Abstract
The receptor tyrosine kinase EphB4 and its ligand EphrinB2 play critical roles in blood vessel maturation, and are frequently overexpressed in a wide variety of cancers. We studied the aberrant expression and biological role of EphB4 in head and neck squamous cell carcinoma (HNSCC). We tested the effect of EphB4-specific siRNA and antisense oligonucleotides (AS-ODN) on cell growth, migration and invasion, and the effect of EphB4 AS-ODN on tumor growth in vivo. All HNSCC tumor samples express EphB4 and levels of expression correlate directly with higher stage and lymph node metastasis. Six of 7 (86%) HNSCC cell lines express EphB4, which is induced either by EGFR activation or by EPHB4 gene amplification. EphrinB2 was expressed in 65% tumors and 5 of 7 (71%) cell lines. EphB4 provides survival advantage to tumor cells in that EphB4 siRNA and AS-ODN significantly inhibit tumor cell viability, induce apoptosis, activate caspase-8, and sensitize cells to TRAIL-induced cell death. Furthermore, EphB4-specific AS-ODN significantly inhibits the growth of HNSCC tumor xenografts in vivo. Expression of EphB4 in HNSCC tumor cells confers survival and invasive properties, and thereby provides a strong rationale for targeting EphB4 as novel therapy for HNSCC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / pharmacology
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Apoptosis*
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / mortality
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Caspase 8
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Caspases / metabolism
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Cell Line, Tumor
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Cell Movement
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Cell Survival
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Enzyme Activation
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Ephrin-B2 / antagonists & inhibitors
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Ephrin-B2 / genetics
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Ephrin-B2 / metabolism
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Gene Amplification
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Head and Neck Neoplasms / metabolism*
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Head and Neck Neoplasms / mortality
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Humans
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Lymphatic Metastasis
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Male
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Membrane Glycoproteins / pharmacology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Invasiveness / pathology
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Neoplasm Staging
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RNA, Small Interfering / pharmacology
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Receptor, EphB4 / antagonists & inhibitors
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Receptor, EphB4 / genetics
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Receptor, EphB4 / metabolism*
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TNF-Related Apoptosis-Inducing Ligand
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Transfection
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Transplantation, Heterologous
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Apoptosis Regulatory Proteins
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Ephrin-B2
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Membrane Glycoproteins
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RNA, Small Interfering
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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ErbB Receptors
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Receptor, EphB4
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8
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Caspases