β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms
/ genetics
Male
Mice
Mutation
Prognosis
Transcription Factors
/ genetics
Tumor Cells, Cultured
YAP-Signaling Proteins
beta Catenin
/ genetics
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:
05 2019
05 2019
Historique:
received:
06
09
2018
revised:
31
01
2019
accepted:
01
02
2019
pubmed:
23
2
2019
medline:
12
2
2020
entrez:
23
2
2019
Statut:
ppublish
Résumé
Hepatoblastoma (HB), the most common pediatric primary liver neoplasm, shows nuclear localization of β-catenin and yes-associated protein 1 (YAP1) in almost 80% of the cases. Co-expression of constitutively active S127A-YAP1 and ΔN90 deletion-mutant β-catenin (YAP1-ΔN90-β-catenin) causes HB in mice. Because heterogeneity in downstream signaling is being identified owing to mutational differences even in the β-catenin gene alone, we investigated if co-expression of point mutants of β-catenin (S33Y or S45Y) with S127A-YAP1 led to similar tumors as YAP1-ΔN90-β-catenin. Co-expression of S33Y/S45Y-β-catenin and S127A-YAP1 led to activation of Yap and Wnt signaling and development of HB, with 100% mortality by 13 to 14 weeks. Co-expression with YAP1-S45Y/S33Y-β-catenin of the dominant-negative T-cell factor 4 or dominant-negative transcriptional enhanced associate domain 2, the respective surrogate transcription factors, prevented HB development. Although histologically similar, HB in YAP1-S45Y/S33Y-β-catenin, unlike YAP1-ΔN90-β-catenin HB, was glutamine synthetase (GS) positive. However, both ΔN90-β-catenin and point-mutant β-catenin comparably induced GS-luciferase reporter in vitro. Finally, using a previously reported 16-gene signature, it was shown that YAP1-ΔN90-β-catenin HB tumors exhibited genetic similarities with more proliferative, less differentiated, GS-negative HB patient tumors, whereas YAP1-S33Y/S45Y-β-catenin HB exhibited heterogeneity and clustered with both well-differentiated GS-positive and proliferative GS-negative patient tumors. Thus, we demonstrate that β-catenin point mutants can also collaborate with YAP1 in HB development, albeit with a distinct molecular profile from the deletion mutant, which may have implications in both biology and therapy.
Identifiants
pubmed: 30794807
pii: S0002-9440(18)30759-4
doi: 10.1016/j.ajpath.2019.02.002
pmc: PMC6521893
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Biomarkers, Tumor
0
CTNNB1 protein, human
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
beta Catenin
0
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
1091-1104Subventions
Organisme : NCI NIH HHS
ID : R01 CA204586
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062277
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK100287
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Références
Gastroenterology. 2017 Feb;152(3):533-545
pubmed: 28003097
J Clin Oncol. 2015 Sep 20;33(27):3047-54
pubmed: 26304909
J Biol Chem. 2012 Jun 29;287(27):22789-98
pubmed: 22613727
Clin Cancer Res. 2001 Apr;7(4):901-8
pubmed: 11309340
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Hum Pathol. 2009 Jun;40(6):843-53
pubmed: 19200578
Pediatr Blood Cancer. 2012 Nov;59(5):818-21
pubmed: 22678761
Nature. 1996 Aug 15;382(6592):638-42
pubmed: 8757136
Liver Int. 2012 Jan;32(1):38-47
pubmed: 22098159
Mod Pathol. 2014 Mar;27(3):472-91
pubmed: 24008558
Biotechniques. 1988 May;6(5):454-8
pubmed: 2908509
Cell. 2014 Jul 3;158(1):157-70
pubmed: 24976009
Gastroenterology. 2015 Jun;148(7):1294-310
pubmed: 25747274
Pharm Res. 2011 Apr;28(4):694-701
pubmed: 21191634
Cancer Res. 2002 Apr 1;62(7):1971-7
pubmed: 11929813
Gastroenterology. 2014 Sep;147(3):690-701
pubmed: 24837480
Hepatology. 2016 Nov;64(5):1587-1605
pubmed: 27097116
Cancer Cell. 2008 Dec 9;14(6):471-84
pubmed: 19061838
Cancer Res. 1999 Jan 15;59(2):269-73
pubmed: 9927029
Eur J Biochem. 1993 May 1;213(3):1067-73
pubmed: 8099326
Hepatology. 2017 May;65(5):1581-1599
pubmed: 27981621
Nat Cell Biol. 2016 Aug;18(8):886-896
pubmed: 27428308
Cancer Res. 2001 Apr 15;61(8):3245-9
pubmed: 11309273
BMC Cancer. 2018 Nov 12;18(1):1093
pubmed: 30419856
Hepatology. 2006 Oct;44(4):967-75
pubmed: 17006929
EMBO Mol Med. 2017 Nov;9(11):1589-1604
pubmed: 28923827
Hum Pathol. 2009 Jun;40(6):783-94
pubmed: 19200579
Toxicology. 2011 Mar 15;281(1-3):7-14
pubmed: 21237236
Dev Cell. 2008 Mar;14(3):388-98
pubmed: 18258486
Hepatology. 2009 Mar;49(3):821-31
pubmed: 19101982
Nat Genet. 2015 May;47(5):505-511
pubmed: 25822088
Mol Ther Methods Clin Dev. 2014 Jul 23;1:14029
pubmed: 26015971
Am J Pathol. 2018 Aug;188(8):1895-1909
pubmed: 29920228
PLoS One. 2016 Apr 21;11(4):e0152695
pubmed: 27100093
Eur J Cancer. 2016 Jan;52:92-101
pubmed: 26655560
Curr Opin Pediatr. 2014 Feb;26(1):19-28
pubmed: 24322718
Int J Biochem Cell Biol. 2011 Feb;43(2):265-70
pubmed: 19646548
Hepatology. 2016 Dec;64(6):2047-2061
pubmed: 27177928