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糖基转移酶超家族在肿瘤转移中的作用
陈茜茜1, 王立萍2, 余雯静2, 王涵玉2, 汪淑晶2 , 张嘉宁1     
1. 大连理工大学生命与医药学院,盘锦 124221;
2. 大连医科大学生物化学与分子生物学教研室,糖生物学研究所,大连 116044
摘要: 蛋白质的糖基化修饰主要包括N-连接糖基化、O-连接糖基化和糖基磷脂酰肌醇锚定连接.与核酸和蛋白质不同,糖链的合成过程并不遵循传统的基因信息传递的中心法则,主要由一系列催化糖苷键形成的糖基转移酶完成.异常糖基化修饰被认为与恶性肿瘤的发生发展和临床预后密切相关.研究表明,糖基转移酶的表达及其糖链结构的异常可通过调节肿瘤细胞与细胞外基质的相互作用,继而影响肿瘤转移的关键步骤,如上皮间质转化(E-钙黏着蛋白、N-钙黏着蛋白)、细胞的移动性(整合素β1和α5)、侵袭(基质金属蛋白酶MMPs)、浸润(唾液酸化Lewis抗原sLeX和sLeA).本文主要就唾液酰基转移酶、岩藻糖基转移酶和N-乙酰氨基葡萄糖转移酶等三大糖基转移酶家族的结构和生物学功能及其在肿瘤转移中的作用作一综述,以期为肿瘤转移的预测和诊断提供新思路.
关键词: 唾液酰基转移酶     岩藻糖基转移酶     N-乙酰氨基葡萄糖转移酶     肿瘤转移    
The Role of Glycosyltransferase Superfamily in Tumor Metastasis
CHEN Xi-Xi1, WANG Li-Ping2, YU Wen-Jing2, WANG Han-Yu2, WANG Shu-Jing2, ZHANG Jia-Ning1     
1. School of Life Science and Medicine, Dalian University of Technology, Panjin 124221, China;
2. Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian 116044, China
*This work was supported by a grant from National Basic Research Program of China (2012CB822103) and The National Natural Science Foundation of China (31470799)
** Corresponding author: Wang Shu-Jing. Tel: +86-411-86110313, E-mail: wangshujing@dmu.edu.cn
Zhang Jia-Ning. Tel: +86-427-2631889, E-mail: jnzhang@dlut.edu.cn
Received: July 27, 2017 Accepted: September 15, 2017
Abstract: Protein glycosylation modification includes N-linked glycosylation, O-linked glycosylation and glycosylphosphatidylinositol anchor glycosylation. Difference from nucleic acids and proteins, the synthetic process of glycans is mainly completed by a series of glycosyltransferases which catalyze glucosidic bond, not followed the traditional central dogma of genetic information transmission. Abnormal glycosylation modification is considered to be closely related to the occurrence, development and clinical prognosis of malignant tumor. Previous studies have shown that the abnormity of glycosyltransferases expression and glycans structure affects key steps of the metastatic cascade, such as epithelial-mesenchymal-transition (E-cadherin, N-cadherin), cell motility (integrin β1 and α5), invasion (matrix-metalloproteinases), extravasation (sLex and sLea), which by regulating the interaction between tumor cells and extracellular matrix. In this review, we mainly focus on the structures and biological functions of three glycosyltransferase families (sialyltransferases, fucosyltransferases and N-acetylglucosaminyltransferases), and their roles in tumor metastasis, hoping it can provide new ideas for the prognosis and diagnosis in tumor metastasis.
Key words: sialyltransferase     fucosyltransferase     N-acetylglucosaminyltransferases     tumor metastasis    

蛋白质的糖基化修饰在细胞识别和黏附、受体活化、信号传递等过程中发挥重要的生物学功能.细胞表面糖链的生物合成主要由糖基转移酶超家族(glycosyltransferases)催化完成,根据底物糖供体以及催化生成糖苷键的性质可将糖基转移酶超家族划分为多个功能亚家族,如唾液酰基转移酶家族、岩藻糖基转移酶家族和N-乙酰氨基葡萄糖转移酶家族,各亚家族通过催化各自特异性底物形成独特的糖苷键.异常的糖基化修饰,即糖基转移酶表达和其糖链结构的异常是恶性肿瘤发生发展及转移的共同特征[1].

