EphB receptor activity suppresses colorectal cancer progression
EphB receptor activity suppresses colorectal cancer progression
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DOI：
10.1038/nature03626
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发表时间：
2005-06-23
期刊：
影响因子：
64.8
通讯作者：
Clevers, H
中科院分区：
文献类型：
--
作者：
Batlle, E;Bacani, J;Clevers, H
大多数散发性结直肠癌是由激活Wnt途径突变引发的（1），其特征是β-连环蛋白的稳定化和β-连环蛋白/T细胞因子-4（Tcf-4）复合物的组成性转录（2，3）。EphB导向受体是Tcf 4靶基因，其通过与Ephrin-B配体的排斥相互作用来控制肠上皮结构（4，5）。在这里，我们表明，虽然Wnt信号仍然组成性活跃，大多数人结直肠癌失去EphB的表达在腺瘤癌的过渡。EphB表达的缺失与恶性程度强烈相关。此外，EphB活性的降低加速Apc（Min/+）小鼠的结肠和直肠中的肿瘤发生，并导致侵袭性腺癌的形成。我们的数据表明EphB表达的丧失代表了结直肠癌进展中的关键步骤。
Most sporadic colorectal cancers are initiated by activating Wnt pathway mutations(1), characterized by the stabilization of beta-catenin and constitutive transcription by the beta-catenin/T cell factor-4 (Tcf-4) complex(2,3). EphB guidance receptors are Tcf4 target genes that control intestinal epithelial architecture through repulsive interactions with Ephrin-B ligands(4,5). Here we show that, although Wnt signalling remains constitutively active, most human colorectal cancers lose expression of EphB at the adenoma-carcinoma transition. Loss of EphB expression strongly correlates with degree of malignancy. Furthermore, reduction of EphB activity accelerates tumorigenesis in the colon and rectum of Apc(Min/+) mice, and results in the formation of aggressive adenocarcinomas. Our data demonstrate that loss of EphB expression represents a critical step in colorectal cancer progression.