title: EphB4 provides survival advantage to squamous cell carcinoma of the head and neck.
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.
authors.affiliation: Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Masood
authors.forename: S Ram
authors.initials: SR
authors.lastname: Kumar
authors.forename: Uttam K
authors.initials: UK
authors.lastname: Sinha
authors.forename: David L
authors.initials: DL
authors.lastname: Crowe
authors.forename: Valery
authors.initials: V
authors.lastname: Krasnoperov
authors.forename: Ramachandra K
authors.initials: RK
authors.lastname: Reddy
authors.forename: Sergey
authors.initials: S
authors.lastname: Zozulya
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Guangbin
authors.initials: G
authors.lastname: Xia
authors.forename: Daniel
authors.initials: D
authors.lastname: Broek
authors.forename: Axel H
authors.initials: AH
authors.lastname: Schönthal
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004789:Enzyme Activation; D036388:Ephrin-B2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005784:Gene Amplification; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D034741:RNA, Small Interfering / Q000494:pharmacology; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D036388:Ephrin-B2; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; D036224:Receptor, EphB4; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases