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Preferential Induction of EphB4 over EphB2 and Its Implication in Colorectal Cancer Progression

Departments of ¹ Pathology, ² Surgery, ³ Colorectal Surgery, ⁴ Medicine, and ⁵ Biochemistry and Molecular Biology, Keck School of Medicine; ⁶ Department of Molecular Pharmacology and Toxicology, School of Pharmacy; and ⁷ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California; and ⁸ Vasgene, Inc., Los Angeles, California

Requests for reprints: Parkash S. Gill, Keck School of Medicine of the University of Southern California, 1441 Eastlake Avenue, NOR 6330, Los Angeles, CA 90033. Phone: 323-865-3909; Fax: 323-865-0092; E-mail: parkashg{at}usc.edu.

Key Words: EphB4 • apoptosis • angiogenesis • TRAIL • colorectal cancer

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/β-catenin pathway is known to suppress differentiation and increase proliferation. We show that the β-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the β-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. [Cancer Res 2009;69(9):3736–45]

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				Correction: Article on EphB4 Is Up-regulated in Colorectal Cancer Cancer Res., May 15, 2009; 69(10): 4554 - 4554. [Full Text] [PDF]