Abstract
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) 3β-mediated degradation of SNAI by regulating phosphorylation of GSK3β. Our data identified a new role for STAT3 in the adenoma-to-carcinoma sequence of intestinal tumors.
Highlights
STAT3 suppresses carcinogenesis of intestinal tumors in Apc min mice
We investigated the mechanisms by which STAT3 inhibits intestinal epithelial tumors using Apcmin/؉/ Stat3IEC-KO mice (intestinal epithelial cell (IEC)-specific deletion of STAT3 in the Apcmin/؉ background) to determine the role of STAT3 in carcinogenesis in vivo as well as colorectal cancer cell lines in vitro
Because GSK3 phosphorylates SNAI, which leads to ubiquitination and proteasomal degradation (13), we investigated whether STAT3 is involved in the ubiquitin-mediated proteasomal degradation of SNAI via GSK3
Summary
STAT3 suppresses carcinogenesis of intestinal tumors in Apc min mice. Results: STAT3 suppresses expression of SNAI in intestinal epithelium by regulating GSK3 activity. Conclusion: STAT3 induces degradation of SNAI by promoting GSK3 activity and thereby suppresses adenoma-to-adenocarcinoma transition in Apc min mice. We demonstrate that STAT3 down-regulates SNAI (Snail-1) expression levels and suppresses epithelial-mesenchymal transition of colorectal cancer cells. STAT3 was shown to inhibit intestinal epithelial cell (IEC) tumor invasion in Apcmin/ϩ mice (4), but the underlying mechanisms remain unclear. Several transcriptional repressors were identified as inducers of EMT, including SNAI, Slug (Snail-2), E47, Twist, and the Zeb factors (8) Main targets of these proteins are cell adhesion molecules such as E-cadherin and claudins (CLDNs) that link epithelial cells together (8 –11). Constitutive activation of -catenin due to a mutation in the APC gene is the major cause of colorectal cancers (CRCs) (21) and induces the multiple intestinal neoplasia (min) phenotype in Apcmin/ϩ mice (21–23). STAT3 interacts with GSK3 and negatively regulates phosphorylation of GSK3, thereby inducing degradation of SNAI
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