Masood Rizwan, Kumar S Ram, Sinha Uttam K, Crowe David L, Krasnoperov Valery, Reddy Ramachandra K, Zozulya Sergey, Singh Jasbir, Xia Guangbin, Broek Daniel, Schönthal Axel H, Gill Parkash S
Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA.
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.
受体酪氨酸激酶EphB4及其配体EphrinB2在血管成熟过程中发挥关键作用，且在多种癌症中经常过度表达。我们研究了EphB4在头颈部鳞状细胞癌（HNSCC）中的异常表达及其生物学作用。我们测试了EphB4特异性小干扰RNA（siRNA）和反义寡核苷酸（AS-ODN）对细胞生长、迁移和侵袭的影响，以及EphB4 AS-ODN对体内肿瘤生长的影响。所有HNSCC肿瘤样本均表达EphB4，其表达水平与更高的分期和淋巴结转移直接相关。7个HNSCC细胞系中有6个（86%）表达EphB4，其表达可由表皮生长因子受体（EGFR）激活或EPHB4基因扩增诱导。EphrinB2在65%的肿瘤和7个细胞系中的5个（71%）中表达。EphB4为肿瘤细胞提供生存优势，因为EphB4 siRNA和AS-ODN可显著抑制肿瘤细胞活力、诱导凋亡、激活半胱天冬酶-8，并使细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞死亡敏感。此外，EphB4特异性AS-ODN可显著抑制HNSCC肿瘤异种移植在体内的生长。EphB4在HNSCC肿瘤细胞中的表达赋予了生存和侵袭特性，从而为将EphB4作为HNSCC的新型治疗靶点提供了有力依据。
