Antagonism between wild-type and mutant β-catenin controls hepatoblastoma differentiation via fascin-1.

Autor:	Gest C; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Sena S; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Dif L; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Neaud V; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Loesch R; INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC), Paris, France., Dugot-Senant N; Plateforme d'Histologie, UMS 005, Bordeaux, France., Paysan L; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Piquet L; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Robbe T; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Allain N; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Dembele D; IGBMC, CNRS UMR 7104 - INSERM U 1258 - Université de Strasbourg, Illkirch, France., Guettier C; Department of Pathology, Bicêtre University Hospital, University of Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France., Bioulac-Sage P; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Rullier A; Department of Pathology, University Bordeaux Hospital, Bordeaux, France., Le Bail B; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France.; Department of Pathology, University Bordeaux Hospital, Bordeaux, France., Grosset CF; MIRCADE Team, University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Saltel F; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Lagrée V; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France., Colnot S; INSERM, Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers (CRC), Paris, France., Moreau V; University of Bordeaux, INSERM, BRIC, U1312, Bordeaux, France.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2023 Feb 01; Vol. 5 (5), pp. 100691. Date of Electronic Publication: 2023 Feb 01 (Print Publication: 2023).
DOI:	10.1016/j.jhepr.2023.100691
Abstrakt:	Background & Aims: 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: 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 KO and β-catenin Δexon3 mice). We used transcriptomic data from mouse and human HB specimens, and used immunohistochemistry to analyse samples. Results: 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: 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: The FSCN1 gene, encoding fascin-1, was reported to be a metastasis-related gene in various cancers. Herein, we uncover its expression in poor-prognosis hepatoblastomas, a paediatric liver cancer. We show that fascin-1 expression is driven by the mutated beta-catenin in liver tumour cells. We provide new insights on the impact of fascin-1 expression on tumour cell differentiation. We highlight fascin-1 as a marker of immature cells in mouse and human hepatoblastomas. Competing Interests: The authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2023 The Author(s).)
Databáze:	MEDLINE
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