HIF-1α promotes hepatocellular carcinoma metastasis by regulating angiogenesis and epithelial-mesenchymal transition

Abstract Background Invasion and metastasis of hepatocellular carcinoma (HCC) still remain to be hard in medical society. However, little knowledge is known regarding the hypoxia impact in HCC with angiogenesis and epithelial-mesenchymal transition (EMT). The aims of this study were to explore the regulating roles of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and EMT of HCC. Methods The levels of HIF-1α, angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF) expression in a cohort of chronic liver diseases were detected by enzyme-linked immunosorbent assays, and their dynamic up-regulations were confirmed in model of rat hepatocyte malignant transformation. After HIF-1α gene transfected with specific miRNA, biological behaviors of HCC cells were analyzed by transwell or invasion assay; angiogenesis and EMT were analyzed at protein level by Western blot or at mRNA by quantitative real-time PCR. Results The levels of circulating HIF-1α, VEGF, and Ang-2 in the HCC group (145.6 ± 32.6 µg/L, 458.9 ± 125.3 µg/L, and 42.9 ± 5.1 µg/L) were significantly higher (P < 0.001) than those in the LC (79.5 ± 8.4 µg/L, 206.8 ± 56.8 µg/L, and 26.2 ± 6.1 µg/L) or the CH (60.1 ± 18.8 µg/L, 178.1 ± 85.4 µg/L, and 21.8 ± 6.9 µg/L) group, respectively. Dynamic up-regulations of HIF-1α and angiogenic factors have been confirmed by rat model with hepatocyte malignant transformation. There were closely positive correlations (P < 0.001) between them of HIF-1α and VEGF or Ang-2. After HCC cells transfected with specific HIF-1α-miRNA, the levels of HIF-1α, VEGF and Ang-2 expression were significantly down-regulated, with inhibiting infiltration or migration, blockading EMT with increasing E-cadherin and decreasing of snail, twist and vimentin. Conclusions These data have highlighted the HIF-1α over-expression could promote the metastasis or invasion of HCC via regulating neovascularization and EMT formation.