Loss of α-Dystroglycan Laminin Binding in Epithelium-derived Cancers Is Caused by Silencing of LARGE
Loss of α-Dystroglycan Laminin Binding in Epithelium-derived Cancers Is Caused by Silencing of LARGE
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DOI：
10.1074/jbc.c900007200
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发表时间：
2009-04-24
影响因子：
4.8
通讯作者：
Campbell, Kevin P.
中科院分区：
文献类型：
--
作者：
de Bernabe, Daniel Beltran-Valero;Inamori, Kei-ichiro;Campbell, Kevin P.
上皮细胞和细胞外基质之间的相互作用对组织结构和功能至关重要，并在癌症进展过程中受到损害。营养不良多糖是一种膜受体，在多种上皮细胞中介导细胞和基底膜之间的相互作用。在许多上皮源性癌症中，β-肌营养不良聚糖表达，但不检测到α-肌营养不良聚糖。在这里，我们报告了α-营养不良聚糖被正确表达并运输到细胞膜，但由于类似乙酰氨基葡萄糖基转移酶(LIG)基因的沉默，在一组来自乳腺癌、宫颈癌和肺癌的高转移上皮细胞系中缺乏层粘连蛋白结合。在这些癌细胞中外源表达Large可以恢复α-dystroglan的正常糖基化和层粘连蛋白结合，导致细胞黏附增强和体外细胞迁移减少。我们的发现表明，在上皮来源的癌细胞中观察到的Dystrocan介导的细胞黏附缺陷是由大的抑制因子引起的，并指出Dystrocan糖基化的缺陷是癌症进展的一个因素。
The interaction between epithelial cells and the extracellular matrix is crucial for tissue architecture and function and is compromised during cancer progression. Dystroglycan is a membrane receptor that mediates interactions between cells and basement membranes in various epithelia. In many epithelium-derived cancers, beta-dystroglycan is expressed, but alpha-dystroglycan is not detected. Here we report that alpha-dystroglycan is correctly expressed and trafficked to the cell membrane but lacks laminin binding as a result of the silencing of the like-acetylglucosaminyltransferase (LARGE) gene in a cohort of highly metastatic epithelial cell lines derived from breast, cervical, and lung cancers. Exogenous expression of LARGE in these cancer cells restores the normal glycosylation and laminin binding of alpha-dystroglycan, leading to enhanced cell adhesion and reduced cell migration in vitro. Our findings demonstrate that LARGE repression is responsible for the defects in dystroglycan-mediated cell adhesion that are observed in epithelium-derived cancer cells and point to a defect of dystroglycan glycosylation as a factor in cancer progression.