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.