转移是肿瘤细胞经血道、淋巴道和腹膜播散导致转移癌发生的多步骤过程.转移性肿瘤细胞需经一系列必要的步骤才能形成转移瘤,包括上皮-间质转化(epithelial-mesenchymal-transition,EMT)、原发性肿瘤组织的脱落、细胞外基质的黏附、细胞外基质蛋白的降解及迁移、邻近组织的侵袭、淋巴管和血管的浸润、身体不同部位的扩散[2].本文主要对糖基转移酶超家族中与肿瘤转移密切相关的唾液酰基转移酶、岩藻糖基转移酶和N-乙酰氨基葡萄糖转移酶及其催化形成的糖链结构进行了描述和总结.

1 唾液酰基转移酶 1.1 唾液酰基转移酶的结构与分类

唾液酸化修饰是糖链末端重要的糖基化修饰方式之一,主要通过唾液酰基转移酶(sialyltransferases,STs)以胞苷一磷酸-β-N-乙酰神经氨酸(CMP-Neu5Ac)为供体底物,催化唾液酸以不同糖苷键(α2-3、α2-6或α2-8) 与糖蛋白和糖脂末端的半乳糖、N-乙酰半乳糖胺或其他唾液酸连接[3].真核细胞内的唾液酰基转移酶与其他糖基转移酶类似,同属于Ⅱ型跨膜蛋白,即C端在胞外区而N端在胞内区.典型的唾液酰基转移酶的结构域主要由干区域和催化结构域组成,其中催化结构域包括具有48~49个氨基酸的唾液酸基模体L: ( )3-C-( )2-V-( )11-G-( )10-R-( )12-D-V-G-( )4和具有23个氨基酸的唾液酸基模体S: ( )3-G-( )10-C-( )8[4].唾液酰基转移酶一般定位于高尔基体,也有部分唾液酰基转移酶能以可溶酶的形式存在[5].20种唾液酰基转移酶分别为(图 1a):催化α2-3唾液酸化的ST3Gal Ⅰ~Ⅵ;催化α2-6唾液酸化的ST6Gal Ⅰ~Ⅱ(N-连接)和ST6GalNAc Ⅰ~Ⅵ(O-连接);催化α2-8唾液酸化的ST8Sia Ⅰ~Ⅵ[6].唾液酰基转移酶介导的糖复合物表面唾液酸化,因唾液酸结构、连接方式和受体结构的复杂多变,使得唾液酸化的糖复合物具备组织特异性、细胞特异性和分子特异性.

Fig. 1 Major glycosyltransferases that are involved in catalyzing of N-or O-glycan 图 1 糖基转移酶催化不同糖链形成的机制 (a)唾液酸化修饰,不同唾液酰基转移酶识别的受体位点以及糖苷键的连接方式. (b)岩藻糖基化修饰,不同岩藻糖基转移酶识别的受体位点以及糖苷键的连接方式. (c) N-聚糖分支合成,不同N-乙酰氨基葡萄糖基转移酶识别的受体位点以及糖苷键的连接方式.
1.2 唾液酸的生物学功能

鉴于唾液酸自身的负电荷性、较强的亲水性以及糖链末端的定位性,决定了唾液酸可以直接或者间接参与到细胞的各种生命活动中.细胞表面糖复合物的唾液酸化不仅参与了细胞膜表面蛋白构象的调节,还参与了细胞与细胞之间的生长增殖、迁移、凋亡等正常信号的传递[7-8].此外,唾液酸化的生物学功能还包括肾小球滤过膜电荷的调节、神经细胞的可塑性及红细胞膜电荷排斥等结构和物理学功能,并且细胞表面糖链末端的唾液酸可通过阻止相应抗原位点的识别标记,保护糖复合物不被免疫系统识别和降解.唾液酸还可以与无机离子、激素、凝集素、抗体等配体相互作用,通过调节细胞间黏附从而介导炎症与免疫反应[9].而细胞表面异常的唾液酸化还参与了肿瘤细胞的发生发展,如增殖、迁移、侵袭和免疫逃逸等过程[10].

