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.
Naokazu Chiba (Thu,) studied this question.