B216: ETV1 and ETV5 as targets and effectors of mutant FGFR3 in bladder cancer
1University of Leeds, Leeds, UK
Alteration of fibroblast growth factors receptor 3 (FGFR3) signalling is a common and early finding in bladder tumours, and can result from activating mutations, overexpression, alternative splicing, or oncogenic gene fusions. However, the molecular mechanisms by which FGFR3 signalling drives bladder malignant transformation are still unclear. In this study we investigate whether the oncogenic properties of FGFR3 are mediated by two transcription factors of the ETS-family, ETV1 and ETV5, which have previously been implicated in the development of other malignancies.
FGFR3, ETV1 and ETV5 expression in normal and malignant bladder cells was modulated and the effects on gene expression profiles, proliferation and contact-independent cell growth were studied.
Overexpression of mutant FGFR3 or stimulation of wild type FGFR3 with FGF1 in normal urothelial cells resulted in ETV1 and ETV5 upregulation, while silencing of mutant FGFR3 in bladder cancer cell lines induced opposite changes, indicating that these transcription factors are downstream targets of FGF signalling in these cells. Silencing of ETV5 expression in bladder cancer cells inhibited proliferation and anchorage independent growth, while silencing of ETV1 had little effect.
Overall, our preliminary data suggest that FGFR3 may drive the malignant transformation of urothelial cells through the upregulation of ETV5. Work is currently under way to asses ETV5 mRNA and protein expression levels in bladder tumours and correlation with FGFR3 mutation and clinicopathological parameters, and to identify downstream targets of this transcription factor which may mediate its phenotypic effects.