ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer

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. Howe...

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Autores principales:	Erica di Martino, Olivia Alder, Carolyn D. Hurst, Margaret A. Knowles
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7bb60571b5e24f2aa7be8f839790e504
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spelling	oai:doaj.org-article:7bb60571b5e24f2aa7be8f839790e5042021-12-02T16:08:53ZETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer10.1038/s41598-018-36456-32045-2322https://doaj.org/article/7bb60571b5e24f2aa7be8f839790e5042019-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-36456-3https://doaj.org/toc/2045-2322Abstract 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.Erica di MartinoOlivia AlderCarolyn D. HurstMargaret A. KnowlesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-12 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Erica di Martino Olivia Alder Carolyn D. Hurst Margaret A. Knowles ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer
description	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.
format	article
author	Erica di Martino Olivia Alder Carolyn D. Hurst Margaret A. Knowles
author_facet	Erica di Martino Olivia Alder Carolyn D. Hurst Margaret A. Knowles
author_sort	Erica di Martino
title	ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer
title_short	ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer
title_full	ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer
title_fullStr	ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer
title_full_unstemmed	ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer
title_sort	etv5 links the fgfr3 and hippo signalling pathways in bladder cancer
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/7bb60571b5e24f2aa7be8f839790e504
work_keys_str_mv	AT ericadimartino etv5linksthefgfr3andhipposignallingpathwaysinbladdercancer AT oliviaalder etv5linksthefgfr3andhipposignallingpathwaysinbladdercancer AT carolyndhurst etv5linksthefgfr3andhipposignallingpathwaysinbladdercancer AT margaretaknowles etv5linksthefgfr3andhipposignallingpathwaysinbladdercancer
_version_	1718384478389272576

ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer

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