Hypoxia upregulates hepatic angiopoietin-2 transcription to promote the progression of hepatocellular carcinoma

<bold>Background: </bold>Angiopoietin-2 (Ang-2) level is related to hepatocellular carcinoma (HCC) progression. However, the dynamic expression and regulatory mechanism of Ang-2 remain unclear. <bold>Aim: </bold>To investigate Ang-2 levels in chronic liver diseases and validate early monitoring value with a dynamic model in hepatocarcinogenesis. <bold>Methods: </bold>Sprague-Dawley rats in hepatocarcinogenesis were induced with diet 2-fluorenylacet-amide, and grouped based on liver histopathology by hematoxylin and eosin staining. Differently expressed genes or Ang-2 mRNA in livers were analyzed by whole-genome microarray. Ang-2 levels in chronic liver diseases were detected by an enzyme-linked immunosorbent assay. <bold>Results: </bold>Clinical observation reveled that the circulating levels of Ang-2 and hypoxia-inducible factor-1 alpha (HIF-1 alpha) in patients with chronic liver diseases were progressively increased from benign to HCC (P < 0.001). Dynamic model validated that the up-regulated Ang-2 in liver and blood was positively correlated with HIF-1 alpha in hepatocarcinogenesis (P < 0.001). Mechanistically, Ang-2 was regulated by HIF-1 alpha. When specific HIF-1 alpha- microRNAs transfected into HCC cells, the cell proliferation significantly inhibited, HIF-1 alpha and Ang-2 down-regulated, and also affected epithelial-mesenchymal transition via increasing E-cadherin to block cell invasion or migration with reducing of snail, twist and vimentin. <bold>Conclusion: </bold>Hypoxia-induced Ang-2 up-regulating expression might serve as a sensitive early monitoring biomarker for hepatocarcinogenesis or HCC metastasis.