Journal
CANCER LETTERS
Volume 329, Issue 1, Pages 74-83Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2012.10.021
Keywords
Hepatocellular carcinoma; Targeted therapy; Drug resistance; Microarray; Epithelial-to-mesenchymal transition
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Sorafenib leads to a survival benefit in patients with advanced hepatocellular carcinoma but its use is hampered by the occurrence of drug resistance. To investigate the molecular mechanisms involved we developed five resistant human liver cell lines in which we studied morphology, gene expression and invasive potential. The cells changed their appearance, lost E-cadherin and KRT19 and showed high expression of vimentin, indicating epithelial-to-mesenchymal transition. Resistant cells showed reduced adherent growth, became more invasive and lost liver-specific gene expression. Furthermore, following withdrawal of sorafenib, the resistant cells showed rebound growth, a phenomenon also found in patients. This cell model was further used to investigate strategies for restoration of sensitivity to sorafenib. (c) 2012 Elsevier Ireland Ltd. All rights reserved.
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