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...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
06 October 2021
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| In: |
BMC cancer
Year: 2021, Volume: 21, Pages: 1-14 |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/s12885-021-08794-5 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1186/s12885-021-08794-5
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| Author Notes: | Marcell Tóth, Lilija Wehling, Lena Thiess, Fabian Rose, Jennifer Schmitt, Sofia M.E. Weiler, Carsten Sticht, Carolina De La Torre, Melina Rausch, Thomas Albrecht, Niels Grabe, Lea Duwe, Jesper B. Andersen, Bruno C. Köhler, Christoph Springfeld, Arianeb Mehrabi, Yakup Kulu, Peter Schirmacher, Stephanie Roessler, Benjamin Goeppert and Kai Breuhahn |
MARC
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| 245 | 1 | 0 | |a Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma |c Marcell Tóth, Lilija Wehling, Lena Thiess, Fabian Rose, Jennifer Schmitt, Sofia M.E. Weiler, Carsten Sticht, Carolina De La Torre, Melina Rausch, Thomas Albrecht, Niels Grabe, Lea Duwe, Jesper B. Andersen, Bruno C. Köhler, Christoph Springfeld, Arianeb Mehrabi, Yakup Kulu, Peter Schirmacher, Stephanie Roessler, Benjamin Goeppert and Kai Breuhahn |
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| 520 | |a 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. | ||
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