Causal relationship between the loss of RUNX3 expression and gastric cancer

다국어 초록 (Multilingual Abstract)

The mammalian runt-related(RUNX) genes encode the α subunit of the Runt domain transcription factor PEBP2/CBF and are homologues of the Drosophila genes runt and lozenge. The mammalian and Drosophila genes share an evolutionarily conserved region of 128 amino acids, termed the Runt domain, which is required for DNA binding and heterodimerization with the β subunit, PEBP2β/CBF. Like their Drosophila homologues, the RUNX family proteins are critical regulators in determining cell fate.
Three RUNX genes, RUNX1 AML1, RUNX2/CBFA1 and RUNX3/PEBP2αC, are known. RUNX1 has a critical role in the formation of hematopoietic stem cells from hematogenic endothelial cells. RUNX3 is expressed by the epithelial cells of the mouse glandular stomach and intestines. The runt homologue in C. elegan, run, is also expressed by gut cells, suggesting possible evolutionarily· conserved roles of runt homologues in the gastrointestinal tract. The major upstream regulatory signal of the RUNX family is elicited by the TGF-β superfamily. The functional relationship between the BMP signaling pathway and the RUNX protein was shown in a report that cleidocranial dysplasia is caused by an inability of mutated RUNX2 to transmit BMP signaling to target genes.
Several lines of evidence suggest the possibility that RUNX3 is involved in gastric carcinogenesis. First, RUNX3 is located on human chromosome, one of the regions that shows high-frequency loss of heterozygosity(LOH) in gastric cancer. Second, it is well known that the TGF-β signal transduction system is often impaired in many different types of cancer. For example, the TGF-β type Ⅱ receptor is disrupted in colon cancer, gastric cancer, and head and neck cancers. Since RUNX3 is a downstream target of TGF-β signaling, malfunction of RUNX3 might be involved in gastric carcinogenesis. It has recently been suggested that escape from apoptosis is the most important characteristic of cancers in the gastrointestinal tract, and most, if not all, cancers, display insensitivity to anti-growth signals and evasion of apoptosis. This line of evidence suggests that RUNX3 is an attractive candidate as a tumor suppressor of gastric cancer.
Here we show that RUNX3 possesses a potent anti-oncogenic activity and is frequently inactivated in gastric cancers by hemizygous deletion and hypermethylation of its promoter region. Although rare, we also found a single mutation(R122C) in the highly conserved Runt domain of RUNX3. This mutation leads to the complete loss of the anti-oncogenic activity in a nude mouse assay. These results strongly suggest that RUNX3 is a tumor suppressor widely involved in gastric cancer.