Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas
Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas
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DOI：
10.1002/path.1662
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发表时间：
2004-12-01
影响因子：
7.3
通讯作者：
Pietsch, T
中科院分区：
文献类型：
--
作者：
Koch, A;Weber, N;Pietsch, T
肝母细胞瘤是儿童最常见的肝脏恶性肿瘤。大多数HB是零星发生的，但在家族性腺瘤性结肠息肉病（FAP）患者中，其发病率非常高。这些患者在腺瘤性结肠息肉病（APC）肿瘤抑制基因中携带种系突变。APC形成参与WNT信号传导途径的多蛋白复合物，其控制β-连环蛋白的稳定性，β-连环蛋白是该级联反应中的中心效应物。尽管APC突变在散发性HB中很少见，但先前在这些肿瘤中发现了导致WNT信号过度激活的高频率β-连环蛋白突变。这条通路由传导蛋白（轴蛋白2）负向控制，代表该信号复合物中的另一个伴侣。为了研究传导蛋白的改变是否也可能参与散发性HB的发病机制，我们采用单链构象多态性（SSCP）分析、逆转录-聚合酶链反应（RT-PCR）和直接测序对37个HB和5个HB细胞系进行了突变筛查。在两个病例中，发现了较大的缺失（52和1624 bp）导致的移码。此外，一个HB携带体细胞点突变。通过竞争性RT-PCR的表达分析表明，与邻近的肝脏样品相比，在HBs中传导蛋白mRNA的上调。蛋白质印迹分析表明，这种mRNA过表达导致了传导蛋白水平的增加。具有活化β-连环蛋白突变的肿瘤显示更高水平的传导蛋白mRNA转录物。这一发现表明，conductin是一个直接的目标基因的WNT信号在HB，已被证明在其他组织。总之，传导蛋白突变可能代表了导致HB中WATT信号转导激活的另一种机制。HBs中传导蛋白mRNA的过表达反映了WNT通路的激活，因为传导蛋白代表肝组织中WNT信号传导的靶基因。版权所有（C）2004大不列颠和爱尔兰病理学会。出版社：John Wiley Sons，Ltd
Hepatoblastoma (HB) is the most frequent malignant liver tumour of childhood. Most HBs develop sporadically but their incidence is highly elevated in patients with familial adenomatous polyposis coli (FAP). These patients carry germline mutations in the adenomatous polyposis coli (APC) tumour suppressor gene. APC forms a multi-protein complex involved in the WNT signalling pathway that controls the stability of P-catenin, the central effector in this cascade. Whereas APC mutations are rare in sporadic HBs, a high frequency of beta-catenin mutations leading to overactivation of WNT signalling was previously found in these tumours. This pathway is negatively controlled by conductin (axin2), representing a further partner in this signalling complex. To investigate whether alterations in conductin may also be involved in the pathogenesis of sporadic HBs, 37 HBs and five HB cell lines were screened for mutations using single-strand conformation polymorphism (SSCP) analysis, reverse transcription-polymerase chain reaction (RT-PCR), and direct sequencing. In two cases, larger deletions (52 and 1624 bp) leading to frameshifts were found. In addition, one HB carried a somatic point mutation. Expression analysis by competitive RT-PCR in HBs revealed up-regulation of conductin mRNA compared with adjacent liver samples. This mRNA overexpression resulted in increased conductin protein levels demonstrated by western blot analysis. Tumours with activating beta-catenin mutations revealed higher levels of conductin mRNA transcripts. This finding indicates that conductin is a direct target gene of WNT signalling in HBs, as has been demonstrated in other tissues. In summary, conductin mutations may represent an alternative mechanism leading to activation of WATT signalling in HBs. The overexpression of conductin mRNA in HBs reflects activation of the WNT pathway because conductin represents a target gene of WNT signalling in liver tissue. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.