Tumor suppressor function of laminin-binding α-dystroglycan requires a distinct β3-N-acetylglucosaminyltransferase
Tumor suppressor function of laminin-binding α-dystroglycan requires a distinct β3-N-acetylglucosaminyltransferase
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DOI：
10.1073/pnas.0904515106
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发表时间：
2009-07-21
影响因子：
11.1
通讯作者：
Fukuda, Minoru
中科院分区：
文献类型：
--
作者：
Bao, Xingfeng;Kobayashi, Motohiro;Fukuda, Minoru
α-肌营养不良聚糖（α-DG）代表高度糖基化的细胞表面分子，其在上皮细胞-基底膜（BM）界面中表达并且在上皮发育和组织组织形成中起重要作用。在浸润性癌中，α-DG介导的上皮细胞-BM相互作用经常受损，但这种受损的相互作用在肿瘤进展中的作用和潜在机制仍不清楚。我们在这里报告的抑制功能层粘连蛋白结合聚糖对α-DG在肿瘤进展。在侵袭性前列腺癌和乳腺癌细胞系中，层粘连蛋白结合聚糖显著减少，尽管α-DG和β-肌营养不良聚糖的量保持不变。层粘连蛋白结合聚糖的减少和随后的细胞迁移增加与β 3-N-乙酰葡糖胺转移酶-1（β 3GnT 1）表达的减少相关。在侵袭性癌细胞中强制表达β 3GnT 1恢复了层粘连蛋白结合聚糖并减少了肿瘤形成。发现β 3GnT 1是层粘连蛋白结合聚糖合成所需的，通过与LARGE形成复合物，从而调节LARGE的功能。BM中层粘连蛋白结合聚糖与层粘连蛋白和其他粘附分子的相互作用通过拮抗ECM中组分诱导的ERK/AKT磷酸化来减弱肿瘤细胞迁移潜力。这些结果确定了先前未描述的碳水化合物依赖性细胞-BM相互作用在肿瘤抑制中的作用及其通过β 3GnT 1和LARGE的控制。
alpha-Dystroglycan (alpha-DG) represents a highly glycosylated cell surface molecule that is expressed in the epithelial cell-basement membrane (BM) interface and plays an essential role in epithelium development and tissue organization. The alpha-DG-mediated epithelial cell-BM interaction is often impaired in invasive carcinomas, yet roles and underlying mechanisms of such an impaired interaction in tumor progression remain unclear. We report here a suppressor function of laminin-binding glycans on alpha-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, laminin-binding glycans are dramatically decreased, although the amount of alpha-DG and beta-dystroglycan is maintained. The decrease of laminin-binding glycans and consequent increased cell migration were associated with the decreased expression of beta 3-N-acetylglucosaminyltransferase-1 (beta 3GnT1). Forced expression of beta 3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. beta 3GnT1 was found to be required for laminin-binding glycan synthesis through formation of a complex with LARGE, thus regulating the function of LARGE. Interaction of the laminin-binding glycans with laminin and other adhesive molecules in BM attenuates tumor cell migratory potential by antagonizing ERK/AKT phosphorylation induced by the components in the ECM. These results identify a previously undescribed role of carbohydrate-dependent cell-BM interaction in tumor suppression and its control by beta 3GnT1 and LARGE.