  • Dextran Sulfate / pharmacology
  • Disease Models, Animal
  • Female
  • Inflammation / chemically induced
  • Inflammation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MutL Protein Homolog 1
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / genetics*
  • Radiation, Ionizing
  • Tumor Suppressor Protein p53 / biosynthesis
  • beta Catenin / biosynthesis

Substances

  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein
  • Cyclin-Dependent Kinase Inhibitor p21
  • Mlh1 protein, mouse
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Dextran Sulfate
  • MutL Protein Homolog 1