Epigenetic Footprint and Instability Support Precancerous Nature of Intestinal Metaplasia

Speaker

Toshikazu USHIJIMA President and Director Institute for Advanced Life Sciences Hoshi University, Tokyo

Toshikazu USHIJIMA
President and Director
Institute for Advanced Life Sciences
Hoshi University, Tokyo

Talk Abstract

Intestinal metaplasia (IM) has been debated as a precancerous or paracancerous lesion in the stomach. Taking advantage of the epigenetic footprint and instability of IM cells, we explored the issue. First, pure gastric glands with or without IM were isolated, and genome-wide DNA methylation analysis was conducted. IM crypts had a unique methylation profile, consisting of hypermethylation present only in IM crypts but not in non-IM crypts. Tumour- suppressor genes were more methylated in IM crypts than in non-IM crypts. Then, based upon the epigenetic footprint, 29 gastric cancers were classified into 25 cancers derived from IM cells and four non-IM cells. Analysis of adjacent gastric mucosa showed that IM cells consisted of only 37 % of the epithelial cells. This showed that IM cells had much higher chance of converting into cancer cells. Third, the mechanism of the high chance of conversion was analyzed by establishing gastric organoids derived from IM and non-IM cells. Organoids from IM cells were shown to have much higher levels of NOS2 expression, with open chromatin and high acetylation of the NOS2 promoter region. NOS2 induction in normal cells led to accelerated induction of aberrant DNA methylation (epigenetic instability) by increasing DNA methyltransferase activity. NOS2 expression in IM- derived organoids was upregulated by interleukin-17A. Taken together, IM cells were considered to have a precancerous nature with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction.