Epigenetic fields for cancerization are involved in development of human cancers, especially those associated with inflammation and multiple occurrences. However, it is still unclear when such field defects are formed and what component of inflammation is involved in induction of aberrant DNA methylation. Here, in a mouse colitis model induced by dextran sulfate sodium (DSS), we identified three CpG islands specifically methylated in colonic epithelial cells exposed to colitis. Their methylation levels started to increase as early as 8 weeks after DSS treatment and continued to increase until colon cancers developed at 15 weeks. In contrast to the temporal profile of DNA methylation levels, infiltration of inflammatory cells spiked immediately after the DSS treatment and then gradually decreased. Exposure of cultured colonic epithelial cells to DSS did not induce DNA methylation and it was indicated that inflammation triggered by the DSS treatment was responsible for methylation induction. To clarify components of inflammation involved, severe combined immunodeficiency (SCID) mice that lack functional T-and B-cells were similarly treated. Even in SCID mice, DNA methylation, along with colon tumors, were induced at the same levels as in their background strain of mice (C.B17). Comparative analysis of inflammation-related genes showed that Ifng, Il1b and Nos2 had expression concordant with methylation induction whereas Il2, Il6, Il10, Tnf did not. These results showed that an epigenetic field defect is formed at early stages of colitis-associated carcinogenesis and that functional T and B cells are non-essential for the formation.
Bibliographical noteFunding Information:
We thank Dr H Fukamachi for his kind provision of the LIF-16 cell line. This study was supported by the Third-term Comprehensive Cancer Control Strategy from the Ministry of Health, Labour and Welfare, Japan; and by the Global Research Laboratory Program from Korea Foundation for International Cooperation of Science & Technology. MK and YS are recipients of Research Resident Fellowships from the Foundation for Promotion of Cancer Research. This study was supported by the Third-term Comprehensive Cancer Control Strategy from the Ministry of Health, Labour and Welfare, Japan (TU), and by the Global Research Laboratory Program from Korea Foundation for International Cooperation of Science & Technology (Y-JK and TU).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cancer Research