When TEAD2 DNA-binding domain was fused with virus protein 16 transcriptional activation domain, it synergized with activated β-catenin to promote HB formation in vivo.
In pediatric patients tested positive for germline mutation of APC gene screening for hepatoblastoma using alpha-fetoprotein and liver ultrasound should be performed.
Thus, we demonstrate that β-catenin point mutants can also collaborate with YAP1 in HB development, albeit with a distinct molecular profile from the deletion mutant, which may have implications in both biology and therapy.
The Wnt/beta-catenin pathway is one of the major developmental pathways and is believed to play an important role in the pathogenesis of HB and CSC formation.
Here, we investigated the oncogenic properties of 14 different HB- and non-HB-associated β-catenin mutants encoded by Sleeping Beauty vectors following their delivery into the mouse liver by hydrodynamic tail-vein injection.
The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown.
Conflicting reports on the frequency of germline adenomatous polyposis coli (APC) gene mutations in patients with hepatoblastoma (HB) have called into question the clinical value of APC mutation testing on apparently sporadic HB.
Hepatoblastoma may present at birth, and screening for hepatoblastoma in infancy in families with FAP prior to APC mutation testing results may be warranted.
The Wnt/β-catenin pathway plays a central role in the pathogenesis of most hepatoblastomas (HBs), that is, up to 60-80% carry activating CTNNB1 mutations.
Also, niclosamide, a Food and Drug Administration approved antihelminth compound, could effectively inhibit HB cell growth in vitro and in vivo via downregulation of Dvl-2 and β-catenin expression.
In summary, the obtained results imply that an APC mutant together with an X-linked WAS mutant, could lead to HB tumorigenesis by activating Wnt and PLK1 signaling, inhibiting TCR signaling, and reducing the antitumor activity of natural killer and dendritic cells.
Recent studies suggest that activation of Yes-associated protein (YAP) is a major molecular event in HB development, as activated YAP synergizes with mutant β-catenin to promote HB formation in mice (YAP/β-catenin).
Genomic profiles of a hepatoblastoma from a patient with Beckwith-Wiedemann syndrome with uniparental disomy on chromosome 11p15 and germline mutation of APC and PALB2.
We detected nuclear β-catenin immunostaining in nearly all untreated HBs, including in fetal and embryonal epithelial components and in mesenchymal elements.
However, variable survival rates of 60-80% and debilitating chemotherapy sequelae argue for more informed treatment selection, which is not possible by grading the Wnt-β-catenin over activity present in most HBL tumors.
To address their roles in the pathogenesis of HB, we generated mice in which Myc and mutant β-catenin were targeted to immature cells of the developing mouse liver.
By contrast, the expression levels of epithelial-cadherin (E-cadherin) and cytosolic accumulation of β-catenin, the two most prominent markers involved in epithelial-mesenchymal transition (EMT), were reduced in liver specimens from patients with metastatic HB compared with that of healthy adjacent control tissue.
We transfected the parental HuH6 hepatoblastoma cell line with a doxycycline-inducible shRNA against CTNNB1 (gene coding for β-catenin) to obtain an isogenic cell line pair with or without aberrant β-catenin signaling.