Format

Send to

Choose Destination
See comment in PubMed Commons below
Clin Cancer Res. 2005 Jun 15;11(12):4295-304.

Elevated expression of Wnt antagonists is a common event in hepatoblastomas.

Author information

1
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.

Abstract

Hepatoblastomas are the most frequent malignant liver tumors of childhood. A high frequency of activating beta-catenin mutations in hepatoblastomas indicates that the Wnt signaling pathway plays an important role in the development of this embryonic neoplasm. Stabilization of beta-catenin leads to an increased formation of nuclear beta-catenin-T-cell factor complexes and altered expression of Wnt-inducible target genes. In this study, we analyzed the mRNA expression levels of nine Wnt genes, including c-JUN, c-MYC, CYCLIN D1, FRA-1, NKD-1, ITF-2, MMP-7, uPAR, and beta-TRCP, by competitive reverse transcription-PCR. We analyzed 23 hepatoblastoma biopsies for which matching liver tissue was available, 6 hepatoblastoma cell lines, and 3 human fetal liver samples. beta-TRCP and NKD-1 were highly expressed in all hepatoblastoma samples, independent of the beta-catenin mutational status, in comparison with their nontumorous counterparts. beta-TRCP mRNA overexpression was associated with accumulation of intracytoplasmic and nuclear beta-TrCP protein. In human liver tumor cells without beta-catenin mutations, Nkd-1 inhibited the Wnt-3a-activated Tcf-responsive-luciferase reporter activity, whereas Nkd-1 in hepatoblastomas with beta-catenin mutations had no antagonistic effect. Our data emphasize the inhibitory effect of beta-TrCP and Nkd-1 on the Wnt signaling pathway in a manner analogous to Conductin (AXIN2) and Dkk-1, inhibitors shown previously to be up-regulated in hepatoblastomas. Our findings indicate that overexpression of the Wnt antagonists Nkd-1 and beta-TrCP reveals an activation of the Wnt signaling pathway as a common event in hepatoblastomas. We propose that Nkd-1 and beta-TrCP may be used as possible diagnostic markers for the activated Wnt signaling pathway in hepatoblastomas.

PMID:
15958610
DOI:
10.1158/1078-0432.CCR-04-1162
[Indexed for MEDLINE]
Free full text

Publication type, MeSH terms, Substances

Publication type

MeSH terms

Substances

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center