YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice.
Adaptor Proteins, Signal Transducing
/ metabolism
Adult
Aged
Animals
Bile Duct Neoplasms
/ metabolism
Cholangiocarcinoma
/ metabolism
Female
Humans
Male
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mice
Middle Aged
Proto-Oncogene Mas
Receptor, Notch1
/ metabolism
Transcription Factors
/ metabolism
YAP-Signaling Proteins
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
11
01
2021
revised:
24
05
2021
accepted:
27
05
2021
pubmed:
16
6
2021
medline:
14
9
2021
entrez:
15
6
2021
Statut:
ppublish
Résumé
Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignant neoplasm with limited therapeutic options. Previous studies have found that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. The current study found that activation of the Yes-associated protein (Yap) proto-oncogene occurs during Notch1-driven iCCA progression. After co-expressing activated Notch1 intracellular domain (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway was detected in Nicd/Yap mouse liver tumors. Significantly, the genetic deletion of Raptor, the major mTORC1 component, completely suppressed iCCA development in Nicd/Yap mice. Elevated expression of Notch1, YAP, amino acid transporters, and members of the mTORC1 pathway was also detected ubiquitously in a collection of human iCCA specimens. Their levels were associated with a poor patient outcome. This study demonstrates that Notch and YAP concomitant activation is frequent in human cholangiocarcinogenesis. Notch and YAP synergize to promote iCCA formation by activating the mTORC1 pathway.
Identifiants
pubmed: 34129844
pii: S0002-9440(21)00252-2
doi: 10.1016/j.ajpath.2021.05.017
pmc: PMC8420864
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
MAS1 protein, human
0
Proto-Oncogene Mas
0
Receptor, Notch1
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Yap1 protein, mouse
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1651-1667Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK026743
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190606
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239251
Pays : United States
Informations de copyright
Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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