Kumar S Ram, Scehnet Jeffrey S, Ley Eric J, Singh Jasbir, Krasnoperov Valery, Liu Ren, Manchanda Parmeet K, Ladner Robert D, Hawes Debra, Weaver Fred A, Beart Robert W, Singh Gagandeep, Nguyen Cu, Kahn Michael, Gill Parkash S
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Cancer Res. 2009 May 1;69(9):3736-45. doi: 10.1158/0008-5472.CAN-08-3232. Epub 2009 Apr 14.
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 and 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-mediated 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.
受体酪氨酸激酶EphB2由结肠祖细胞表达；然而，只有39%的结直肠癌表达EphB2，且表达水平随疾病进展而下降。相反，EphB4在正常结肠中不存在，但在所分析的所有102例结直肠癌标本中均有表达，其表达水平与更高的肿瘤分期和分级相关。EphB4和EphB2均受Wnt通路调控，该通路的激活是结直肠癌进展的关键需求。已知Wnt/β-连环蛋白通路对转录共激活因子环磷酸腺苷反应元件结合蛋白结合蛋白（CBP）的使用优于p300，可抑制分化并增加增殖。我们发现，与β-连环蛋白-p300复合物相反，β-连环蛋白-CBP复合物诱导EphB4并抑制EphB2。EphB4的增加为肿瘤细胞提供生存优势，并使其对天然肿瘤坏死因子相关凋亡诱导配体介导的细胞死亡产生抗性。敲低EphB4可抑制肿瘤生长和转移。我们的研究首次表明，与EphB2相反，EphB4在结直肠癌中被优先诱导，从而使肿瘤细胞获得生存优势。
