Signal Transducer and Activator of Transcription 3 (STAT3) Protein Suppresses Adenoma-to-carcinoma Transition in Apcmin/+ Mice via Regulation of Snail-1 (SNAI) Protein Stability

STAT3 was recently reported to suppress tumor invasion in Apc(min/+) mice. We investigated the mechanisms by which STAT3 inhibits intestinal epithelial tumors using Apc(min/+)/Stat3(IEC-KO) mice (intestinal epithelial cell (IEC)-specific deletion of STAT3 in the Apc(min/+) background) to determine the role of STAT3 in carcinogenesis in vivo as well as colorectal cancer cell lines in vitro. To inhibit invasion of IEC tumors, STAT3 functions as a molecular adaptor rather than a transcription factor. Accordingly, the tumors in Apc(min/+)/Stat3(IEC-KO) mice undergo adenoma-to-carcinoma transition and acquire an invasive phenotype. Similarly, STAT3 knockdown in a colorectal cell line enhances IEC invasion. We demonstrate that STAT3 down-regulates SNAI (Snail-1) expression levels and hence suppresses epithelial-mesenchymal transition of colorectal cancer cells. Mechanistically, STAT3 facilitates glycogen synthase kinase (GSK) 3 beta-mediated degradation of SNAI by regulating phosphorylation of GSK3 beta. Our data identified a new role for STAT3 in the adenoma-to-carcinoma sequence of intestinal tumors.