| Summary: | 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 <i>SSTR2</i> promoter in inflammation and gastric tumor formation. A whole-genome bisulfite sequencing analysis revealed that the <i>SSTR2</i> 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 <i>SSTR2</i> promoter methylation in primary gastric tumors and intestinal metaplasia, and even aged gastric mucosae infected with <i>Helicobacter pylori</i>, suggesting that aberrant methylation is initiated in normal gastric mucosa. The loss-of-function of <i>SSTR2</i> in SNU638 cell-induced cell proliferation in vitro, while stable transfection of <i>SSTR2</i> 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 <i>SSTR2</i>-KO SNU638 cell. By contrast, inflammation-related pathways were inhibited in AGS and MKN74 cells ectopically expressing <i>SSTR2</i>. Collectively, we propose that <i>SSTR2</i> silencing upon promoter methylation is initiated in aged gastric mucosae infected with <i>H. pylori</i> and promotes the establishment of an inflammatory microenvironment via the intrinsic pathway. These findings provide novel insights into the initiation of gastric carcinogenesis.
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