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

OBJECTIVE: 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. DESIGN: Using 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{triangleup}exon3 mice). We used transcriptomic data from mouse and human HB specimens and analyzed samples by immunohistochemistry. RESULTS: We 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, we found that Fascin-1 is highly expressed in undifferentiated tumors. Finally, we found that Fascin-1 is a specific marker of the embryonal component in human HBs. CONCLUSION: In 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.