Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia M A
Unité de Recombinasion et Expression Génétique INSERM U163, Institut Pasteur, Paris, France.
Oncogene. 2000 Jan 27;19(4):498-504. doi: 10.1038/sj.onc.1203356.
Wnt/beta-catenin signaling is frequently activated in cancer cells by stabilizing mutations of beta-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of beta-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the beta-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3beta phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of beta-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear beta-catenin immunostaining in undifferentiated cells. Membranous beta-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that beta-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of beta-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.
Wnt/β-连环蛋白信号通路在癌细胞中经常通过β-连环蛋白的稳定突变或APC肿瘤抑制基因的功能丧失突变而被激活。我们分析了β-连环蛋白在肝母细胞瘤（HB）发病机制中的作用，肝母细胞瘤是一种主要发生在2岁以下儿童的胚胎性肝脏肿瘤。对18例上皮性和混合性肝母细胞瘤中β-连环蛋白NH2末端结构域的序列分析显示，12例肿瘤（67%）中GSK3β磷酸化基序存在错义突变或间隙缺失。在其余病例中，未发现APC的截短突变。对11例肝母细胞瘤进行β-连环蛋白免疫组织化学分析，结果显示在所有分析的肿瘤中该蛋白均有核/胞质积聚，在未分化细胞中β-连环蛋白免疫染色主要位于细胞核。仅在胎儿型肿瘤性肝细胞中保留膜性β-连环蛋白定位，且与E-钙黏蛋白表达相关。此外，我们发现β-连环蛋白在多种肿瘤成分中异常过度表达，包括不同分化阶段的肝细胞样细胞以及鳞状、类骨和软骨样组织等异源性成分，偶尔也在其他间充质来源的细胞中表达。这些数据强烈表明，β-连环蛋白信号通路的激活是肝母细胞瘤发病机制中的一个必要步骤，并增加了其干扰在肝分化早期指定不同组织类型的发育信号的可能性。
