The RUNX3 Tumor Suppressor Upregulates Bim in Gastric Epithelial Cells Undergoing Transforming Growth Factorβ-Induced Apoptosis

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Abstract
Genes involved in the transforming growth factor β (TGF-β) signaling pathway are frequently altered in several types of cancers, and a gastric tumor suppressor RUNX3 appears to be an integral component of this pathway. We reported previously that apoptosis is notably reduced in Runx3−/− gastric epithelial cells. In the present study, we show that a proapoptotic gene Bim was transcriptionally activated by RUNX3 in the gastric cancer cell lines SNU16 and SNU719 treated with TGF-β. The human Bim promoter contains RUNX sites, which are required for its activation. Furthermore, a dominant negative form of RUNX3 comprised of amino acids 1 to 187 increased tumorigenicity of SNU16 by inhibiting Bim expression. In Runx3−/− mouse gastric epithelium, Bim was down-regulated, and apoptosis was reduced to the same extent as that in Bim−/− gastric epithelium. We confirmed comparable expression of TGF-β1 and TGF-β receptors between wild-type and Runx3−/− gastric epithelia and reduction of Bim in TGF-β1−/− stomach. These results demonstrate that RUNX3 is responsible for transcriptional up-regulation of Bim in TGF-β-induced apoptosis.