Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors
Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors
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DOI：
10.1158/0008-5472.can-05-2580
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Arango, D
中科院分区：
文献类型：
--
作者：
Alazzouzi, H;Davalos, V;Arango, D
受体酪氨酸激酶EPHB2最近被证明是TCF/ β -连环蛋白的直接转录靶点。结肠癌前病变表达高水平的EPHB2，但在大多数结直肠癌中，该激酶的表达减少或缺失。此外，EPHB2的失活已被证明可以加速结肠和直肠APC突变引发的肿瘤发生。在这项研究中，我们研究了大肠肿瘤中EPHB2失活的分子机制。我们在29例微卫星不稳定性腺瘤（NISI）中的6例和246例MSI癌中的101例（分别为21%和41%）中发现EPHB2外显子17重复序列突变。此外，我们在101例结肠直肠癌中发现54例（53%）EPHB2启动子超甲基化。重要的是，用DNA甲基转移酶抑制剂5-aza-2'-脱氧胞苷处理EPHB2甲基化的结肠癌细胞后，EPHB2的表达得以恢复。总之，在本研究中，我们阐明了EPHB2失活的分子机制，并首次揭示了MSI结直肠肿瘤中移码突变的高发生率以及这一重要抑癌基因调控序列的异常甲基化。
The receptor tyrosine kinase EPHB2 has recently been shown to be a direct transcriptional target of TCF/beta-catenin. Premalignant lesions of the colon express high levels of EPHB2 but the expression of this kinase is reduced or lost in most colorectal carcinomas. In addition, inactivation of EPHB2 has been shown to accelerate tumorigenesis initiated by APC mutation in the colon and rectum. In this study, we investigated the molecular mechanisms responsible for the inactivation of EPHB2 in colorectal tumors. We show here the presence of mutations in repetitive sequences in exon 17 of EPHB2 in 6 of 29 adenomas with microsatellite instability (NISI), and 101 of 246 MSI carcinomas (21% and 41%, respectively). Moreover, we found EPHB2 promoter hypermethylation in 54 of the 101 colorectal tumors studied (53%). Importantly, EPHB2 expression was restored after treatment of EPHB2-methylated colon cancer cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. In conclusion, in this study, we elucidate the molecular mechanisms of inactivation of EPHB2 and show for the first time the high incidence of frameshift mutations in MSI colorectal tumors and aberrant methylation of the regulatory sequences of this important tumor suppressor gene.