1.3 唾液酰基转移酶与肿瘤转移

1.3.1 α2, 3-唾液酰基转移酶与肿瘤转移

α2, 3-唾液化修饰是指在ST3Gal Ⅰ~Ⅵ的催化下,唾液酸以α2, 3糖苷键的形式转移到Gal残基的3′-羟基的过程.肿瘤特异性转移与肿瘤细胞-特定血管内皮细胞间的黏附密切相关,多种黏附分子如E-选择素及其配体sLeX和sLeA在肿瘤转移中发挥重要作用,而α2, 3-唾液酰基转移酶是催化形成sLeX和sLeA的主要酶类[11].在胰腺癌细胞MDAPanc-28中过表达ST3Gal Ⅳ,促进了sLeX的表达且增强了E-选择素介导的黏附和迁移[12].Yoshihama等[13]发现CD82可通过下调ST3GAL4基因而降低sLea/x的表达,进而减弱非小细胞肺癌细胞H1299对血管的黏附作用,最终抑制肿瘤转移.已有研究表明,ST3Gal Ⅳ介导的α2, 3连接唾液酸的过表达可促进胃癌细胞发生转移,且与胃癌患者预后不良相关[14].miR-26a通过直接靶向ST3Gal Ⅵ抑制Akt/mTOR通路的活化来调控肝癌细胞的生长、迁移和侵袭的功能[15].此外,沉默ST3Gal Ⅵ降低了多发性骨髓瘤细胞与骨髓基质细胞和纤连蛋白的黏附能力,同时抑制了体外实验的跨内皮迁移[16].由此可见,α2, 3-唾液酰基转移酶主要是通过催化形成N-糖链末端唾液酸化Lewis糖类抗原与黏附分子相互作用,进而影响肿瘤细胞与血管内皮细胞间的黏附作用.

1.3.2 α2, 6-唾液酰基转移酶与肿瘤转移

α2-6唾液酸化是由ST6Gal Ⅰ~Ⅱ(N-连接)和ST6GalNAc Ⅰ~Ⅵ(O-连接)催化Neu5Ac以α2-6糖苷键的形式连接到β-半乳糖或N-乙酰半乳糖胺的过程,其中ST6GalⅠ是催化合成唾液酸α2-6连接N-聚糖的关键酶.肿瘤细胞可通过膜表面受体(如整合素)与细胞外基质成分(如胶原蛋白)的黏附,诱导细胞释放蛋白酶降解基底膜和基质,促使肿瘤细胞发生血道或淋巴道转移.已有文献报道,ST6Gal Ⅰ可通过调节整合素β1的α2-6唾液酸化,介导卵巢癌细胞对胶原蛋白1的黏附和迁移[17].本课题组研究发现,小鼠肝癌细胞表面整合素α5的α2, 6-唾液酸化介导了整合素α5β1依赖的细胞黏附及FAK信号传递α2, 6-唾液酸与凝集素样糖蛋白Siglec-2的识别参与小鼠肝癌细胞与淋巴结的黏附[18-19].此外,ST6Gal Ⅰ在肝癌、前列腺癌、骨肉瘤、结肠癌等肿瘤中高表达,且其表达可正性介导肿瘤细胞发生迁移和侵袭[20-23].然而,ST6GalⅠ表达水平变化引起肿瘤细胞转移的确切分子机制仍需进一步研究和探讨.

