UC San Diego

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is involved in various biological processes, such as growth factor signaling, angiogenesis and apoptosis. It has been suggested that constitutive activation of STAT3 in tumor cells contribute to inducing cell proliferation and preventing apoptosis. Due to the role of STAT3 in tumor progression and metastasis in nearly 70% of solid and hematological tumors, STAT3 has been implicated as a prominent molecular target for cancer treatment. Apcmin/+ mice are widely used mouse model of human colorectal cancer, which these mice develop polyps confined in mucosa layer within 7-8 weeks after birth. To determine the role of STAT3-induced signaling in colorectal cancer, we deleted STAT3 in Apcmin/+ mice. STAT3 deletion induced invasion of tumor intestinal epithelial cells (IEC) in Apcmin/+ mice. STAT3 negatively regulates an epithelial-mesenchymal transition (EMT) inducer SNAI via spontaneous degradation. Furthermore, the deletion of STAT3 in colorectal cancer cell lines induced more invasiveness, but deletion in both STAT3 and SNAI suppressed CRC cell invasion. Mechanistically, we identified that STAT3 is necessary for GSK3[Beta]-mediated ubiquitination and proteasomal degradation of SNAI