Frequent Loss of RUNX3 Expression by Promoter Hypermethylation in Gastric Carcinoma

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Abstract
The RUNX3 gene is a member of the Runt domain family of transcription factors that are master regulators of gene expression in major developmental pathways. Recently, lack of RUNX3 function was found to be associated with genesis and progression of gastric carcinoma. We studied methylation of CpG islands in the RUNX3 gene by methylation-specific PCR in 80 gastric carcinoma specimens, 45 corresponding non-neoplastic mucosae, and 7 gastric carcinoma cell lines. We also measured levels of RUNX3 mRNA in 50 of the gastric carcinoma cases by quantitative RT-PCR and in the gastric carcinoma cell lines by RT-PCR. Hypermethylation of the RUNX3 promoter was found in 57 (71%) of 80 gastric carcinomas, and promoter hypermethylation of RUNX3 occurred more frequently in intestinal and diffuse-adherent type tumors than in diffuse-scattered type tumors (p = 0.046). Reduced RUNX3 expression was associated with promoter hypermethylation (p = 0. 036), however, there was no correlation between RUNX3 mRNA expression levels and T grade, N grade, tumor stage, or histological type. In corresponding non-neoplastic mucosae, hypermethylation of the RUNX3 promoter was found in 38 (84%) of 45 specimens. Among seven gastric carcinoma cell lines, three cell lines (MKN-28, MKN-74, TMK-1) with diminished expression of RUNX3 had promoter methylation and three cell lines (MKN-1, MKN-7, MKN-45) with RUNX3 expression showed no promoter methylation. Our results overall suggest that transcriptional inactivation of RUNX3 by promoter hypermethylation may participate in the stomach carcinogenesis.