RRC ID 69584
著者 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.
タイトル Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma.
ジャーナル BMC Cancer
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.
巻・号 21(1)
ページ 1079
公開日 2021-10-6
DOI 10.1186/s12885-021-08794-5
PII 10.1186/s12885-021-08794-5
PMID 34615513
PMC PMC8496054
MeSH Adaptor Proteins, Signal Transducing / antagonists & inhibitors Adaptor Proteins, Signal Transducing / metabolism* Bile Duct Neoplasms / genetics* Bile Ducts, Extrahepatic Bile Ducts, Intrahepatic Cell Count Cell Line, Tumor Cholangiocarcinoma / genetics* Cholangiocarcinoma / metabolism Cholangiocarcinoma / pathology Chromosomal Instability / genetics* Histones / metabolism Humans Immunohistochemistry Intracellular Signaling Peptides and Proteins / antagonists & inhibitors Intracellular Signaling Peptides and Proteins / metabolism* Prognosis Tissue Array Analysis Transcription Factors / antagonists & inhibitors Transcription Factors / metabolism* Transcriptional Coactivator with PDZ-Binding Motif Proteins YAP-Signaling Proteins
IF 3.15
リソース情報
ヒト・動物細胞 G-415(RCB2640)