The beta-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas

Abstract

BACKGROUND & AIMS{beta}-catenin is a well-known effector of the Wnt pathway and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of {beta}-catenin are highly frequent in pediatric liver primary tumors. Those mutations are mostly heterozygous allowing the co-expression of wild-type (WT) and mutated {beta}-catenins in tumor cells. We investigated the interplay between WT and mutated {beta}-catenins in liver tumor cells, and searched for new actors of the {beta}-catenin pathway. METHODSUsing an RNAi strategy in {beta}-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of {beta}-catenin, carried mainly by, respectively, WT and mutated proteins. Their impact was characterized using transcriptomic and functional analyses. We studied mice that develop liver tumors upon activation of {beta}-catenin in hepatocytes (APCKO and {beta}-catenin{Delta}exon3 mice). We made use of transcriptomic data from mouse and human HB specimens and analyzed samples by immunohistochemistry. RESULTSWe highlighted an antagonist role of WT and mutated {beta}-catenins on hepatocyte differentiation as attested by alteration of hepatocyte markers expression and bile canaliculi formation. We characterized Fascin-1 as a target of {beta}-catenin involved in hepatocyte differentiation. Using mouse models that allow the formation of two phenotypically distinct tumors (differentiated or undifferentiated), we found that Fascin-1 expression is higher in undifferentiated tumors. Finally, we found that Fascin-1 is a specific marker of the embryonal component in human HBs. CONCLUSIONSIn mice and human, Fascin-1 expression is linked to loss of differentiation and polarity of hepatocytes. Thus, we highlighted Fascin-1 as a new player in the modulation of hepatocyte differentiation associated to {beta}-catenin pathway alteration in the liver. Data Transparency Statementstudy materials will be made available to other researchers upon request.