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Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma
BACKGROUND: Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496054/ https://www.ncbi.nlm.nih.gov/pubmed/34615513 http://dx.doi.org/10.1186/s12885-021-08794-5 |
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author | Tóth, Marcell Wehling, Lilija Thiess, Lena Rose, Fabian Schmitt, Jennifer Weiler, Sofia M. E. Sticht, Carsten De La Torre, Carolina Rausch, Melina Albrecht, Thomas Grabe, Niels Duwe, Lea Andersen, Jesper B. Köhler, Bruno C. Springfeld, Christoph Mehrabi, Arianeb Kulu, Yakup Schirmacher, Peter Roessler, Stephanie Goeppert, Benjamin Breuhahn, Kai |
author_facet | Tóth, Marcell Wehling, Lilija Thiess, Lena Rose, Fabian Schmitt, Jennifer Weiler, Sofia M. E. Sticht, Carsten De La Torre, Carolina Rausch, Melina Albrecht, Thomas Grabe, Niels Duwe, Lea Andersen, Jesper B. Köhler, Bruno C. Springfeld, Christoph Mehrabi, Arianeb Kulu, Yakup Schirmacher, Peter Roessler, Stephanie Goeppert, Benjamin Breuhahn, Kai |
author_sort | Tóth, Marcell |
collection | PubMed |
description | BACKGROUND: Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes. METHODS: Immunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated. Target genes expression after combined YAP/TAZ inhibition was analyzed. RESULTS: Immunohistochemical analysis of iCCA and eCCA revealed YAP or TAZ positivity in up to 49.2%; however, oncogene co-expression was less frequent (up to 23%). In contrast, both proteins were jointly detectable in most CCA cell lines and showed nuclear/cytoplasmic shuttling in a cell density-dependent manner. Next to the pro-proliferative function of YAP/TAZ, both transcriptional co-activators cooperated in the regulation of a gene signature that indicated the presence of chromosomal instability (CIN). A correlation between YAP and the CIN marker phospho-H2A histone family member X (pH2AX) was particularly observed in tissues from iCCA and distal CCA (dCCA). The presence of the CIN genes in about 25% of iCCA was statistically associated with worse prognosis. CONCLUSIONS: YAP and TAZ activation is not uncoupled from cell density in CCA cells and both factors cooperatively contribute to proliferation and expression of CIN-associated genes. The corresponding group of CCA patients is characterized by CIN and may benefit from YAP/TAZ-directed therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-08794-5. |
format | Online Article Text |
id | pubmed-8496054 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-84960542021-10-07 Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma Tóth, Marcell Wehling, Lilija Thiess, Lena Rose, Fabian Schmitt, Jennifer Weiler, Sofia M. E. Sticht, Carsten De La Torre, Carolina Rausch, Melina Albrecht, Thomas Grabe, Niels Duwe, Lea Andersen, Jesper B. Köhler, Bruno C. Springfeld, Christoph Mehrabi, Arianeb Kulu, Yakup Schirmacher, Peter Roessler, Stephanie Goeppert, Benjamin Breuhahn, Kai BMC Cancer Research BACKGROUND: Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes. METHODS: Immunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated. Target genes expression after combined YAP/TAZ inhibition was analyzed. RESULTS: Immunohistochemical analysis of iCCA and eCCA revealed YAP or TAZ positivity in up to 49.2%; however, oncogene co-expression was less frequent (up to 23%). In contrast, both proteins were jointly detectable in most CCA cell lines and showed nuclear/cytoplasmic shuttling in a cell density-dependent manner. Next to the pro-proliferative function of YAP/TAZ, both transcriptional co-activators cooperated in the regulation of a gene signature that indicated the presence of chromosomal instability (CIN). A correlation between YAP and the CIN marker phospho-H2A histone family member X (pH2AX) was particularly observed in tissues from iCCA and distal CCA (dCCA). The presence of the CIN genes in about 25% of iCCA was statistically associated with worse prognosis. CONCLUSIONS: YAP and TAZ activation is not uncoupled from cell density in CCA cells and both factors cooperatively contribute to proliferation and expression of CIN-associated genes. The corresponding group of CCA patients is characterized by CIN and may benefit from YAP/TAZ-directed therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-021-08794-5. BioMed Central 2021-10-06 /pmc/articles/PMC8496054/ /pubmed/34615513 http://dx.doi.org/10.1186/s12885-021-08794-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Tóth, Marcell Wehling, Lilija Thiess, Lena Rose, Fabian Schmitt, Jennifer Weiler, Sofia M. E. Sticht, Carsten De La Torre, Carolina Rausch, Melina Albrecht, Thomas Grabe, Niels Duwe, Lea Andersen, Jesper B. Köhler, Bruno C. Springfeld, Christoph Mehrabi, Arianeb Kulu, Yakup Schirmacher, Peter Roessler, Stephanie Goeppert, Benjamin Breuhahn, Kai Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma |
title | Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma |
title_full | Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma |
title_fullStr | Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma |
title_full_unstemmed | Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma |
title_short | Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma |
title_sort | co-expression of yap and taz associates with chromosomal instability in human cholangiocarcinoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496054/ https://www.ncbi.nlm.nih.gov/pubmed/34615513 http://dx.doi.org/10.1186/s12885-021-08794-5 |
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