Journal
CANCER LETTERS
Volume 315, Issue 2, Pages 178-188Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2011.09.039
Keywords
Hepatocellular carcinoma; Hypoxia; Pathway analysis
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We demonstrated in an in vitro model (human HepG2 liver cells) that chronic hypoxia induced gene expression is associated with an aggressive phenotype in patients with hepatocellular carcinoma (HCC). The aim of this study was to characterize this model further using gene expression microarray, real-time PCR and immunocytochemistry. Subsequently, pathway analysis software was used to identify relevant processes. After examination, we selected 2% O-2 during 72 h as conditions to study chronic hypoxia. The most affected signaling is centered on TGF-beta 1 and PPAR alpha/RXR alpha. Cells at 2% O-2 showed a shift in expression of Epithelial-to-Mesenchymal-Transition (EMT) related genes. Furthermore, a downregulation of liver specific detoxification pathways including cytochrome P450's and glutathione-S-transferases was observed. Both up- and downregulation events within different signaling cascades indicated a cellular adaptation and the onset of a new equilibrium. The prominent role of TGF-beta 1- and PPAR alpha/RXR alpha signaling and cell motility pathways warrants their further investigation for therapeutic targets in HCC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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