Serine Protease Inhibitor 1 (SERPINE1) Regulates Epithelial-Mesenchymal Transition Gene Expression to Promote Migration and Invasion in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is characterized by a high capacity for invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key mechanism that promotes tumor migration and invasion. However, the role of serine protease inhibitor 1 (SERPINE1) as a regulatory factor that may enhance tumor progression by directly modulating EMT-related gene expression in HCC has not been fully elucidated. Objectives: To investigate the role of SERPINE1 in regulating EMT-related gene expression and its effects on tumor invasion and migration in hepatocellular carcinoma (HCC). Methods: A comprehensive experimental approach integrating in vitro cell models, animal experiments, and clinical sample analyses was employed. qPCR, immunohistochemistry, and Western blotting were performed to determine SERPINE1 expression in HCC cell lines and tissues. SERPINE1 expression was modulated by RNA interference and overexpression, and the effects on HCC cell migration and invasion, as well as the expression of EMT markers, were evaluated. Results: SERPINE1 expression was approximately 3.2-fold and 2.8-fold higher in metastatic liver cancer cells and cancer tissues, respectively (P < 0.01). SERPINE1 expression was significantly negatively correlated with E-cadherin (r = -0.72) and positively correlated with vimentin (r = 0.65). After SERPINE1 knockdown, E-cadherin protein expression increased 2.1-fold, whereas N-cadherin and vimentin expression decreased by 68% and 55%, respectively; cell migration and invasion decreased by 62% and 57%, respectively (P < 0.01). Conversely, SERPINE1 overexpression reduced E-cadherin to 0.4-fold of the control level, whereas N-cadherin and vimentin increased 2.3-fold and 2.0-fold, respectively, and migration and invasion increased 1.9-fold and 2.1-fold, respectively. In the in vivo orthotopic lung metastasis model, SERPINE1 knockdown reduced the number of lung metastatic foci from 4.8 ± 1.1 to 1.5 ± 0.6 (P < 0.01), and the incidence of metastasis decreased from 83.3% to 33.3%. Mechanistic studies revealed that, after SERPINE1 knockdown, the p-AKT/AKT and p-ERK/ERK ratios decreased by 64% and 57%, respectively, and the EMT transcription factors Snail and Slug were downregulated; PI3K agonists partially reversed the inhibition of the EMT phenotype. These results suggest that SERPINE1 activates the PI3K/AKT and MAPK signaling pathways, upregulates EMT-related gene expression, and thereby promotes liver cancer cell migration, invasion, and lung metastasis. Conclusions: SERPINE1 facilitates the migration and invasion of HCC cells by modulating EMT-related gene expression. SERPINE1 is upregulated in liver cancer tissues and may contribute to liver cancer progression.