Abstract
Activating mutations of fibroblast growth factor receptor 3 (FGFR3) are common in urothelial carcinoma of the bladder (UC). Silencing or inhibition of mutant FGFR3 in bladder cancer cell lines is associated with decreased malignant potential, confirming its important driver role in UC. However, understanding of how FGFR3 activation drives urothelial malignant transformation remains limited. We have previously shown that mutant FGFR3 alters the cell-cell and cell-matrix adhesion properties of urothelial cells, resulting in loss of contact-inhibition of proliferation. In this study, we investigate a transcription factor of the ETS-family, ETV5, as a putative effector of FGFR3 signalling in bladder cancer. We show that FGFR3 signalling induces a MAPK/ERK-mediated increase in ETV5 levels, and that this results in increased level of TAZ, a co-transcriptional regulator downstream of the Hippo signalling pathway involved in cell-contact inhibition. We also demonstrate that ETV5 is a key downstream mediator of the oncogenic effects of mutant FGFR3, as its knockdown in FGFR3-mutant bladder cancer cell lines is associated with reduced proliferation and anchorage-independent growth. Overall this study advances our understanding of the molecular alterations occurring during urothelial malignant transformation and indicates TAZ as a possible therapeutic target in FGFR3-dependent bladder tumours.
Highlights
Fibroblast growth factors (FGF) and their four tyrosine kinase receptors (FGFR1-4) activate multiple downstream cellular signalling pathways, such as MAPK/ERK, PLCγ1, PI3K and STATs, and regulate a variety of physiological processes, encompassing embryogenesis, angiogenesis, metabolism, and wound healing[1,2,3]
ETV5 mRNA levels were measured in confluent TERT-normal human urothelial cells (NHUC) ectopically expressing three different fibroblast growth factor receptor 3 (FGFR3) mutant proteins (S249C, Y375C, and K652E)
Members of the ETS-family of transcription factors are downstream effectors of FGF-signalling during embryonic development[31,32,33] but their role in urothelial carcinomas driven by FGFR3 mutation has not been investigated so far
Summary
Fibroblast growth factors (FGF) and their four tyrosine kinase receptors (FGFR1-4) activate multiple downstream cellular signalling pathways, such as MAPK/ERK, PLCγ1, PI3K and STATs, and regulate a variety of physiological processes, encompassing embryogenesis, angiogenesis, metabolism, and wound healing[1,2,3]. FGFR3 mutations are a very common occurrence in UC, in low stage and grade tumours, reaching frequencies of over 80% in this subtype[10]. They are thought to be an early change during urothelial transformation, as they are found in flat urothelial hyperplasia, a proposed precursor lesion for UC11. Numerous functional studies silencing or targeting mutant FGFR3 in bladder cancer cell lines have shown decreased cell proliferation and tumorigenic potential both in vitro and in vivo[17,18,19,20]. In this study we investigate whether ETV5 and its downstream targets are crucial mediators of the oncogenic effects of mutant FGFR3 in urothelial cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
