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

Cancer Science

Takamitsu Morioka⁵  Tomoko Miyoshi-Imamura⁶  Benjamin J. Blyth⁶  Mutsumi Kaminishi⁶  Toshiaki Kokubo²  Mayumi Nishimura⁵  Seiji Kito²  Yutaka Tokairin¹  Shusuke Tani⁶  Kimiko Murakami-Murofushi⁴  Naoki Yoshimi³  Yoshiya Shimada⁵ 

[1] Department of Esophageal and Surgery, Tokyo Medical and Dental University, Tokyo, Japan;Research, Development and Support Center, National Institute of Radiological Sciences, Chiba, Japan;Department of Pathology and Oncology, Graduate School of Medical Science, University of the Ryukyus, Okinawa, Japan;Genetic Counseling Program, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan;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

关键词: Colon carcinogenesis;    inflammation;    Lynch syndrome;    Mlh1;    radiation;   

DOI  :  10.1111/cas.12591

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.