Journal
TUMOR BIOLOGY
Volume 35, Issue 8, Pages 8103-8114Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1007/s13277-014-2056-0
Keywords
Hepatocellular carcinoma (HCC); Hypoxia-inducible factors (HIFs); Epithelial-mesenchymal transition (EMT); Migration; Neoplastic capacities
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Funding
- Natural Science Foundations of China [81272713, 81100253]
- Natural Science Foundations of Jiangsu Province [JS20130508]
- Nanjing Medical University [2011NJMU244]
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Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Although the involvement of the epithelial-to-mesenchymal transition (EMT) in HCC progression is established, the mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that hypoxia-inducible factors (HIFs), HIF-1 alpha and HIF-2 alpha, modulate the EMT through Twist1, a regulator of the EMT. The levels of HIF-1 alpha and HIF-2 alpha in HCC tissues were higher than those in matched, non-tumor surrounding tissues. In HCC samples, the levels of HIF-1 alpha and HIF-2 alpha negatively correlated with the levels of E-cadherin but positively correlated with the levels of vimentin. In highly metastatic MHCC97H cells, the levels of HIF-1 alpha, HIF-2 alpha, and Twist1 were higher than those in weakly metastatic HepG2 cells. In HepG2 cells, over-expression of HIFs enhanced levels of Twist1 and the EMT, which elevated the migratory and neoplastic capacities of cells. For MHCC97H cells, inhibition of HIFs reduced Twist1 levels and the EMT, which reduced their migratory and neoplastic capacity. Thus, the promotion of EMT by HIFs via Twist1 enhanced the migration and neoplastic capacities of HCC cells.
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