Di Martino, E, Alder, O orcid.org/0000-0002-7975-9727, Hurst, CD orcid.org/0000-0001-7719-1325 et al. (1 more author) (2019) ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer. Scientific Reports, 9. ARTN: 5740. ISSN 2045-2322
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 bladder 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 bladder malignant transformation and indicates TAZ as a possible therapeutic target in FGFR3-dependent bladder tumours.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Oncology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Section of Experimental Oncology (Leeds) |
Funding Information: | Funder Grant number Yorkshire Cancer Research L372 |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 Nov 2018 13:58 |
Last Modified: | 07 May 2019 15:01 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/s41598-018-36456-3 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:138691 |