The ß-catenin-target Fascin-1, altering hepatocyte differentiation, is a new marker of immature cells in hepatoblastomas
biorxiv(2021)
摘要
BACKGROUND & AIMS ß-catenin is a well-known effector of the Wnt pathway and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of ß-catenin are highly frequent in pediatric liver primary tumors. Those mutations are mostly heterozygous allowing the co-expression of wild-type (WT) and mutated ß-catenins in tumor cells. We investigated the interplay between WT and mutated ß-catenins in liver tumor cells, and searched for new actors of the ß-catenin pathway.
METHODS Using an RNAi strategy in ß-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-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 ß-catenin in hepatocytes (APCKO and ß-cateninΔexon3 mice). We made use of transcriptomic data from mouse and human HB specimens and analyzed samples by immunohistochemistry.
RESULTS We highlighted an antagonist role of WT and mutated ß-catenins on hepatocyte differentiation as attested by alteration of hepatocyte markers expression and bile canaliculi formation. We characterized Fascin-1 as a target of ß-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.
CONCLUSIONS 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 ß-catenin pathway alteration in the liver.
Data Transparency Statement study materials will be made available to other researchers upon request.
### Competing Interest Statement
The authors have declared no competing interest.
* BC
: bile canaliculus
CFDA
: 5-carboxyfluorescein diacetate
HB
: hepatoblastoma
HCC
: hepatocellular carcinoma
HNF4a
: hepatocyte nuclear factor-4 alpha
KD
: knock-down
STED
: stimulated emission depletion
WT
: wild-type
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关键词
hepatocyte differentiation,immature cells,catenin-target
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