Aberrant Methylation of Somatostatin Receptor 2 Gene Is Initiated in Aged Gastric Mucosa Infected with and Consequential Gene Silencing Is Associated with Establishment of Inflammatory Microenvironment In Vitro Study.

The loss-of-function variants are thought to be associated with inflammation in the stomach. We here aimed to evaluate the extent and role of methylation at the promoter in inflammation and gastric tumor formation. A whole-genome bisulfite sequencing analysis revealed that the promoter was significantly hypermethylated in gastric tumors, dysplasia, and intestinal metaplasia compared to non-tumor tissues from patients with gastric cancer. Using public data, we confirmed promoter methylation in primary gastric tumors and intestinal metaplasia, and even aged gastric mucosae infected with , suggesting that aberrant methylation is initiated in normal gastric mucosa. The loss-of-function of in SNU638 cell-induced cell proliferation in vitro, while stable transfection of in AGS and MKN74 cells inhibited cell proliferation and tumorigenesis in vitro and in vivo. As revealed by a comparison of target genes differentially expressed in these cells with hallmark molecular signatures, inflammation-related pathways were distinctly induced in -KO SNU638 cell. By contrast, inflammation-related pathways were inhibited in AGS and MKN74 cells ectopically expressing . Collectively, we propose that silencing upon promoter methylation is initiated in aged gastric mucosae infected with and promotes the establishment of an inflammatory microenvironment via the intrinsic pathway. These findings provide novel insights into the initiation of gastric carcinogenesis.