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首页> 外文期刊>Human Molecular Genetics >E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia.
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E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia.

机译：E-钙黏着蛋白错义突变与遗传性弥漫性胃癌（HDGC）综合征相关联，表现出与果蝇上皮细胞Wnt和Notch途径不同的侵袭行为和遗传相互作用。

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Germline mutations in the human E-cadherin (hEcad) gene, CDH1, are initiating events in cases of human hereditary diffuse gastric cancer (HDGC) indicating that hEcad is a tumor suppressor. Among the hEcad mutations identified so far, some are missense, but the pathological relevance of these missense mutants is still unclear. In vitro assays show that missense mutations result in full-length hEcad molecules that retain some distinct biological activity, but in vivo functional studies in animal models are still lacking. Here we verify the potential of a Drosophila model to in vivo characterize the functional consequences of HDGC-associated germline missense mutations and to identify signaling pathways affected by these mutations. To this end, we have generated transgenic fly strains expressing the wild-type hEcad gene or its missense mutations. Similar to the fly Ecad, expression of wild-type hEcad and missense forms in fly epithelia resulted in their localization to the subapical region. In addition, we verify a genotype-phenotype correlation associated to the specific domain affected by the mutations, because cells expressing normal or missense mutant hEcad display different migratory and invasive behaviors in fly epithelia. We show that some of these effects might be mediated through hEcad interacting with the endogenous fly ss-catenin, Armadillo, thus interfering with the Wnt signaling pathway. Therefore, the use of this simple in vivo system will contribute to characterize the effects that missense hEcad have on cell behavior in a tissue environment, and might help to understand their significance in gastric cancer onset.
机译：人类E-钙粘蛋白（hEcad）基因CDH1中的种系突变是人类遗传性弥漫性胃癌（HDGC）病例的起始事件，表明hEcad是肿瘤抑制因子。到目前为止，已鉴定出的hEcad突变中有一些是错义的，但这些错义突变的病理相关性仍不清楚。体外测定表明，错义突变导致全长hEcad分子保留了一些独特的生物学活性，但仍缺乏在动物模型中进行的体内功能研究。在这里，我们验证了果蝇模型在体内表征HDGC相关种系错义突变的功能后果并确定受这些突变影响的信号通路的潜力。为此，我们已经产生了表达野生型hEcad基因或其错义突变的转基因蝇品系。与苍蝇Ecad相似，野生型hEcad和错义形式在苍蝇上皮细胞中的表达导致它们定位于根尖下区域。此外，我们验证了与受突变影响的特定域相关的基因型与表型的相关性，因为表达正常或错义突变的hEcad的细胞在果蝇上皮细胞中表现出不同的迁移和侵袭行为。我们表明，其中一些影响可能是通过与内源性蝇s-catenin，犰狳相互作用的hEcad介导的，从而干扰了Wnt信号通路。因此，使用这种简单的体内系统将有助于表征错义hEcad对组织环境中细胞行为的影响，并可能有助于了解其在胃癌发作中的意义。

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