α2-6-linked sialic acids on N-glycans modulate carcinoma differentiation in vivo
α2-6-linked sialic acids on N-glycans modulate carcinoma differentiation in vivo
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DOI：
10.1158/0008-5472.can-07-1340
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发表时间：
2008-01-15
期刊：
影响因子：
11.2
通讯作者：
Varki, Nissi M.
中科院分区：
文献类型：
--
作者：
Hedlund, Maria;Ng, Elisa;Varki, Nissi M.
脊椎动物细胞表面的唾液酸介导许多生物学作用。某些唾液酸类型或其连接的表达改变可在人类癌症中具有预后意义。一个经典但无法解释的例子是由高尔基体酶β-半乳糖苷：α 2- 6-唾液酸转移酶（ST 6 Gal-I）的过表达引起的N-聚糖上的α 2-6-唾液酸化增强。先前支持所得Sia α 2-3Gal β 1 - 4GlcNAc（Sia 6LacNAc）结构在肿瘤生物学中的作用的数据是基于转染癌细胞中的体外研究，其中β 1-整联蛋白上增加的Sia 6LacNAc增强了它们与配体的结合，并刺激了细胞运动性。在这里，我们研究了第一次在自发性乳腺癌的小鼠乳腺肿瘤病毒启动子驱动的多瘤病毒中间T抗原，其中β 1-整联蛋白的功能是重要的肿瘤发生和维持肿瘤细胞的增殖状态的转基因小鼠的生长和分化的ST 6 Gal-I酶的体内作用。通过组织学分析和蛋白质表达谱，在St 6 gal 1-null动物中诱导的肿瘤与野生型背景中的肿瘤相比更加分化。此外，我们发现St 6 gal-null肿瘤选择性改变了与黏着斑信号相关的基因表达，并降低了黏着斑激酶（β 1-整合素的下游靶点）的磷酸化。使用一种新方法证实了ST 6 Gal-I在肿瘤进展中的作用的第一个体内证据，该方法在来源于无效肿瘤的细胞系中有条件地恢复了St 6 gal 1。这些发现表明ST 6 Gal-I作为肿瘤进展的介体的作用，其表达通过增强的β 1-整联蛋白功能引起分化程度较低的表型。
Sialic acids on vertebrate cell surfaces mediate many biological roles. Altered expression of certain sialic acid types or their linkages can have prognostic significance in human cancer. A classic but unexplained example is enhanced alpha 2-6-sialylation on N-glycans resulting from overexpression of the Golgi enzyme beta-galactoside:alpha 2-6-sialyltransferase (ST6Gal-I). Previous data supporting a role for the resulting Sia alpha 2-3Gal beta 1 -4GlcNAc (Sia6LacNAc) structure in tumor biology were based on in vitro studies in transfected carcinoma cells, in which increased Sia6LacNAc on beta 1-integrins enhanced their binding to ligands, and stimulated cell motility. Here, we examine for the first time the in vivo role of the ST6Gal-I enzyme in the growth and differentiation of spontaneous mammary cancers in mice transgenic for a mouse mammary tumor virus promoter-driven polyomavirus middle T antigen, a tumor in which beta 1-integrin function is important for tumorigenesis and in maintaining the proliferative state of tumor cells. Tumors induced in St6gal1-null animals were more differentiated compared with those in the wild-type background, both by histologic analysis and by protein expression profiles. Furthermore, we show the St6gal1-null tumors have selectively altered expression of genes associated with focal adhesion signaling and have decreased phosphorylation of focal adhesion kinase, a downstream target of beta 1-integrins. This first in vivo evidence for a role of ST6Gal-I in tumor progression was confirmed using a novel approach, which conditionally restored St6gal1 in cell lines derived from the null tumors. These findings indicate a role for ST6Gal-I as a mediator of tumor progression, with its expression causing a less differentiated phenotype, via enhanced beta 1-integrin function.