Mucin 16 is a functional selectin ligand on pancreatic cancer cells
Mucin 16 is a functional selectin ligand on pancreatic cancer cells
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DOI：
10.1096/fj.11-195669
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发表时间：
2012-03-01
期刊：
影响因子：
4.8
通讯作者：
Konstantopoulos, Konstantinos
中科院分区：
文献类型：
--
作者：
Chen, Shih-Hsun;Dallas, Matthew R.;Konstantopoulos, Konstantinos
选择素通过介导肿瘤细胞上的选择素配体与微血管中表达选择素的宿主细胞之间的特异性相互作用来促进转移。利用亲和层析结合串联质谱和生物信息学工具，我们确定了粘蛋白16（MUC 16）作为一种新的选择素配体表达的转移性胰腺癌细胞。虽然在许多胰腺癌中上调，但唾液酸岩藻糖基化MUC 16的生物学功能尚未完全阐明。为了解决这个问题，我们采用了印迹滚动和基于无细胞流动的粘附测定，使用从胰腺癌细胞免疫纯化的MUC 16，发现它有效地结合E-和L-选择素，但不结合P-选择素。选择素结合决定簇是显示在O-和N-连接聚糖上的唾液酸岩藻糖基化结构。通过RNAi沉默MUC 16表达显著降低胰腺癌细胞在流动下与E-和L-选择素的结合。这些发现为与MUC 16过表达相关的增强转移潜力和选择素在转移中的作用提供了一个新的综合视角。陈思H、达拉斯，M. R.，Balzer，E. M.，Konstantopoulos，K.粘蛋白16是胰腺癌细胞上的功能性选择素配体。FASEB J.26，1349-1359（2012）。www.fasebj.org
Selectins promote metastasis by mediating specific interactions between selectin ligands on tumor cells and selectin-expressing host cells in the microvasculature. Using affinity chromatography in conjunction with tandem mass spectrometry and bioinformatics tools, we identified mucin 16 (MUC16) as a novel selectin ligand expressed by metastatic pancreatic cancer cells. While up-regulated in many pancreatic cancers, the biological function of sialofucosylated MUC16 has yet to be fully elucidated. To address this, we employed blot rolling and cell-free flow-based adhesion assays using MUC16 immunopurified from pancreatic cancer cells and found that it efficiently binds E-and L-but not P-selectin. The selectin-binding determinants are sialofucosylated structures displayed on O- and N-linked glycans. Silencing MUC16 expression by RNAi markedly reduces pancreatic cancer cell binding to E-and L-selectin under flow. These findings provide a novel integrated perspective on the enhanced metastatic potential associated with MUC16 overexpression and the role of selectins in metastasis.-Chen, S.-H., Dallas, M. R., Balzer, E. M., Konstantopoulos, K. Mucin 16 is a functional selectin ligand on pancreatic cancer cells. FASEB J. 26, 1349-1359 (2012). www.fasebj.org