Smad2 Cooperating with TGIF2 Contributes to EMT and Cancer Stem Cells Properties in Pancreatic Cancer via Co-Targeting SOX2

The underlying mechanisms between cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) remain unclear. In this study, we identified TGIF2 as a target gene of CSC using sncRNA and machine learning. TGIF2 is closely related to the expression of SOX2, EGFR, and E-cadherin, indicating poor prognosis. Mechanistically, TGIF2 promoted the EMT phenotype and CSC properties following the activation of SOX2, Slug, CD44, and ERGF/MAPK signaling, which were rescued by SOX2 silencing. TGIF2 silencing contributes to the opposite phenotype via SOX2. Notably, Smad2 cooperates with TGIF2 to co-regulate the SOX2 promoter, which in turn promotes EMT and CSC signaling by transactivating Slug and EGFR, respectively. The transactivation of EGFR/MAPK signaling by SOX2 promotes TGIF2 nuclear translocation, forming a positive feedback loop <i>in vitro</i>. Moreover, the interaction of TGIF2 and SOX2 with EGFR inhibitors promoted subcutaneous tumors and liver metastasis <i>in vivo</i>. Thus, the TGIF2/SOX2 axis contributes to CSC, EMT, and chemoresistance, providing a promising target for PC therapy.