Page 142 - D. Cancer biology

[D. Cancer biology-93]

Functional Roles of Fibroblast Growth Factor Receptors

Signaling in EWS-Oct-4-mediated Cell Transformation

Jung hoon Kim¹, Jung ho Kim¹˙*

¹Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul 04107, Korea

Certain bone and soft tissue tumors harbor a chromosomal translocation [t(6;22)(p21;q12)], which fuses the Ewing’s
sarcoma (EWS) gene at 22q12 with the octamer-binding transcription factor 4 (Oct-4) gene at 6p21, resulting in the
chimeric EWS-Oct-4 protein that possesses high transactivation ability. To identify the genes involved in the FGF

signaling pathway and potentially regulated by EWS-Oct-4, we performed RNA-Seq analysis, electrophoretic mobility

shift assays, chromatin immunoprecipitation assays, and xenograft assays. Treating GBS6 or ZHBTc4 cells-expressing
EWS-Oct-4 with the small molecule FGF receptor inhibitors PD173074 suppressed cellular proliferation. Computer-
assisted analysis identified a putative EWS-Oct-4-binding site at +3017/+3024, suggesting that EWS-Oct-4 regulates

Fgf-4 expression in human BST tumors. Fgf-4 enhancer constructs showed that EWS-Oct-4 transactivated the Fgf-4
gene reporter in vitro, and that overexpression of EWS-Oct-4 stimulated endogenous Fgf-4 gene expression in vivo.

Finally, PD173074 significantly decreased tumor volume in mice. these data suggest that FGF-4 signaling is involved
in EWS-Oct-4-mediated tumorigenesis, and that its inhibition significantly impairs tumor growth in vivo.