<i>14-3-3σ</i> Functions as an Intestinal Tumor Suppressor.

Abstract

Although the <i>14-3-3σ</i> 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 <i>14-3-3σ</i> expression is significantly downregulated in primary human colorectal cancer when compared with adjacent normal colonic tissue in patient samples. Downregulation of <i>14-3-3σ</i> in primary colorectal cancers was significantly associated with <i>p53</i> mutation, increasing tumor stage, distant metastasis, and poor patient survival. Poor survival was more significantly associated with decreased <i>14-3-3σ</i> expression in <i>p53</i> wild-type than in <i>p53-</i>mutant colorectal cancers. <i>14-3-3σ</i> 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, <i>14-3-3σ</i> expression was upregulated in differentiated areas. Deletion of <i>14-3-3σ</i> in <i>Apc^Min</i> mice increased the number and size of adenomas in the small intestine and colon, shortening the median survival by 64 days. <i>14-3-3σ</i>-deficient adenomas displayed increased proliferation and decreased apoptosis, as well as increased dysplasia. In adenomas, loss of <i>14-3-3σ</i> 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 <i>14-3-3σ</i>, potentially contributing to the enhanced tumor formation and growth. Taken together, these results provide genetic evidence of a tumor-suppressor function of <i>14-3-3σ</i> in the intestine. SIGNIFICANCE: Downregulation of <i>14-3-3σ</i> 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.