Differential expression of glutamine synthetase and cytochrome P450 isoforms in human hepatoblastoma

Toxicology. 2011 Mar 15;281(1-3):7-14. doi: 10.1016/j.tox.2011.01.006. Epub 2011 Jan 13.


Carcinogenesis is often linked to aberrant activation of Wnt/β-catenin signalling, in many cases caused by activating CTNNB1 mutations (encoding β-catenin). Recently, β-catenin was established as a decisive regulator of hepatic glutamine synthetase (GS) and cytochrome P450 (CYP) expression in mouse hepatocarcinogenesis. This study was aimed to analyse the connection of β-catenin signalling and GS/CYP expression in human paediatric tumours. Samples from 23 paediatric tumours were analysed for activating mutations in CTNNB1. Protein expression of the model β-catenin target GS and of various CYP isoforms was analysed and correlated with CTNNB1 mutational status and histological findings. Activating CTNNB1 mutations were frequent in hepatoblastoma (80%) and nephroblastoma (31%). In CTNNB1-mutated hepatoblastoma, expression of GS was only detected in tumour areas with epithelial, not with mesenchymal differentiation. Particularly high expression of glutamine synthetase was found in hepatoblastoma cells directly neighbouring a mesenchymal-type tumour area or stroma cells, associated with above-average cell proliferation. GS expression was not observed in CTNNB1-mutated nephroblastoma. Hepatoblastoma with activated β-catenin expressed different CYPs relevant for the metabolism of cytostatic drugs, but with high interindividual variance and heterogeneity within a single tumour. GS and different CYPs are co-expressed in hepatoblastoma with activated β-catenin. Moreover, other factors like histological subtype of tumour cells and cell-cell-interactions at the borders between different areas of the tumours affect expression of these β-catenin target genes. Analysis of CYP expression in resected tumour tissue might be useful for the selection of appropriate cytostatics for post-operative chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic / genetics
  • Glutamate-Ammonia Ligase / biosynthesis*
  • Hepatoblastoma / enzymology*
  • Hepatoblastoma / genetics
  • Humans
  • Isoenzymes / biosynthesis
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / genetics
  • Point Mutation / genetics
  • beta Catenin / genetics


  • CTNNB1 protein, human
  • Isoenzymes
  • beta Catenin
  • Cytochrome P-450 Enzyme System
  • Glutamate-Ammonia Ligase