Dennis J W, Granovsky M, Warren C E
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Rm. 876, M5G 1X5, Toronto, Ont., Canada.
Biochim Biophys Acta. 1999 Dec 6;1473(1):21-34. doi: 10.1016/s0304-4165(99)00167-1.
Glycosylation of glycoproteins and glycolipids is one of many molecular changes that accompany malignant transformation. GlcNAc-branched N-glycans and terminal Lewis antigen sequences have been observed to increase in some cancers, and to correlate with poor prognosis. Herein, we review evidence that beta1, 6GlcNAc-branching of N-glycans contributes directly to cancer progression, and we consider possible functions for the glycans. Mgat5 encodes N-acetylglucosaminyltransferase V (GlcNAc-TV), the Golgi enzyme required in the biosynthesis of beta1,6GlcNAc-branched N-glycans. Mgat5 expression is regulated by RAS-RAF-MAPK, a signaling pathway commonly activated in tumor cells. Ectopic expression of GlcNAc-TV in epithelial cells results in morphological transformation and tumor growth in mice, and over expression in carcinoma cells has been shown to induce metastatic spread. Ectopic expression of GlcNAc-TIII, an enzyme that competes with GlcNAc-TV for acceptor, suppresses metastasis in B16 melanoma cells. Furthermore, breast cancer progression and metastasis induced by a viral oncogene expressed in transgenic mice is markedly suppressed in a GlcNAc-TV-deficient background. Mgat5 gene expression and beta1, 6GlcNAc-branching of N-glycans are associated with cell motility, a required phenotype of malignant cells.
糖蛋白和糖脂的糖基化是伴随恶性转化的众多分子变化之一。已观察到在某些癌症中，N-聚糖的GlcNAc分支和末端Lewis抗原序列增加，且与预后不良相关。在此，我们综述了N-聚糖的β1,6GlcNAc分支直接促进癌症进展的证据，并探讨了这些聚糖可能的功能。Mgat5编码N-乙酰葡糖胺基转移酶V（GlcNAc-TV），这是β1,6GlcNAc分支N-聚糖生物合成所需的高尔基体酶。Mgat5的表达受RAS-RAF-MAPK信号通路调控，该信号通路在肿瘤细胞中通常被激活。在小鼠上皮细胞中异位表达GlcNAc-TV会导致形态转化和肿瘤生长，并且已证实在癌细胞中过表达会诱导转移扩散。GlcNAc-TIII是一种与GlcNAc-TV竞争受体的酶，其异位表达可抑制B16黑色素瘤细胞的转移。此外，在GlcNAc-TV缺陷背景下，转基因小鼠中由病毒癌基因诱导的乳腺癌进展和转移会受到显著抑制。Mgat5基因表达和N-聚糖的β1,6GlcNAc分支与细胞运动性相关，而细胞运动性是恶性细胞的一种必要表型。
