The Bisecting GlcNAc on N-Glycans Inhibits Growth Factor Signaling and Retards Mammary Tumor Progression
The Bisecting GlcNAc on N-Glycans Inhibits Growth Factor Signaling and Retards Mammary Tumor Progression
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DOI：
10.1158/0008-5472.can-09-2719
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Stanley, Pamela
中科院分区：
文献类型：
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作者：
Song, Yinghui;Aglipay, Jason A.;Stanley, Pamela
附着在生长因子受体上的复杂N-糖链的分支通过延长生长因子信号来促进肿瘤进展。将一分式GlcNAc加入到复合N-糖链中，对细胞黏附、细胞迁移和肝癌的形成有不同的影响。在这里，我们证明了表达MGAT3和多瘤中T(PYMT)抗原的中国仓鼠卵巢细胞减少了细胞增殖和依赖于半乳糖凝集素晶格的生长因子信号。MGAT3基因在处女乳腺中不表达，在哺乳期表达上调，在小鼠乳腺肿瘤病毒(MMTV)/PYMT肿瘤中表达。缺乏Mgat3的小鼠不能将一分为二的GlcNAc转移到N-糖链上，从而更快地获得PyMT诱导的乳腺肿瘤，并增加了肿瘤负担，增加了肿瘤细胞的迁移，并增加了对肺的早期转移。肿瘤和缺乏MGAT3的肿瘤来源的细胞通过RAS途径表现出信号增强和功能糖基化的α-营养不良糖链的减少。MMTV/MGAT3基因的结构性过表达抑制了早期乳腺肿瘤的发展和肿瘤细胞的迁移。因此，将一分为二的GlcNAc添加到乳腺肿瘤细胞糖蛋白受体的N-糖链上是一种细胞自主机制，通过减少生长因子信号来延缓肿瘤的进展。癌症资源；70(8)；3361-71。(C)2010年AACR。
The branching of complex N-glycans attached to growth factor receptors promotes tumor progression by prolonging growth factor signaling. The addition of the bisecting GlcNAc to complex N-glycans by Mgat3 has varying effects on cell adhesion, cell migration, and hepatoma formation. Here, we show that Chinese hamster ovary cells expressing Mgat3 and the polyoma middle T (PyMT) antigen have reduced cell proliferation and growth factor signaling dependent on a galectin lattice. The Mgat3 gene is not expressed in virgin mammary gland but is upregulated during lactation and is expressed in mouse mammary tumor virus (MMTV)/PyMT tumors. Mice lacking Mgat3 that cannot transfer the bisecting GlcNAc to N-glycans acquire PyMT-induced mammary tumors more rapidly and have an increased tumor burden, increased migration of tumor cells, and increased early metastasis to lung. Tumors and tumor-derived cells lacking Mgat3 exhibit enhanced signaling through the Ras pathway and reduced amounts of functionally glycosylated alpha-dystroglycan. Constitutive overexpression of an MMTV/Mgat3 transgene inhibits early mammary tumor development and tumor cell migration. Thus, the addition of the bisecting GlcNAc to complex N-glycans of mammary tumor cell glycoprotein receptors is a cell autonomous mechanism serving to retard tumor progression by reducing growth factor signaling. Cancer Res; 70(8); 3361-71. (C) 2010 AACR.