Gastric cancer is a major cause of death worldwide, and is particularly common in certain Asian populations. Now, with the goal of understanding the molecular events causing the disease, Suk-Chul Bae, Yoshiaki Ito and colleagues describe in the 5 April issue of Cell a link between the development of gastric cancer and reduced expression of RUNX3, a gene encoding a transcription factor influenced by the transforming growth factor-β (TGF-β) signaling system.

Beginning their studies in laboratory mice, Bae, Ito and colleagues found that the absence of Runx3 leads to increased cell growth in the stomach mucosa (on right) compared with wild-type tissue (left). Wild-type stomachs were slightly larger and their walls thinner. The authors go on to show that Runx3 is required for the growth suppressive actions of TGF-β in this tissue. They conclude that Runx3 probably functions under normal conditions to rein in the growth of gastric epithelial cells. In humans, expression of the corresponding RUNX3 gene was also significantly reduced, when examined in clinical specimens from gastric tumors. The RUNX3 gene itself was found to be deleted in some gastric cancer specimens, most frequently in advanced tumors.

One hallmark of cancer cells is that genes encoding proteins that put a brake on cell growth—commonly known as tumor suppressor genes—are turned off by DNA methylation. The authors duly describe that DNA sequences regulating expression of the RUNX3 gene are methylated in tumor specimens but not in normal gastric epithelia. A search for DNA sequence mutations in RUNX3 which might affect the encoded protein's function, and thereby predispose individuals to develop gastric cancer, yielded only one abnormality in more than 100 tumor samples. Paradoxically, the apparent rareness of RUNX3 mutations provides a possible therapeutic route for future testing—RUNX3 genes silenced by DNA methylation could potentially be reactivated by the use of chemical agents such as histone deacetylase inhibitors, which can unmask genes that have been turned off by DNA methylation.