title: Differential expression of glutamine synthetase and cytochrome P450 isoforms in human hepatoblastoma.
abstract: 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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmidt
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Peter
authors.initials: P
authors.lastname: Ruck
authors.forename: Guido
authors.initials: G
authors.lastname: Seitz
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
authors.forename: Joerg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis*; D018197:Hepatoblastoma / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; D007527:Isoenzymes; D051176:beta Catenin; D003577:Cytochrome P-450 Enzyme System; D005974:Glutamate-Ammonia Ligase