title: Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice.
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.
authors.affiliation: Radiation Effect Accumulation and Prevention Project, Fukushima Project Headquarters, National Institute of Radiological Sciences, Chiba, Japan; Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Morioka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi-Imamura
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blyth
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Kaminishi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kokubo
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nishimura
authors.forename: Seiji
authors.initials: S
authors.lastname: Kito
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tokairin
authors.forename: Shusuke
authors.initials: S
authors.lastname: Tani
authors.forename: Kimiko
authors.initials: K
authors.lastname: Murakami-Murofushi
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimi
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Shimada
authors.forename: Shizuko
authors.initials: S
authors.lastname: Kakinuma
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics*; D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000276:immunology / Q000528:radiation effects; D003092:Colitis / Q000139:chemically induced; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D053843:DNA Mismatch Repair / Q000235:genetics; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics*; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D016264:Dextran Sulfate; D000070957:MutL Protein Homolog 1
keywords: Colon carcinogenesis; Lynch syndrome; Mlh1; inflammation; radiation