Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression
Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression
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DOI：
10.1158/0008-5472.can-08-3232
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Gill, Parkash S.
中科院分区：
文献类型：
--
作者：
Kumar, S. Ram;Scehnet, Jeffrey S.;Gill, Parkash S.
受体酪氨酸激酶EphB2由结肠祖细胞表达；然而，只有39%的结直肠肿瘤表达EphB2，且表达水平随着疾病进展而下降。相反，EphB4在正常结肠中不存在，但在102例结肠中均有表达。对肿瘤标本进行分析，其表达水平与较高的肿瘤分期和分级相关。EphB4和EphB2均受Wnt通路的调控，Wnt通路的激活对结直肠癌的进展至关重要。已知Wnt/ β -catenin途径在p300上使用转录辅助激活因子环amp响应元件结合蛋白结合蛋白（CBP）可抑制分化并增加增殖。我们发现β -catenin- cbp复合物诱导EphB4并抑制EphB2，与β -catenin-p300复合物相反。获得EphB4可为肿瘤细胞提供生存优势，并抵抗先天性肿瘤坏死因子相关的凋亡诱导配体介导的细胞死亡。敲低EphB4抑制肿瘤生长和转移。我们的工作首次表明，EphB4在结直肠癌中优先被诱导，而EphB2则相反，肿瘤细胞获得生存优势。[癌症研究2009；69 (9): 3736 - 45)
The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal. cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein-binding protein (CBP) over p300 by the Wnt/beta-catenin pathway is known to suppress differentiation an increase proliferation. We show that the beta-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the beta-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand-mediate cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. [Cancer Res 2009;69(9):3736-45]