Antagonism between wild-type and mutant β-catenin controls hepatoblastoma differentiation via fascin-1.
Beta-catenin
Differentiation
Fascin-1
Hepatoblastoma
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
received:
26
07
2022
revised:
13
01
2023
accepted:
17
01
2023
medline:
8
5
2023
pubmed:
8
5
2023
entrez:
8
5
2023
Statut:
epublish
Résumé
β-catenin is a well-known effector of the Wnt pathway, and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of β-catenin are very frequent in paediatric liver primary tumours. Those mutations are mostly heterozygous, which allows the co-expression of wild-type (WT) and mutated β-catenins in tumour cells. We investigated the interplay between WT and mutated β-catenins in liver tumour cells, and searched for new actors of the β-catenin pathway. Using an RNAi strategy in β-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, which are carried mainly by WT and mutated proteins, respectively. Their impact was characterised using transcriptomic and functional analyses. We studied mice that develop liver tumours upon activation of β-catenin in hepatocytes (APC We highlighted an antagonistic role of WT and mutated β-catenins with regard to hepatocyte differentiation, as attested by alterations in the expression of hepatocyte markers and the formation of bile canaliculi. We characterised fascin-1 as a transcriptional target of mutated β-catenin involved in tumour cell differentiation. Using mouse models, we found that fascin-1 is highly expressed in undifferentiated tumours. Finally, we found that fascin-1 is a specific marker of primitive cells including embryonal and blastemal cells in human HBs. Fascin-1 expression is linked to a loss of differentiation and polarity of hepatocytes. We present fascin-1 as a previously unrecognised factor in the modulation of hepatocyte differentiation associated with β-catenin pathway alteration in the liver, and as a new potential target in HB. The
Sections du résumé
Background & Aims
UNASSIGNED
β-catenin is a well-known effector of the Wnt pathway, and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of β-catenin are very frequent in paediatric liver primary tumours. Those mutations are mostly heterozygous, which allows the co-expression of wild-type (WT) and mutated β-catenins in tumour cells. We investigated the interplay between WT and mutated β-catenins in liver tumour cells, and searched for new actors of the β-catenin pathway.
Methods
UNASSIGNED
Using an RNAi strategy in β-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, which are carried mainly by WT and mutated proteins, respectively. Their impact was characterised using transcriptomic and functional analyses. We studied mice that develop liver tumours upon activation of β-catenin in hepatocytes (APC
Results
UNASSIGNED
We highlighted an antagonistic role of WT and mutated β-catenins with regard to hepatocyte differentiation, as attested by alterations in the expression of hepatocyte markers and the formation of bile canaliculi. We characterised fascin-1 as a transcriptional target of mutated β-catenin involved in tumour cell differentiation. Using mouse models, we found that fascin-1 is highly expressed in undifferentiated tumours. Finally, we found that fascin-1 is a specific marker of primitive cells including embryonal and blastemal cells in human HBs.
Conclusions
UNASSIGNED
Fascin-1 expression is linked to a loss of differentiation and polarity of hepatocytes. We present fascin-1 as a previously unrecognised factor in the modulation of hepatocyte differentiation associated with β-catenin pathway alteration in the liver, and as a new potential target in HB.
Impact and implications
UNASSIGNED
The
Identifiants
pubmed: 37153687
doi: 10.1016/j.jhepr.2023.100691
pii: S2589-5559(23)00022-8
pmc: PMC10159820
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100691Informations de copyright
© 2023 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.
Références
Gastroenterology. 2019 Sep;157(3):807-822
pubmed: 31194980
Hepatology. 2014 Jun;59(6):2344-57
pubmed: 24214913
Cell. 2012 Dec 21;151(7):1443-56
pubmed: 23245942
Cancer Res. 2007 Jul 15;67(14):6844-53
pubmed: 17638895
J Surg Oncol. 2009 Dec 1;100(7):575-9
pubmed: 19697358
Hepatology. 2012 Jun;55(6):1766-75
pubmed: 22234932
Exp Cell Res. 1994 Oct;214(2):642-53
pubmed: 7925657
Hepatology. 2010 Oct;52(4):1410-9
pubmed: 20722001
Differentiation. 2016 Jan-Mar;91(1-3):42-9
pubmed: 26856660
Oncogene. 2000 Oct 5;19(42):4864-75
pubmed: 11039904
J Pathol. 2007 Jul;212(3):345-52
pubmed: 17487939
Annu Rev Pathol. 2018 Jan 24;13:351-378
pubmed: 29125798
Med Sci Monit. 2016 Sep 29;22:3479-3485
pubmed: 27680563
J Hepatol. 2022 Aug;77(2):559-560
pubmed: 35452695
Gastroenterology. 2014 Sep;147(3):690-701
pubmed: 24837480
Cancer Cell. 2008 Dec 9;14(6):471-84
pubmed: 19061838
Front Oncol. 2020 Apr 21;10:440
pubmed: 32373510
Mol Biol Cell. 2007 Jun;18(6):2313-21
pubmed: 17429067
Sci Rep. 2014 Oct 30;4:6835
pubmed: 25355493
Semin Liver Dis. 2021 Jan;41(1):28-41
pubmed: 33764483
Exp Cell Res. 2018 Sep 15;370(2):227-236
pubmed: 29940177
J Hepatol. 2022 Aug;77(2):424-435
pubmed: 35257829
Gut. 2016 Jun;65(6):1024-34
pubmed: 25792709
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8847-51
pubmed: 9671767
Gastroenterology. 2010 Mar;138(3):1035-45.e1-2
pubmed: 19818782
Nat Rev Gastroenterol Hepatol. 2019 Feb;16(2):121-136
pubmed: 30451972
Cell. 2012 Jun 8;149(6):1393-406
pubmed: 22658674
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17216-21
pubmed: 15563600
Hepatology. 2017 Jan;65(1):104-121
pubmed: 27775819
Hepatology. 2018 Jul;68(1):89-102
pubmed: 29152775
Int J Biochem Cell Biol. 2011 Feb;43(2):265-70
pubmed: 19646548
Mod Pathol. 2014 Mar;27(3):472-91
pubmed: 24008558
In Vitro Cell Dev Biol. 1989 Mar;25(3 Pt 1):267-75
pubmed: 2466823