Elevated expression of Wnt antagonists is a common event in hepatoblastomas
Elevated expression of Wnt antagonists is a common event in hepatoblastomas
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DOI：
10.1158/1078-0432.ccr-04-1162
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发表时间：
2005-06-15
影响因子：
11.5
通讯作者：
Pietsch, T
中科院分区：
文献类型：
--
作者：
Koch, A;Waha, A;Pietsch, T
肝母细胞瘤是儿童最常见的肝脏恶性肿瘤。肝母细胞瘤中激活β-连环蛋白突变的频率很高，这表明Wnt信号通路在肝母细胞瘤的发生发展中起着重要作用。β-连环蛋白的稳定导致核内β-连环蛋白-T细胞因子复合体的形成增加，并改变Wnt诱导的靶基因的表达。本研究采用竞争性逆转录-聚合酶链式反应技术，分析了9个Wnt基因，包括c-、Iun、c-myc、细胞周期蛋白D1、FRA-1、NKD-1、ITF-2、MMP-7、uPAR和β-TRCP的mRNA表达水平。我们分析了23例肝母细胞瘤活检组织，5个肝母细胞瘤细胞系和3个人胎肝样本。与非肿瘤组织相比，β-TRCP和NKD-1在所有肝母细胞瘤组织中均高表达，与β-连环蛋白突变状态无关。β-TrCP mRNA的过度表达与胞浆内和胞核中的β-TrCP蛋白积聚有关。在无β-catenin突变的人肝肿瘤细胞中，NKD-1抑制Wnt-3a激活的Tcf反应荧光素酶报告活性，而在有β-catenin突变的肝母细胞瘤中，NKD-1没有拮抗作用。我们的数据强调了β-TrCP和NKD-1对Wnt信号通路的抑制作用，其方式类似于之前在肝母细胞瘤中上调的Concluctin(AXIN2)和DKK-1。我们的发现表明，Wnt拮抗剂NKD-1和β-TrCP的过度表达表明Wnt信号通路的激活是肝母细胞瘤中的常见事件。我们认为NKD-1和β-TrCP可作为肝母细胞瘤中激活的Wnt信号通路的可能诊断标志物。
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-,IUN, 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, 5 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 Concluctin (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.