Chandrasekaran E V, Xue Jun, Neelamegham Sriram, Matta Khushi L
Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Carbohydr Res. 2006 Jun 12;341(8):983-94. doi: 10.1016/j.carres.2006.02.017. Epub 2006 Mar 20.
Carbohydrate chains of cancer glycoprotein antigens contain major outer changes dictated by tissue-specific regulation of glycosyltransferase genes, the availability of sugar nucleotides, and competition between enzymes for acceptor intermediates during glycan elongation. However, it is evident from recent studies with recombinant mucin probes that the final glycosylation profiles of mucin glycoproteins are mainly determined by the cellular repertoire of glycosyltransferases. Hence, we examined various cancer cell lines for the levels of fucosyl-, beta-galactosyl, beta-N-acetylgalactosaminyl-, sialyl-, and sulfotransferase activities that generate the outer ends of the oligosaccharide chains. We have identified glycosyltransferases activities at the levels that would give rise to O-glycan chains as reported by others in breast cancer cell lines, T47D, ZR75-1, MCF-7, and MDA-MB-231. Most breast cancer cells express Gal-3-O-sulfotransferase specific for T-hapten Gal beta1-->3GalNAc alpha-, whereas the enzyme from colon cancer cells exhibits a vast preference for the Gal beta1,4GlcNAc terminal unit in O-glycans. We also studied ovarian cancer cells SW626 and PA-1 and hepatic cancer cells HepG2. Our studies show that alpha1,2-L-fucosyl-T, alpha(2,3) sialyl-T, and 3-O-Sulfo-T capable of acting on the mucin core 2 tetrasaccharide, Gal beta1,4GlcNAc beta1,6(Gal beta1,3)GalNAc alpha-, can also act on the Globo H antigen backbone, Gal beta1,3GalNAc beta1,3Gal alpha-, suggesting the existence of unique carbohydrate moieties in certain cancer-associated glycolipids. Briefly, our study indicates the following: (i) 3'-Sulfo-T-hapten has an apparent relationship to the tumorigenic potential of breast cancer cells; (ii) the 3'-sulfo Lewis(x), the 3-O-sulfo-Globo unit, and the 3-fucosylchitobiose core could be uniquely associated with colon cancer cells; (iii) synthesis of a polylactosamine chain and T-hapten are favorable in ovarian cancer cells due to negligible sialyltransferase activities; and (iv) a 6'-sialyl LacNAc unit and 3'-sialyl T-hapten appear to be prevalent structures in hepatic cancer cell glycans. Thus, it is apparent that different cancer cells are expressing unique glycan epitopes, which could be novel targets for cancer diagnosis and treatment.
癌症糖蛋白抗原的碳水化合物链包含主要的外部变化，这些变化由糖基转移酶基因的组织特异性调控、糖核苷酸的可用性以及聚糖延长过程中酶对受体中间体的竞争所决定。然而，最近使用重组粘蛋白探针的研究表明，粘蛋白糖蛋白的最终糖基化谱主要由糖基转移酶的细胞组成决定。因此，我们检测了各种癌细胞系中岩藻糖基、β-半乳糖基、β-N-乙酰半乳糖胺基、唾液酸基和磺基转移酶的活性水平，这些酶可生成寡糖链的外端。我们已经鉴定出在乳腺癌细胞系T47D、ZR75-1、MCF-7和MDA-MB-231中，如其他人所报道的那样，能产生O-聚糖链水平的糖基转移酶活性。大多数乳腺癌细胞表达对T抗原决定簇Galβ1→3GalNAcα特异的Gal-3-O-磺基转移酶，而结肠癌细胞中的该酶对O-聚糖中的Galβ1,4GlcNAc末端单元表现出极大的偏好。我们还研究了卵巢癌细胞SW626和PA-1以及肝癌细胞HepG2。我们的研究表明，能够作用于粘蛋白核心2四糖Galβ1,4GlcNAcβ1,6(Galβ1,3)GalNAcα-的α1,2-L-岩藻糖基转移酶、α(2,3)唾液酸基转移酶和3-O-磺基转移酶，也能作用于Glob H抗原主链Galβ1,3GalNAcβ1,3Galα-，这表明在某些癌症相关糖脂中存在独特的碳水化合物部分。简而言之，我们的研究表明：(i) 3'-磺基-T抗原决定簇与乳腺癌细胞的致瘤潜力有明显关系；(ii) 3'-磺基路易斯(x)、3-O-磺基-Globo单元和3-岩藻糖基壳二糖核心可能与结肠癌细胞独特相关；(iii) 由于唾液酸基转移酶活性可忽略不计，聚乳糖胺链和T抗原决定簇的合成在卵巢癌细胞中是有利的；(iv) 6'-唾液酸基乳糖胺单元和3'-唾液酸基-T抗原决定簇似乎是肝癌细胞聚糖中的普遍结构。因此，很明显不同的癌细胞表达独特的聚糖表位，这可能是癌症诊断和治疗的新靶点。
