Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines.
Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines.
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DOI：
10.1158/1078-0432.ccr-08-1733
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发表时间：
2009-01-15
期刊：
影响因子：
--
通讯作者：
McConkey DJ
中科院分区：
文献类型：
--
作者：
Haddad Y;Choi W;McConkey DJ
Although the epidermal growth factor receptor (EGFR) is overexpressed in a majority of HNSCCs, only a minority of patients derives substantial clinical benefit from EGFR inhibitors. We initiated the present study to identify the mechanisms underlying erlotinib resistance in a panel of HNSCC cell lines. We used 3H-thymidine incorporation to characterize the heterogeneity of responsiveness to erlotinib-mediated growth inhibition in a panel of 27 human HNSCC cells. We characterized the molecular mechanisms involved in resistance using a representative subset of 6 erlotinib-sensitive and -resistant HNSCC lines. Erlotinib had heterogeneous effects on DNA synthesis in HNSCC cells that correlated closely with molecular markers of epithelial to mesenchymal transition (EMT). Specifically, the drug-sensitive lines expressed high levels of E-cadherin and demonstrated limited invasion and migration capabilities. In contrast, the erlotinib-resistant HNSCC lines expressed high levels of the E-cadherin repressor deltaEF1 (Zeb-1) and other mesenchymal markers and low levels of E-cadherin, and they were highly invasive and migratory. siRNA-mediated knockdown of deltaEF1 in the erlotinib-resistant cell lines (1386LN and UMSCC1) resulted in upregulation of E-cadherin and increased sensitivity to erlotinib in an E-cadherin-dependent manner. DeltaEF1 controls the mesenchymal phenotype and drives erlotinib resistance in HNSCC cells. E-cadherin and deltaEF1 may prove to be useful markers in predicting EGFR inhibitor responsiveness.
