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Elevated Expression of Wnt Antagonists Is a Common Event in Hepatoblastomas

Authors' Affiliations: ¹ Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany; ² Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas; ³ Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia; and ⁴ Department of Pediatric Surgery, Ludwig-Maximilians-University, Munich, Germany

Requests for reprints: Torsten Pietsch, Department of Neuropathology, University of Bonn Medical Center, Sigmund Freud Street 25, D-52105 Bonn, Germany. Phone: 49-228-287-4398; Fax: 49-228-287-4331; E-mail: t.pietsch-{at}uni-bonn.de.

Hepatoblastomas are the most frequent malignant liver tumors of childhood. A high frequency of activating ß-catenin mutations in hepatoblastomas indicates that the Wnt signaling pathway plays an important role in the development of this embryonic neoplasm. Stabilization of ß-catenin leads to an increased formation of nuclear ß-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 ß-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. ß-TRCP and NKD-1 were highly expressed in all hepatoblastoma samples, independent of the ß-catenin mutational status, in comparison with their nontumorous counterparts. ß-TRCP mRNA overexpression was associated with accumulation of intracytoplasmic and nuclear ß-TrCP protein. In human liver tumor cells without ß-catenin mutations, Nkd-1 inhibited the Wnt-3a-activated Tcf-responsive-luciferase reporter activity, whereas Nkd-1 in hepatoblastomas with ß-catenin mutations had no antagonistic effect. Our data emphasize the inhibitory effect of ß-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 ß-TrCP reveals an activation of the Wnt signaling pathway as a common event in hepatoblastomas. We propose that Nkd-1 and ß-TrCP may be used as possible diagnostic markers for the activated Wnt signaling pathway in hepatoblastomas.

Key Words: Wnt signaling • hepatoblastoma • gene expression

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