Ogawa K, Yamada Y, Kishibe K, Ishizaki K, Tokusashi Y
Department of Pathology, Asahikawa Medical College, Japan.
Cancer Res. 1999 Apr 15;59(8):1830-3.
Activating mutations in the region of the beta-catenin gene corresponding to the NH2-terminal phosphorylation sites of glycogen synthetase kinase 3beta have been causally implicated in carcinogenesis. In this study, the beta-catenin exon 3 was examined in hepatic lesions induced by diethylnitrosamine in B6C3F1 mice. PCR and DNA sequencing detected seven beta-catenin mutations in 13 samples dissected from hepatocellular carcinoma tissues, but none in 14 hepatic adenomas. All of the mutations were found in codon 41 encoding a threonine residue, one of the possible glycogen synthetase kinase-3beta phosphorylation sites. Although beta-catenin protein was immunohistochemically stained mainly on the cell membrane in preneoplastic hepatocytic foci and most adenomas, as observed in normal hepatocytes, it was detected in the cytoplasm and nuclei in addition to the cell membrane, indicating stabilization of the protein in HCCs. This shift in staining was observed not only in tumors with mutations, but also in examples lacking exon 3 mutations. Our data demonstrate that beta-catenin alterations may be important for malignant progression during multistep hepatic carcinogenesis in mice.
糖原合成酶激酶3β的NH2末端磷酸化位点所对应的β-连环蛋白基因区域中的激活突变已被证实与致癌作用存在因果关系。在本研究中，对B6C3F1小鼠经二乙基亚硝胺诱导产生的肝脏病变中的β-连环蛋白外显子3进行了检测。聚合酶链反应（PCR）和DNA测序在从肝细胞癌组织中切取的13个样本中检测到7个β-连环蛋白突变，但在14个肝腺瘤中未检测到任何突变。所有突变均位于编码苏氨酸残基的密码子41处，该位点是糖原合成酶激酶-3β可能的磷酸化位点之一。尽管如在正常肝细胞中所观察到的那样，β-连环蛋白在癌前肝细胞灶和大多数腺瘤中主要定位于细胞膜，但在肝细胞癌中，除细胞膜外，还在细胞质和细胞核中检测到该蛋白，这表明该蛋白在肝细胞癌中发生了稳定化。不仅在有突变的肿瘤中观察到了这种染色变化，在缺乏外显子3突变的样本中也观察到了。我们的数据表明，β-连环蛋白改变可能在小鼠多步骤肝癌发生过程中的恶性进展中起重要作用。
