Tselepis C, Chidgey M, North A, Garrod D
Epithelial Morphogenesis Research Group, School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom.
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8064-9. doi: 10.1073/pnas.95.14.8064.
Recent studies of human disease and transgenic animal experiments have clearly demonstrated the importance of desmosomes in normal tissue architecture. Furthermore, desmosomal components are down-regulated in certain types of carcinomas, suggesting a possible role for desmosomes in suppression of invasion and metastasis. However, there is no functional evidence to support such a hypothesis. To obtain such evidence, we needed to generate desmosomal adhesion in an invasive cell line. We show that expression of multiple desmosomal components (the desmosomal cadherins, desmocollin and desmoglein, and the armadillo protein, plakoglobin) in nonadhesive L929 fibroblasts generates adhesion in aggregation assays. This adhesion is specifically blocked by short peptides corresponding to the putative cell adhesion recognition sites of desmocollin and desmoglein. This result provides an experimental demonstration of the functional importance of the cell adhesion recognition sites of desmocollin and desmoglein and indicates that both desmosomal cadherins are specifically involved in this adhesion. Moreover, whereas parental L929 cells are strongly invasive into collagen gels, we show that invasion is substantially inhibited in cells transfected with desmosomal components. Invasion is restored by treating the transfected cells with anti-adhesion peptides, indicating that desmosomal adhesion specifically blocks invasion in culture. Our results support the suggestion that desmosomes have a role in suppression of tumor spreading.
近期对人类疾病的研究以及转基因动物实验已清楚地证明了桥粒在正常组织结构中的重要性。此外，在某些类型的癌组织中桥粒成分表达下调，这表明桥粒在抑制侵袭和转移方面可能发挥作用。然而，尚无功能证据支持这一假说。为获得此类证据，我们需要在一种侵袭性细胞系中诱导桥粒黏附。我们发现，在非黏附性的L929成纤维细胞中表达多种桥粒成分（桥粒钙黏蛋白、桥粒芯蛋白和桥粒糖蛋白，以及犰狳蛋白、桥粒斑珠蛋白）可在聚集实验中产生黏附作用。这种黏附作用可被与桥粒芯蛋白和桥粒糖蛋白假定的细胞黏附识别位点相对应的短肽特异性阻断。这一结果为桥粒芯蛋白和桥粒糖蛋白的细胞黏附识别位点的功能重要性提供了实验证明，并表明两种桥粒钙黏蛋白都特异性参与了这种黏附作用。此外，虽然亲本L929细胞能强烈侵袭胶原凝胶，但我们发现，转染了桥粒成分的细胞侵袭能力显著受到抑制。用抗黏附肽处理转染细胞可恢复其侵袭能力，这表明桥粒黏附在培养中能特异性阻断侵袭。我们的结果支持了桥粒在抑制肿瘤扩散中发挥作用这一观点。
