Up-regulation of EphB4 in mesothelioma and its biological significance.
OBJECTIVE
Mesothelioma is a rare malignancy that is incurable and carries a short survival despite surgery, radiation, or chemotherapy. This study was designed to identify novel targets for diagnostic, prognostic, and therapeutic approaches.


METHODS
The expression and functional significance of the receptor tyrosine kinase EphB4 was studied in vitro and in a murine model of mesothelioma.


RESULTS
EphB4 was highly expressed in mesothelioma cell lines and primary tumor tissues but not in normal mesothelium. Knockdown of EphB4 using small interfering RNA and antisense oligodeoxynucleotide showed reduction in cell survival, migration, and invasion. EphB4 knockdown initiated a caspase-8-mediated apoptosis and down-regulation of the anti-apoptotic protein bcl-xl. EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription. In addition, murine tumor xenograft studies using EphB4 oligodeoxynucleotides showed a marked reduction in tumor growth accompanied by a specific decline in EphB4 protein levels, reduced cell division, apoptosis in tumor tissue, and decreased microvascular density.


CONCLUSIONS
EphB4 is expressed in mesothelioma, provides a survival advantage to tumor cells, and is therefore a potential novel therapeutic target.
Xia
Guangbin
G
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033-9172, USA.
Kumar
S Ram
SR
Masood
Rizwan
R
Koss
Michael
M
Templeman
Claire
C
Quinn
David
D
Zhu
Sutao
S
Reddy
Ramachandra
R
Krasnoperov
Valery
V
Gill
Parkash S
PS
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D036224:Receptor, EphB4 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D036224:Receptor, EphB4