Elevated expression of Wnt antagonists is a common event in hepatoblastomas
Standard
Elevated expression of Wnt antagonists is a common event in hepatoblastomas. / Koch, Arend; Waha, Andreas; Hartmann, Wolfgang; Hrychyk, Aksana; Schüller, Ulrich; Waha, Anke; Wharton, Keith A; Fuchs, Serge Y; von Schweinitz, Dietrich; Pietsch, Torsten.
in: CLIN CANCER RES, Jahrgang 11, Nr. 12, 15.06.2005, S. 4295-304.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Elevated expression of Wnt antagonists is a common event in hepatoblastomas
AU - Koch, Arend
AU - Waha, Andreas
AU - Hartmann, Wolfgang
AU - Hrychyk, Aksana
AU - Schüller, Ulrich
AU - Waha, Anke
AU - Wharton, Keith A
AU - Fuchs, Serge Y
AU - von Schweinitz, Dietrich
AU - Pietsch, Torsten
PY - 2005/6/15
Y1 - 2005/6/15
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Carrier Proteins
KW - Cell Line, Tumor
KW - Child
KW - Cyclin D1
KW - Cytoskeletal Proteins
KW - DNA-Binding Proteins
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Hepatoblastoma
KW - Humans
KW - Intercellular Signaling Peptides and Proteins
KW - Liver Neoplasms
KW - Male
KW - Matrix Metalloproteinase 7
KW - Middle Aged
KW - Mutation
KW - Proto-Oncogene Proteins c-fos
KW - Proto-Oncogene Proteins c-jun
KW - Proto-Oncogene Proteins c-myc
KW - RNA, Messenger
KW - Receptors, Cell Surface
KW - Receptors, Urokinase Plasminogen Activator
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction
KW - TCF Transcription Factors
KW - Trans-Activators
KW - Transcription Factor 7-Like 2 Protein
KW - Transcription Factors
KW - Wnt Proteins
KW - beta Catenin
KW - beta-Transducin Repeat-Containing Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1158/1078-0432.CCR-04-1162
DO - 10.1158/1078-0432.CCR-04-1162
M3 - SCORING: Journal article
C2 - 15958610
VL - 11
SP - 4295
EP - 4304
JO - CLIN CANCER RES
JF - CLIN CANCER RES
SN - 1078-0432
IS - 12
ER -
