SOX8 mediates the crosstalk between KRAS and TGF-β pathways to promote the malignant progression of pancreatic cancer

The mechanisms of metastasis and invasion in pancreatic cancer are promoted by the interaction between KRAS mutations and the transforming growth factor-β (TGF-β) pathway. However, the molecular mechanisms linking these pathways remain unclear. Downstream genes of KRAS pathway were identified by RNA sequencing in Panc-1 and MIA-PaCa2 cells. The function of the identified SOX8 was analyzed by using migration assays, western blotting of epithelial-mesenchymal transition (EMT) markers, and chemotherapy sensitivity. The correlation between SOX8 and TGF-β signaling was examined under recombinant TGF-β or TGF-β inhibitor treatment. SOX8 expression was also analyzed in resected specimens. SOX8 expression suppressed by KRAS knockdown, identifying it as a downstream regulated gene. SOX8 knockdown inhibited TGF-β signaling, reduced cell migration, altered EMT marker expression, and enhanced chemotherapy sensitivity. Furthermore, SOX8 knockdown activated the AKT/mTOR pathway, which was reversed by TGF-β inhibition. Clinically, high SOX8 expression correlated with poor prognosis. In conclusions, SOX8 functions as a molecular hub linking KRAS and TGF-β pathways, promoting epithelial-mesenchymal transition (EMT), invasive capacity, and chemotherapy resistance. This novel KRAS-SOX8-TGF-β axis plays the important role in invasion and metastasis of pancreatic cancer, suggesting SOX8 as a useful prognostic biomarker and therapeutic target.