Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene.
Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene.
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发表时间：
1999-01
期刊：
影响因子：
11.2
通讯作者：
A. Koch;D. Denkhaus;S. Albrecht;I. Leuschner;D. Schweinitz;T. Pietsch
中科院分区：
文献类型：
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作者：
A. Koch;D. Denkhaus;S. Albrecht;I. Leuschner;D. Schweinitz;T. Pietsch
肝母细胞瘤（HB）是影响幼儿的胚胎性肿瘤，是儿童最常见的恶性肝脏肿瘤。HB的分子发病机制知之甚少。虽然大多数病例是散发的，但在家族性腺瘤性结肠息肉病患者中发病率非常高。这些患者携带APC肿瘤抑制基因的种系突变。APC控制癌基因产物β-连环蛋白在丝氨酸/苏氨酸残基上的NH 2-末端磷酸化后的降解。APC，以及β-连环蛋白，已被发现是一个中央效应器的生长促进无翅信号通路在发展。为了确定这一通路是否参与散发性乙型肝炎的发病机制，我们检测了52个活检组织和3个散发性乙型肝炎细胞系中APC和β-连环蛋白基因的突变。利用单链构象多态性分析、PCR缺失筛查和直接测序，我们发现散发性乙型肝炎病毒中β-连环蛋白突变频率很高（48%）。这些突变影响编码β-连环蛋白降解靶向盒的外显子3，导致胞浆内和核内β-连环蛋白蛋白的积累。β-连环蛋白基因的高频率激活突变表明在HB的发病机制中起重要作用。
Hepatoblastomas (HBs) are embryonal tumors affecting young children and representing the most frequent malignant liver tumors in childhood. The molecular pathogenesis of HB is poorly understood. Although most cases are sporadic, the incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations of the APC tumor suppressor gene. APC controls the degradation of the oncogene product beta-catenin after its NH2-terminal phosphorylation on serine/threonine residues. APC, as well as beta-catenin, has been found to be a central effector of the growth promoting wingless signaling pathway in development. To find out if this pathway is involved in the pathogenesis of sporadic HBs, we examined 52 biopsies and three cell lines from sporadic HBs for mutations in the APC and beta-catenin genes. Using single-strand conformational polymorphism analysis, deletion screening by PCR, and direct sequencing, we found a high frequency of beta-catenin mutations in sporadic HBs (48%). The mutations affected exon 3 encoding the degradation targeting box of beta-catenin leading to accumulation of intracytoplasmic and nuclear beta-catenin protein. The high frequency of activating mutations in the beta-catenin gene indicates an important role in the pathogenesis of HB.