ST6GalNAc Ⅰ催化形成的sTn抗原能够调节恶性表型并诱导更具侵袭性的细胞行为,例如减弱细胞间的聚集以及促进细胞外基质黏附、迁移和侵袭.Tamura等[24]报道,下调ST6GalNAc Ⅰ后,sTn抗原的表达降低,减弱了胃癌细胞的生长、迁移和侵袭能力,同时抑制了由STAT5b信号通路诱导的胰岛素样生长因子1(IGF-1) 的表达.我们课题组发现,沉默ST6GalNAcⅠ通过PI3K/AKT/NF-κB通路抑制肝癌细胞的增殖、迁移和侵袭能力[25].ST6GalNAc Ⅴ通常被限制于大脑,但其在乳腺癌中的表达可以特异性介导肿瘤细胞发生脑转移,这说明了细胞表面糖基化在器官特异性转移的重要性[26].

1.3.3 α2, 8-唾液酰基转移酶与肿瘤转移

α2-8唾液酸化修饰是指在ST8Sia Ⅰ~Ⅵ的催化下,Neu5Ac以α2-8糖苷键的形式连接到其他唾液酸的过程.其中,ST8SiaⅠ(或GD3合成酶)催化唾液酸从CMP-唾液酸转移至GM3以产生神经节苷脂GD3和GT3.已有文献报道,ST8Sia Ⅰ与GD3在神经外胚层衍生的恶性肿瘤如黑色素瘤、胶质母细胞瘤、成神经细胞瘤和雌激素受体(ER)阴性乳腺癌中高表达,其在肿瘤细胞增殖、迁移、黏附和血管形成中也发挥重要作用[27-30].Sarkar等[31]研究发现,在乳腺癌细胞中,GD3合成酶的表达与c-Met信号通路的激活相关,进而导致干细胞特性和转移能力增强,而同基因野生型小鼠模型中,抑制GD3合成酶的表达能预防乳腺癌自发性转移,此外,GD3合成酶的表达与三阴性人乳腺肿瘤的预后不良相关.ST8SIA2基因编码的多聚唾液酸转移酶ST8SiaⅡ(或STX)能将活化的CMP-Neu5Ac传送到神经细胞黏附分子NCAM的N-糖链上,并且STX是催化合成多聚唾液酸(PSA)的关键酶[32].Jia等[33-34]发现,唾液酸化可能作为内部因素,通过ST6Gal Ⅰ或ST8Sia Ⅱ调节PI3K/Akt通路的活性,进一步调节肝癌细胞的侵袭和化学敏感性.PSA和STX在多种癌症中高表达,如神经母细胞瘤和非小细胞肺癌,并且PSA和STX的表达水平与肿瘤进展密切相关[35-36].可见,α2, 8-唾液酰基转移酶在调控肿瘤转移中也发挥重要作用.

2 岩藻糖基转移酶 2.1 岩藻糖基转移酶的结构与分类

岩藻糖基转移酶超家族(fucosyltransferases,FUTs)是一类催化岩藻糖基从GDP-fucose供体转移到相应受体上的酶蛋白,从而形成岩藻糖基化修饰的糖蛋白或糖脂.疏水聚类分析(hydrophobic cluster analysis,HCA)发现,岩藻糖基转移酶有5种保守的肽基序,分别为:α-3-基序Ⅰ( )11-S-( )6-G-( )1,α-3-基序Ⅱ( )1-Y-( )1-F-( )1-L-( )2-E-N-( )5-Y-I-T-E-K-( )10-V-P-V-(-)1,α-2-基序Ⅲ ( )1-T-F-( )2-W-( )5,α-6-基序Ⅲ I-( )1-D-I-( )2-L-( )3-D-( )1-L-V,α-2/6-基序Ⅰ(V/I-G-V/I-H-V/I-R-R/H-G/T-D/N)[37-38].到目前为止,共发现13种岩藻糖基转移酶基因,包括POFUT1POFUT2(GDP-fucose protein O-fucosyltransferase 1 & 2),以及FUT1~11[39].岩藻糖基转移酶包括以下4类(图 1b):识别蛋白质丝、苏氨酸侧链羟基的蛋白O-岩藻糖基转移酶(POFUT1和POFUT2);识别Ⅱ型糖链Galβ1, 4GlcNAc结构末端半乳糖残基的α1, 2岩藻糖基转移酶(FUTⅠ和FUTⅡ);识别糖链N-乙酰葡萄糖氨残基的α1, 3/4岩藻糖基转移酶(FUTⅢ~Ⅶ,FUTⅨ~Ⅺ);识别与天冬酰胺相连的N-乙酰葡萄糖氨残基的α1, 6岩藻糖基转移酶(FUTⅧ)[40].根据连接岩藻糖基化修饰的位置又可分为3类,核心岩藻糖基化修饰(FUTⅧ),末端岩藻糖基化修饰(FUTⅠ~Ⅶ,FUTⅨ~Ⅺ)和蛋白O-岩藻糖基化修饰(POFUTⅠ和POFUTⅡ).岩藻糖基转移酶的表达呈现出复杂的细胞和组织特异性,大部分岩藻糖基转移酶定位于高尔基体,而蛋白O-岩藻糖基转移酶被发现定位于内质网[41].

