Increased Genetic Susceptibility to Intestinal-Type Gastric Cancer Is Associated With Increased Activity of the RUNX3 Distal Promoter

Abstract

BACKGROUND: The runt-related transcription factor RUNX3 plays essential roles in various types of tumors, including gastric cancer. Epigenetic changes in the methylation of the RUNX3 proximal promoter, but not common genetic changes in RUNX3, have been associated with both changes in the gene expression and development of the cancer. METHODS: A case-control association study was conducted by genotyping 865 unrelated Korean subjects. Subsequent functional studies were performed to reveal functional implication of genetic association. RESULTS: Several single-nucleotide polymorphisms (SNPs) in RUNX3 were significantly associated with susceptibility to intestinal-type gastric cancer (.0028 <= P <= .022) but not diffuse-type gastric cancer (. 70 <= P <= .96). The risk-associated, minor variant of an intestinal-type gastric cancer-associated SNP in the RUNX3 distal promoter (rs7528484) significantly increased promoter activity in a CREB1-dependent manner. The distal promoter-derived, 33 kDa isoform of RUNX3 increased the activity of transcription factor nuclear factor kappa B (NF-kappa B), which had been activated by Helicobacter pylori infection, a risk factor for intestinal-type gastric cancer, and the expression of the interleukin-1 beta gene (IL1B), an NF-kappa B target genetically and functionally associated with gastric cancer. In contrast, the proximal promoter-derived, 44 kDa isoform of RUNX3 decreased both NF-kappa B activity and IL1B expression. CONCLUSIONS: In addition to epigenetic changes in the RUNX3 proximal promoter, genetic changes in the distal promoter may be associated with susceptibility to intestinal-type gastric cancer by increasing promoter activity. Functionally, 2 RUNX3 isoforms may contribute differentially to intestinal-type gastric cancer susceptibility, at least in part through regulating NF-kappa B activity and IL1B expression Cancer 2011;117:5161-71. (C) 2011 American Cancer Society.