The stomach is a complex and hard-working organ that experiences considerable wear and tear as it goes about its work. To cope with this, the inner lining of a stomach (or the “epithelium”) undergoes a constant process of self-renewal. This is made possible by a special group of cells known as the gastric stem cells. Through cell division, stem cells give rise to progenies that would gradually mature into specialised cells that serve different functions. The specialisation (or “differentiation”) of gastric epithelial cells is a highly coordinated process governed by the many external cues they receive from their tissue environment. These external instructions, once interpreted by the cells, would lead to the activation or shutdown of specific genes to endow gastric epithelial cells specialised capabilities, such as the production of acid or digestive enzymes.
RUNX3 is a transcription factor, which is a protein that helps determine what genes should be active in normal gastric epithelial cells as they differentiate and mature. In previous studies, our group discovered that RUNX3 plays an important role in balancing the expansion (i.e. proliferation) and programmed cell death (i.e. apoptosis) of gastric epithelial cells. It was further found that RUNX3 serves these functions in conjunction with the growth signals that gastric epithelial cells receive from their surrounding tissue environment. As a reflection of these important functions, the loss of RUNX3 occurs very frequently in human gastric cancers. This is why RUNX3 is considered a major tumour suppressor gene in human gastric cancer.
In our latest study, we observed that mouse gastric epithelial cells that lack Runx3 are prone to losing their cellular identity and become more stem-cell like. This gives rise to tumour-forming cells. We showed that this is caused by the spontaneous initiation of a genetic programme known as epithelial-mesenchymal transition (EMT). EMT is an important step during the normal development of our body. However, when wrongly reactivated during cancer, it is a major cause of secondary tumours (i.e. metastasis). Because EMT has a potent ability to genetically reprogramme cells, it can generate “cancer stem cells” that are resistant to drugs and radiotherapies. We showed that without Runx3, gastric epithelial cells would misinterprete growth signals to mistakenly activate EMT and produce tumour-forming cells. These findings reveal a new facet of RUNX3’s safeguarding of gastric epithelial cells against cancer. At the same time, it offers fresh insights into how gastric cancers come about. Understanding this very complex problem is key to devising an effective therapeutic strategy.
Dominic Chih-Cheng Voon1,‡, Huajing Wang1,‡, Jason Kin Wai Koo1, Tu Anh Pham Nguyen2, Yit Teng Hor1, Yeh-Shiu Chu2, Kosei Ito3, Hiroshi Fukamachi4,Shing Leng Chan1, Jean Paul Thiery2,5,Yoshiaki Ito1,2,*
- Cancer Biology Programme, Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
- Institute of Molecular and Cell Biology, Singapore 138673
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan 852-8588
- Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan 113-8519
- Cancer Stem Cells Programme, Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
‡ These authors contributed equally to this work