EphB4 provides survival advantage to squamous cell carcinoma of the head and neck

Int J Cancer. 2006 Sep 15;119(6):1236-48. doi: 10.1002/ijc.21926.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / pharmacology
  • Apoptosis*
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / mortality
  • Caspase 8
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Survival
  • Enzyme Activation
  • Ephrin-B2 / antagonists & inhibitors
  • Ephrin-B2 / genetics
  • Ephrin-B2 / metabolism
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Gene Amplification
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / mortality
  • Humans
  • Lymphatic Metastasis
  • Male
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness / pathology
  • Neoplasm Staging
  • RNA, Small Interfering / pharmacology
  • Receptor, EphB4 / antagonists & inhibitors
  • Receptor, EphB4 / genetics
  • Receptor, EphB4 / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Transplantation, Heterologous
  • Tumor Necrosis Factor-alpha / pharmacology


  • Apoptosis Regulatory Proteins
  • Ephrin-B2
  • Membrane Glycoproteins
  • RNA, Small Interfering
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • ErbB Receptors
  • Receptor, EphB4
  • CASP8 protein, human
  • Casp8 protein, mouse
  • Caspase 8
  • Caspases