Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas.
Wnt/beta-catenin signaling is frequently activated in cancer cells by stabilizing mutations of beta-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of beta-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the beta-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3beta phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of beta-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear beta-catenin immunostaining in undifferentiated cells. Membranous beta-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that beta-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of beta-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.
Wei
Y
Y
Unité de Recombinasion et Expression Génétique INSERM U163, Institut Pasteur, Paris, France.
Fabre
M
M
Branchereau
S
S
Gauthier
F
F
Perilongo
G
G
Buendia
M A
MA
D001692:Biological Transport; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3; D018197:Hepatoblastoma / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000196:embryology; D008113:Liver Neoplasms / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015398:Signal Transduction; D015534:Trans-Activators; D014162:Transfection; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003062:Codon; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D015534:Trans-Activators; D051176:beta Catenin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3