2.2 岩藻糖基化的生物学功能

在哺乳动物中,细胞表面的岩藻糖基化修饰都是由岩藻糖基转移酶参与完成的.人类ABO血型抗原和Lewis系统是通过糖基转移酶的顺序作用合成的寡糖,其中岩藻糖基转移酶起关键作用,如LeY血型抗原分子(一种双岩藻糖的寡糖,其表面α1, 3岩藻糖基化主要由FUTⅣ催化完成)[42].蛋白质的岩藻糖基化在真核生物的多种生理过程中发挥重要作用,这些过程包括发育期细胞黏附、炎症反应、白细胞运输或淋巴细胞归巢以及受精作用.而在免疫或肿瘤等病理情况下,机体常常出现异常表达的岩藻糖基化[43].异常岩藻糖基化是肝细胞癌中最重要的异常糖基化修饰,岩藻糖基化的甲胎蛋白(AFP-L3) 在2005年于美国被应用为肝细胞癌的肿瘤标志物[44].

2.3 岩藻糖基转移酶与肿瘤转移

2.3.1 核心岩藻糖基转移酶与肿瘤转移

核心岩藻糖基化是由唯一的α1, 6岩藻糖基转移酶(FUTⅧ)催化岩藻糖基以α1, 6形式连接到N聚糖核心最内侧的GlcNAc残基的过程.已有研究表明,核心岩藻糖基转移酶FUTⅧ在肺癌、胰腺癌、卵巢癌、肝癌、结肠癌等肿瘤中出现表达和活性异常[45-49].癌细胞中高表达FUTⅧ可导致肿瘤具有更强的迁移和转移潜力,而在乳腺癌或非小细胞肺癌中,高表达FUTⅧ还与患者总体存活率和无复发生存率的降低有关[50-51].Osumi和Shao等[52-53]却发现,在结直肠癌细胞中,E-钙黏着蛋白的核心岩藻糖基化增强了细胞与细胞间的黏附和聚集,导致细胞迁移能力下降.由此可见,FUTⅧ对癌症患者预后的影响并不取决于黏附分子E-钙黏着蛋白.在E-钙黏着蛋白缺失的胃癌中,癌细胞表面核心岩藻糖基化的结构较少并且FUTⅧ的表达降低[54].此外,FUTⅧ还可能通过抑制整合素与其配体的识别,抑制整合素介导的黏附作用,继而抑制肿瘤转移.

