The EPHB6 Receptor Tyrosine Kinase Is a Metastasis Suppressor That Is Frequently Silenced by Promoter DNA Hypermethylation in Non-Small Cell Lung Cancer
The EPHB6 Receptor Tyrosine Kinase Is a Metastasis Suppressor That Is Frequently Silenced by Promoter DNA Hypermethylation in Non-Small Cell Lung Cancer
复制标题
DOI：
10.1158/1078-0432.ccr-09-2000
复制
发表时间：
2010-04-15
影响因子：
11.5
通讯作者：
Mueller-Tidow, Carsten
中科院分区：
文献类型：
--
作者：
Yu, Jun;Bulk, Etmar;Mueller-Tidow, Carsten
目的：早期非小细胞肺癌 (NSCLC) 中 EPHB6 受体酪氨酸激酶表达的丧失与随后发生远处转移有关。在此，我们分析了EPHB6在肺癌转移中的调控和功能。实验设计：根据患者病史比较正常肺组织（n = 9）、无转移NSCLC（n = 39）和有转移NSCLC（n = 39）中EPHB6的表达水平。此外，还分析了 24 名 NSCLC 患者的匹配肿瘤-正常对的 EPHB6 表达水平。在 14 对肿瘤正常样本中确定了启动子 DNA 甲基化状态及其与 EPHB6 表达水平的关联。在转移小鼠模型中体外和体内评估了 EPHB6 的转移潜力。采用过表达和RNA干扰（RNAi）方法分析EPHB6的生物学功能。结果：与匹配的正常肺组织相比，NSCLC肿瘤中EPHB6 mRNA和蛋白水平显着降低。 EPHB6 表达水平降低与 NSCLC 患者发生转移的风险增加相关。表达缺失与 EPHB6 高甲基化相关。在 NSCLC 细胞系中，5-aza-2'-脱氧胞苷处理可诱导 EPHB6 表达。肺腺癌细胞中 EPHB6 表达的恢复增加了粘附并减少了迁移。肺癌细胞中 EPHB6 的重新表达几乎完全消除了非肥胖糖尿病 (NOD)/严重联合免疫缺陷小鼠的转移形成。结论：总而言之，这些分析表明 EPHB6 是一种转移抑制基因，在 NSCLC 中经常因其启动子的高甲基化而被沉默。临床癌症研究； 16（8）； 2275-83。 (C) 2010 AACR。
Purpose: Loss of EPHB6 receptor tyrosine kinase expression in early-stage non-small cell lung carcinoma (NSCLC) is associated with the subsequent development of distant metastasis. Here, we analyzed the regulation and function of EPHB6 in lung cancer metastasis.Experimental Design: The expression levels of EPHB6 were compared among normal lung tissue (n = 9), NSCLC without metastasis (n = 39), and NSCLC with metastasis (n = 39) according to the history of the patients. In addition, EPHB6 expression levels of matched tumor-normal pairs from 24 NSCLC patients were analyzed. The promoter DNA methylation status and its association with the expression levels of EPHB6 were determined among 14 pairs of tumor-normal samples. Metastatic potential of EPHB6 was assessed in vitro and in vivo in a metastasis mouse model. Overexpression and RNA interference (RNAi) approaches were used for analysis of the biological functions of EPHB6.Results: EPHB6 mRNA and protein levels were significantly reduced in NSCLC tumors compared with matched normal lung tissue. Decreased EPHB6 expression levels were associated with an increased risk for metastasis development in NSCLC patients. Loss of expression correlated with EPHB6 hypermethylation. EPHB6 expression was induced by 5-aza-2'-deoxycytidine treatment in an NSCLC cell line. Restoration of EPHB6 expression in lung adenocarcinoma cells increased adhesion and decreased migration. Reexpression of EPHB6 in lung cancer cells almost entirely abolished metastasis formation in non obese diabetic (NOD)/severe combined immunodeficient mice.Conclusions: Taken together, these analyses show that EPHB6 is a metastasis inhibitory gene that is frequently silenced by hypermethylation of its promoter in NSCLC. Clin Cancer Res; 16(8); 2275-83. (C) 2010 AACR.