EphB4 provides survival advantage to squamous cell carcinoma of the head and neck.
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.
Masood
Rizwan
R
Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA.
Kumar
S Ram
SR
Sinha
Uttam K
UK
Crowe
David L
DL
Krasnoperov
Valery
V
Reddy
Ramachandra K
RK
Zozulya
Sergey
S
Singh
Jasbir
J
Xia
Guangbin
G
Broek
Daniel
D
Schönthal
Axel H
AH
Gill
Parkash S
PS
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
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