Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma.
Adaptor Proteins, Signal Transducing
/ antagonists & inhibitors
Bile Duct Neoplasms
/ genetics
Bile Ducts, Extrahepatic
Bile Ducts, Intrahepatic
Cell Count
Cell Line, Tumor
Cholangiocarcinoma
/ genetics
Chromosomal Instability
/ genetics
Histones
/ metabolism
Humans
Immunohistochemistry
Intracellular Signaling Peptides and Proteins
/ antagonists & inhibitors
Prognosis
Tissue Array Analysis
Transcription Factors
/ antagonists & inhibitors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
YAP-Signaling Proteins
CIN25
Cell density
Genomic instability
Hippo pathway
Liver cancer
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
06 Oct 2021
06 Oct 2021
Historique:
received:
14
07
2021
accepted:
16
09
2021
entrez:
7
10
2021
pubmed:
8
10
2021
medline:
21
10
2021
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 34615513
doi: 10.1186/s12885-021-08794-5
pii: 10.1186/s12885-021-08794-5
pmc: PMC8496054
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
H2AX protein, human
0
Histones
0
Intracellular Signaling Peptides and Proteins
0
Transcription Factors
0
Transcriptional Coactivator with PDZ-Binding Motif Proteins
0
WWTR1 protein, human
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1079Informations de copyright
© 2021. The Author(s).
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