Suriano Gianpaolo, Mulholland David, de Wever Olivier, Ferreira Paulo, Mateus Ana Rita, Bruyneel Eric, Nelson Colleen C, Mareel Marc M, Yokota Jun, Huntsman David, Seruca Raquel
Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200 Porto, Portugal.
Oncogene. 2003 Aug 28;22(36):5716-9. doi: 10.1038/sj.onc.1206672.
E-cadherin germline missense mutations have been shown to be responsible for significant loss of protein activity. A new cytoplasmic E-cadherin germline missense mutation (V832 M) was recently identified in a hereditary diffuse gastric cancer (HDGC) Japanese family. This E-cadherin mutant was cloned in a Chinese hamster ovary cell model system and functionally characterized, in terms of aggregation and invasion. Cells expressing the germline V832M mutant fail to aggregate and invade into collagen, supporting the pathogenic role of this germline missense mutation in gastric cancer. We also tested the ability of this mutation to activate the TCF-LEF trascriptional activity, in comparison with three other E-cadherin missense mutations (T340A, A634V and A617T), associated to loss of E-cadherin function. All the E-cadherin mutants reduced TCF-LEF activation to a similar extent as the wild-type protein, suggesting that the oncogenic effect of the E-cadherin mutants is unlikely to be transmitted through a beta-catenin-dependent activation of the WNT pathway.
E-钙黏蛋白种系错义突变已被证明会导致蛋白质活性显著丧失。最近在一个日本遗传性弥漫性胃癌（HDGC）家族中发现了一种新的细胞质E-钙黏蛋白种系错义突变（V832M）。该E-钙黏蛋白突变体在中国仓鼠卵巢细胞模型系统中进行了克隆，并就聚集和侵袭方面进行了功能表征。表达种系V832M突变体的细胞无法聚集并侵入胶原蛋白，这支持了这种种系错义突变在胃癌中的致病作用。我们还测试了与其他三种与E-钙黏蛋白功能丧失相关的E-钙黏蛋白错义突变（T340A、A634V和A617T）相比，这种突变激活TCF-LEF转录活性的能力。所有E-钙黏蛋白突变体将TCF-LEF激活降低到与野生型蛋白相似的程度，这表明E-钙黏蛋白突变体的致癌作用不太可能通过β-连环蛋白依赖性激活WNT途径来传递。