2.3.2 末端岩藻糖基转移酶与肿瘤转移

末端岩藻糖基化是在许多N-聚糖、黏着蛋白O-GalNAc聚糖和糖脂上发现的常见修饰,由岩藻糖基转移酶FUTⅠ~Ⅶ和FUTⅨ~Ⅺ催化完成.FUTⅦ是唾液酸路易斯抗原(sLex)合成及调控合成水平过程的关键酶[55-56].唾液酸路易斯抗原作为促进选择素介导的滚动和黏附作用的副产物,在促进癌症迁移和转移中起重要作用.Läubli等[57]研究发现,FUTⅦ能诱导L-选择蛋白配体参与血管内肿瘤细胞栓塞中白细胞与内皮细胞的相互作用,从而促进L-选择蛋白介导的肿瘤转移.研究显示由FUTⅦ过表达引起的sLeX表达上调可以导致肝癌细胞迁移能力增强[58].Mathieu等[59]发现,肝癌细胞HepG2中过表达FUTⅠ能选择性阻止sLex与内皮E-选择蛋白的相互作用,从而抑制其对活化的内皮细胞的黏附和滚动.在乳腺癌中,FUTⅠ的表达与低预后和远处转移相关[60].此外,钙网蛋白在3′-UTR中调节FUTⅠ mRNA的降解,导致整合素β1的岩藻糖基化增加而激活整合素β1,进而影响膀胱癌细胞的黏附和转移[61].因此,N-聚糖末端岩藻糖基化sLex抗原或整合素β1与肿瘤转移密切相关,其表达升高通常预示着肿瘤恶性程度较高.

2.3.3 蛋白O-岩藻糖基转移酶与肿瘤转移

蛋白O-岩藻糖基化,是由蛋白O-岩藻糖基转移酶POFUTⅠ和POFUTⅡ分别催化岩藻糖基从GDP-岩藻糖转移到表皮生长因子样(epidermal growth factor like,EGF like)重复序列和血小板反应蛋白1型重复序列(thrombospondin type 1 repeats,TSR)的丝氨酸或苏氨酸残基的过程[62].POFUTⅠ的表达水平在口腔癌、肝癌、胃癌和乳腺癌中明显升高,且POFUTⅠ的表达水平与口腔癌原发肿瘤大小、侵袭性胃癌的表型、乳腺癌的淋巴结转移,病理分级和TNM等密切相关[63-66].同时,在胃癌中POFUTⅠ与细胞黏附和细胞凋亡呈负相关,在肝癌细胞中过表达POFUTⅠ能提高细胞的增殖和迁移能力[64-65].此外,POFUTⅠ可以调控细胞表面Notch受体和配体的岩藻糖基化,因此是影响Notch信号通路的关键因子.我们的研究发现,下调POFUTⅠ的表达通过Notch信号通路而抑制肝细胞L02的增殖和黏附能力,但细胞迁移未受影响[67].POFUTⅡ基因在预测胶质母细胞瘤患者的存活方面具有重要意义,但其在肿瘤进展中的作用尚未明确[68].由此可知,蛋白O-岩藻糖基转移酶在肿瘤转移中的作用主要是由POFUTⅠ介导Notch信号途径完成的.

