Critical Role for the Receptor Tyrosine Kinase EPHB4 in Esophageal Cancers
Critical Role for the Receptor Tyrosine Kinase EPHB4 in Esophageal Cancers
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DOI：
10.1158/0008-5472.can-12-0915
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发表时间：
2013-01-01
期刊：
影响因子：
11.2
通讯作者：
Salgia, Ravi
中科院分区：
文献类型：
--
作者：
Hasina, Rifat;Mollberg, Nathan;Salgia, Ravi
食管癌的发病率正在增加，治疗选择很少。在研究与食管癌相关的受体酪氨酸激酶时，我们已经确定EPHB 4在细胞系和原发性肿瘤组织中强烈过表达。共94例鳞状细胞癌，82例腺癌，25例异型增生，13例Barrett食管和25例相邻或无关的正常食管组织进行了免疫组化评价。在所有不同的组织学类型中，EPHB 4的表达均显著高于邻近的正常组织。在13个食管癌细胞系中，9个SCC细胞系中的3个和4个腺癌中的2个表达非常高水平的EPHB 4。在过表达患者样本和细胞系的一个子集中，发现基因拷贝数增加了4至20个拷贝。我们已经开发了一种新的4-硝基喹啉1-氧化物（4-NQO）诱导的食管癌小鼠模型，该模型重现了EPHB 4在人类中的表达。EPHB 4的特异性小分子抑制剂以时间和剂量依赖性方式降低了4种细胞系中3种的细胞活力。小分子抑制剂和EPHB 4 siRNA也降低了细胞迁移（治疗组关闭12%-40%，未治疗组关闭60%-80%），降低了各种含酪氨酰蛋白EphB 4及其下游靶点p125 FAK的磷酸化。最后，在异种移植肿瘤模型中，与未处理的对照相比，EPHB 4抑制剂消除了约60%的肿瘤生长。EphB 4是稳定表达的，并可能作为食管癌靶向治疗的新生物标志物。Cancer Res; 73（1）; 184-94. (C)2012年AACR。
Esophageal cancer incidence is increasing and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identified EPHB4 to be robustly overexpressed in cell lines and primary tumor tissues. In total, 94 squamous cell carcinoma, 82 adenocarcinoma, 25 dysplasia, 13 Barrett esophagus, and 25 adjacent or unrelated normal esophageal tissues were evaluated by immunohistochemistry. EPHB4 expression was significantly higher in all the different histologic categories than in adjacent normal tissues. In 13 esophageal cancer cell lines, 3 of the 9 SCC cell lines and 2 of the 4 adenocarcinomas expressed very high levels of EPHB4. An increased gene copy number ranging from 4 to 20 copies was identified in a subset of the overexpressing patient samples and cell lines. We have developed a novel 4-nitroquinoline 1-oxide (4-NQO)-induced mouse model of esophageal cancer that recapitulates the EPHB4 expression in humans. A specific small-molecule inhibitor of EPHB4 decreased cell viability in a time- and dose-dependent manner in 3 of the 4 cell lines tested. The small-molecule inhibitor and an EPHB4 siRNA also decreased cell migration (12%-40% closure in treated vs. 60%-80% in untreated), with decreased phosphorylation of various tyrosyl-containing proteins, EphB4, and its downstream target p125FAK. Finally, in a xenograft tumor model, an EPHB4 inhibitor abrogated tumor growth by approximately 60% compared with untreated control. EphB4 is robustly expressed and potentially serves as a novel biomarker for targeted therapy in esophageal cancers. Cancer Res; 73(1); 184-94. (C) 2012 AACR.