A FoxM1/Smad4 positive feedback loop promotes pancreatic cancer progression

Pancreatic cancer is a highly lethal disease characterized by rapid onset, aggressive progression, and limited treatment options. The involvement of FoxM1 in the TGF-β/Smad signaling pathway has been linked to pancreatic cancer progression; however, the mechanisms behind the cooperative regulation of TGF-β signaling by FoxM1 and Smad4 remain poorly understood. In this study, we utilized molecular cytology techniques, animal models, and human pancreatic cancer tissues to investigate the role of FoxM1 in Smad4 stabilization and its regulation of TGF-β signaling. Our findings reveal that FoxM1 inhibits ubiquitin-proteasome-mediated degradation of Smad4, resulting in its stabilization. Once translocated into the nucleus, Smad4 binds to the FoxM1 promoter region, inducing FoxM1 expression and forming a positive feedback loop. Furthermore, we observed significantly higher expression of this feedback loop in pancreatic cancer tissues compared to adjacent normal tissues, with markedly elevated levels in poorly differentiated tissues compared to well-differentiated ones. Therefore, the loop aberrantly activates the TGF-β pathway, driving pancreatic cancer progression. These findings uncover a novel mechanism of TGF-β pathway activation and provide potential new targets for the prevention and treatment of pancreatic cancer. This study elucidates that FoxM1 functions to impede the ubiquitin proteasome-mediated degradation of Smad4, consequently stabilizing it. Following nuclear translocation, Smad4 binds to the FoxM1 promoter region, initiating FoxM1 expression and establishing a positive feedback loop. This loop plays a pivotal role in promoting pancreatic cancer development and migration by aberrantly activating the TGF-β pathway.