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SHR Neuro Cancer Cardio Lipid Metab Microb

Tóth, M; Wehling, L; Thiess, L; Rose, F; Schmitt, J; Weiler, SME; Sticht, C; De, La, Torre, C; Rausch, M; Albrecht, T; Grabe, N; Duwe, L; Andersen, JB; Köhler, BC; Springfeld, C; Mehrabi, A; Kulu, Y; Schirmacher, P; Roessler, S; Goeppert, B; Breuhahn, K.
Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma.
BMC Cancer. 2021; 21(1): 1079 Doi: 10.1186/s12885-021-08794-5 [OPEN ACCESS]
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Leading authors Med Uni Graz: Toth Marcell
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Abstract:: 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.
Find related publications in this database (using NLM MeSH Indexing): Adaptor Proteins, Signal Transducing - antagonists & inhibitors, metabolism; Bile Duct Neoplasms - genetics; Bile Ducts, Extrahepatic - administration & dosage; Bile Ducts, Intrahepatic - administration & dosage; Cell Count - administration & dosage; Cell Line, Tumor - administration & dosage; Cholangiocarcinoma - genetics, metabolism, pathology; Chromosomal Instability - genetics; Histones - metabolism; Humans - administration & dosage; Immunohistochemistry - administration & dosage; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors, metabolism; Prognosis - administration & dosage; Tissue Array Analysis - administration & dosage; Transcription Factors - antagonists & inhibitors, metabolism; Transcriptional Coactivator with PDZ-Binding Motif Proteins - administration & dosage; YAP-Signaling Proteins - administration & dosage
Find related publications in this database (Keywords): Hippo pathway; CIN25; Liver cancer; Cell density; Genomic instability