3 N-鄄乙酰氨基葡萄糖转移酶 3.1 N-鄄乙酰氨基葡萄糖转移酶的结构与分类

N-乙酰氨基葡萄糖转移酶(N-acetylglucosaminyltransferases,GnTs)定位于真核生物的高尔基体,是一类催化N -聚糖核心的D-甘露糖(Man)与UDP-N-乙酰氨基葡萄糖(UDP-GlcNAc)中的GlcNAc连接,形成N-糖链多分支结构(每个分支又称为天线)的酶类[69].GnTs属于2型跨膜蛋白,包括胞内结构域、跨膜结构域、茎区和催化结构域、而GnTs的催化结构域中存在保守的肽区域DxD基序(EDD或EED),这表明GnTs存在类似的三维整体结构[70].GnTs根据催化起始位置的不同可分为以下6种(图 1c):GnTⅠ(α-3-D-甘露糖苷β-1, 2-N-乙酰葡糖胺基转移酶Ⅰ);GnTⅡ(α-6-D-甘露糖苷β-1, 2-N-乙酰葡糖胺基转移酶Ⅱ);GnTⅢ (β1, 4甘露糖苷β-1, 4-N-乙酰葡糖胺基转移酶Ⅲ);GnTⅣ(α-3-D-甘露糖苷β-1, 4-N-乙酰葡糖胺基转移酶Ⅳ);GnTⅤ(α-6-D-甘露糖苷β-1, 6-N-乙酰葡糖胺基转移酶Ⅴ);GnTⅥ(催化GlcNAc以β1, 4连接方式转移到N-聚糖三聚体核心中的GlcNAcβ1、6Manα1、6Manβ)[71].目前研究最热门、N–聚糖合成中最重要的酶为GnTⅢ和GnTⅤ.GnTⅢ催化形成β1, 4甘露糖平分型GlcNAc后就不会再形成分支,还可连接β1, 4-Gal和β1, 3-GlcNAc,但其他糖基转移酶如GnTⅠ、GnTⅣ和GnTⅤ不能再发挥作用.因此,GnTⅢ是N-聚糖合成的关键酶.GnTⅤ对N -糖链类型及复杂型糖链结构有重要作用,催化形成N-聚糖β1, 6分支,构成N聚糖的三天线或者四天线结构[72].

3.2 N-鄄乙酰氨基葡萄糖化的生物学功能

N-乙酰氨基葡萄糖转移酶由于其种类多样性及高度专一性,参与细胞黏附、信号转导等生命活动,其介导的聚糖N-乙酰氨基葡萄糖化与细胞的多种生理与病理过程密切相关.Mgat1(编码GnTⅠ的基因)依赖性N-聚糖对脊椎动物和无脊椎后生动物的正常发育至关重要[73].细胞表面的N-乙酰氨基葡萄糖化修饰可能对稳定蛋白酶的结构有作用,如GnTⅤ参与基质蛋白酶的翻译后修饰,通过增加β1, 6分支从而提高其稳定性,不被胰蛋白酶降解[74-75].此外,GnTⅤ可修饰细胞膜上受体糖蛋白,如GnTⅤ高表达通过增加表皮生长因子受体(EGFR)上的β1, 6分支,促进表皮生长因子(EGF)与其受体结合,从而改变下游信号转导[76].已有文献报道,由GnT-Ⅴ表达增加引起的靶蛋白GlcNAc βl, 6分支增多可促进肿瘤的发生发展和转移[77].GnTⅢ可通过影响神经生长因子或表皮生长因子的糖链修饰而改变相关的信号途径,进一步影响肿瘤细胞的迁移、侵袭和凋亡等生物学行为,并且β1, 6分支寡糖已经被认为是结肠癌和乳腺癌肿瘤恶化的标志[78-79].

3.3 N-鄄乙酰氨基葡萄糖转移酶与肿瘤转移

3.3.1 N-乙酰氨基葡萄糖转移酶Ⅲ(GnTⅢ)与肿瘤转移

GnT -Ⅲ以连接成β1, 4的方式使UDP-GlcNAc中的GlcNAc连接到N -聚糖核心的β Man上,形成β1, 4甘露糖平分型N-乙酰葡糖胺.GnTⅢ是N-聚糖合成过程中起关键作用的酶,对肿瘤细胞的迁移和转移有重要影响.已有文献报道,过表达GnTⅢ能抑制多种类型的癌细胞发生转移,GnTⅢ通常被认为是肿瘤转移抑制因子[80-82].GnTⅢ催化复合N-聚糖中加入平分型GlcNAc,并影响其与半乳凝集素的相互作用,从而调节一些糖蛋白(如生长因子受体和黏附分子)的功能[71].正常上皮细胞中,由于GnTⅢ酶的活性,E-钙黏着蛋白主要含有平分型N-聚糖,而在肿瘤细胞中,GnT-Ⅲ因启动子甲基化而表达下调,其对应的GnT V上调导致钙黏着蛋白和其他蛋白质形成三、四天线糖链结构,这引起E-钙黏着蛋白内化到细胞质而破坏细胞与细胞间接触,损害相关信号通路,最终导致上皮间质转化(EMT)、侵袭和转移[83].可见,GnTⅢ催化糖链形成平分型GlcNAc后不再形成分支,通过影响黏附分子的功能,继而影响肿瘤细胞发生EMT和转移.

