Verteporfin targeting YAP1/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Cell Growth Processes
/ drug effects
Cell Line, Tumor
DNA-Binding Proteins
/ genetics
Drug Resistance, Neoplasm
Humans
Hyaluronan Receptors
/ biosynthesis
Male
Mice
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Neoplastic Stem Cells
/ drug effects
Nuclear Proteins
/ genetics
Stomach Neoplasms
/ drug therapy
TEA Domain Transcription Factors
Trans-Activators
/ genetics
Transcription Factors
/ genetics
Transcription, Genetic
/ drug effects
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Up-Regulation
Verteporfin
/ pharmacology
Xenograft Model Antitumor Assays
YAP-Signaling Proteins
CD44
CSC
gastric carcinoma
hippo pathway
patient-derived xenografts
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 04 2020
15 04 2020
Historique:
received:
05
02
2019
accepted:
07
08
2019
pubmed:
7
9
2019
medline:
19
5
2020
entrez:
7
9
2019
Statut:
ppublish
Résumé
Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation-44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T-TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration-approved drug preventing Y/T-TEAD interaction, on gastric CSC tumorigenic properties. Y/T-TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient-derived GC and cell lines. Verteporfin effects on Y/T-TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient-derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T-TEAD molecular signature was enriched in CD44+ patient-derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T-TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere-forming CD44
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CD44 protein, human
0
DNA-Binding Proteins
0
Hyaluronan Receptors
0
Nuclear Proteins
0
TEA Domain Transcription Factors
0
TEAD1 protein, human
0
Trans-Activators
0
Transcription Factors
0
Transcriptional Coactivator with PDZ-Binding Motif Proteins
0
WWTR1 protein, human
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Verteporfin
0X9PA28K43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2255-2267Informations de copyright
© 2019 UICC.
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