RUNX3 is a tumor suppressor where the loss of its expression and the mislocalization of its protein have been linked to the pathogenesis of increasing number of cancers. Recent studies have shown that the Notch signalling pathway plays an important role in regulating the intestinal epithelium development. Mice harbouring the constitutively active Notch Intracellular Domain (NICD), a known oncogene, as a transgene display increased populations of proliferating intestinal epithelial precursor cells. Interestingly, our RUNX3 null mice also show a similar phenotype. We, therefore, hypothesize that RUNX3 antagonizes the effect of the Notch signalling pathway in the development and maintenance of the intestinal epithelium. Our data show that the intestinal epithelia of Runx3 null mice, when compared to those of wildtype mice, exhibit upregulation in the gene expression of Hes1 which is a well-known gene target of the Notch signaling pathway. The gene expression of Hes1 is activated by a transcription activation complex containing NICD, RBP-Jk and Mastermind-like 1 (MAML1). We are able to show that RUNX3 associates with RBP-Jk, MAML1 and NICD. Furthermore, such associations result in RUNX3 inhibiting Hes1 gene expression. Finally, we will be examining the possibility that RUNX3 functions as a tumor suppressor in human colorectal cancer by inhibiting the Notch-dependent proliferative effect on human colorectal cancer cell lines.
First AACR Centennial Conference on Translational Cancer Medicine-- Nov 4-8, 2007; Singapore