Elevated Expression of Wnt Antagonists Is a Common Event in Hepatoblastomas
- 15 June 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 11 (12), 4295-4304
- https://doi.org/10.1158/1078-0432.ccr-04-1162
Abstract
Hepatoblastomas are the most frequent malignant liver tumors of childhood. A high frequency of activating β-catenin mutations in hepatoblastomas indicates that the Wnt signaling pathway plays an important role in the development of this embryonic neoplasm. Stabilization of β-catenin leads to an increased formation of nuclear β-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 β-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. β-TRCP and NKD-1 were highly expressed in all hepatoblastoma samples, independent of the β-catenin mutational status, in comparison with their nontumorous counterparts. β-TRCP mRNA overexpression was associated with accumulation of intracytoplasmic and nuclear β-TrCP protein. In human liver tumor cells without β-catenin mutations, Nkd-1 inhibited the Wnt-3a-activated Tcf-responsive-luciferase reporter activity, whereas Nkd-1 in hepatoblastomas with β-catenin mutations had no antagonistic effect. Our data emphasize the inhibitory effect of β-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 β-TrCP reveals an activation of the Wnt signaling pathway as a common event in hepatoblastomas. We propose that Nkd-1 and β-TrCP may be used as possible diagnostic markers for the activated Wnt signaling pathway in hepatoblastomas.Keywords
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