14-3-3σFunctions as an Intestinal Tumor Suppressor

Abstract Although the 14-3-3σ gene was initially identified as a p53 target gene in colorectal cancer cells, its potential role in intestinal tumorigenesis has remained unknown. Here we determined that 14-3-3σ expression is significantly downregulated in primary human colorectal cancer when compared with adjacent normal colonic tissue in patient samples. Downregulation of 14-3-3σ in primary colorectal cancers was significantly associated with p53 mutation, increasing tumor stage, distant metastasis, and poor patient survival. Poor survival was more significantly associated with decreased 14-3-3σ expression in p53 wild-type than in p53-mutant colorectal cancers. 14-3-3σ expression was detected in enterocytes of the transit amplifying zone and gradually increased towards the apical villi in the small intestinal epithelium. In small and large intestinal epithelia and adenomas, 14-3-3σ expression was upregulated in differentiated areas. Deletion of 14-3-3σ in ApcMin mice increased the number and size of adenomas in the small intestine and colon, shortening the median survival by 64 days. 14-3-3σ–deficient adenomas displayed increased proliferation and decreased apoptosis, as well as increased dysplasia. In adenomas, loss of 14-3-3σ promoted acquisition of a mesenchymal-like gene expression signature, which was also found in colorectal cancers from patients with poor relapse-free survival. The transcriptional programs controlled by the 14-3-3σ-interacting factors SNAIL, c-JUN, YAP1, and FOXO1 were activated by deletion of 14-3-3σ, potentially contributing to the enhanced tumor formation and growth. Taken together, these results provide genetic evidence of a tumor-suppressor function of 14-3-3σ in the intestine. Significance: Downregulation of 14-3-3σ in colorectal cancer is associated with metastasis and poor survival of patients, and its inactivation in a murine tumor model drives intestinal tumor formation and epithelial-mesenchymal transition.