Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression.
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.
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
S Ram
SR
Kumar
Jeffrey S
JS
Scehnet
Eric J
EJ
Ley
Jasbir
J
Singh
Valery
V
Krasnoperov
Ren
R
Liu
Parmeet K
PK
Manchanda
Robert D
RD
Ladner
Debra
D
Hawes
Fred A
FA
Weaver
Robert W
RW
Beart
Gagandeep
G
Singh
Cu
C
Nguyen
Michael
M
Kahn
Parkash S
PS
Gill
D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D036183:Receptor, EphB2 / Q000096:biosynthesis*; D036224:Receptor, EphB4 / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; D034741:RNA, Small Interfering; D051176:beta Catenin; D036183:Receptor, EphB2; D036224:Receptor, EphB4