3.3.2 N-乙酰氨基葡萄糖转移酶Ⅴ(GnTⅤ)与肿瘤转移

GnTⅤ可将UDP-Glc-NAc中GlcNAc加到N-聚糖核心的甘露糖(Man)残基上从而形成β1, 6分支糖链结构,这种结构有利于糖链的延伸.GnTⅤ参与调节细胞黏附过程中蛋白质的活性和定位(如E-钙黏着蛋白),而影响肿瘤细胞的迁移、转移和肿瘤血管生成.在胃癌细胞中过表达GnTⅤ可诱导E-钙黏着蛋白从细胞膜错误定位于细胞质[84].GnTⅤ催化E-钙黏着蛋白形成N-聚糖β1, 6GlcNAc分支,这反过来导致细胞非功能性黏附连接,损害细胞黏附和下游信号传导,并有助于侵袭和转移[85-87].在纤维肉瘤细胞中下调GnTⅤ的表达导致复合聚糖水平降低,细胞间接触增加,迁移和侵袭减少以及外在信号增强(如ERK磷酸化)[88].GnTⅤ在癌细胞中的高表达通常导致1-6 GlcNAc分支的增加,这对于与转移表型相关的三、四天线糖链结构的形成是必需的[89].因此,在HT1080纤维肉瘤细胞中,GnTⅤ的过表达导致纤维连接蛋白表达减少,但由于整合素β1上N-聚糖分支增加导致肿瘤细胞的迁移和侵袭能力增加[90].胃癌细胞中过表达GnTⅤ引起的N-聚糖支链增加,对整合素α1β1的聚集,细胞运动和黏附均有影响[91].在免疫组织化学研究中,GnTⅤ与肝细胞癌和肾癌的转移和预后差相关[92-93].近期研究表明,GnTⅤ还存在分泌型,分泌型的GnTⅤ可以通过促进肿瘤血管的生成而促进肿瘤细胞的转移.由此可见,GnTⅤ及其催化形成的N-聚糖β1, 6GlcNAc分支与肿瘤细胞黏附、迁移、侵袭等过程密切相关,更好地了解GnTⅤ的表达调控方式以及相关信号通路,将有助于找到阻滞肿瘤转移的靶点,为发现新型糖蛋白或糖链为核心的肿瘤分子标志物提供实验基础.

4 总结与展望

本文综述了近来关于糖基转移酶超家族的结构、功能及其在肿瘤转移中的作用,且肿瘤转移相关的糖基转移酶总结于表 1.20年来聚糖在癌症进展中的关键作用已逐渐得到认可.不同聚糖结构以及某些异常表达的糖基转移酶已被定义为肿瘤实体的预后和检测的生物标志物[94].蛋白质的糖基化修饰包括唾液酸化、岩藻糖基化和N-聚糖分支,它们能够影响肿瘤转移的关键步骤,如上皮间质转化、细胞的移动性、侵袭和浸润.唾液酰基转移酶家族成员一方面可催化形成N-糖链末端唾液酸化Lewis糖类抗原而影响肿瘤细胞与血管内皮细胞间的黏附作用,另一方面可调节膜表面受体与细胞外基质成分的黏附而促使肿瘤细胞发生血道或淋巴道转移.岩藻糖基转移酶家族主要是通过调节唾液酸化Lewis抗原、整合素或Notch受体和配体的岩藻糖基化而影响肿瘤细胞的黏附和转移.而N-乙酰氨基葡萄糖转移酶家族可通过催化E-钙黏着蛋白或整合素形成N-聚糖β1, 6GlcNAc分支,继而影响肿瘤细胞发生上皮间质转化和转移.此外,肿瘤细胞中特定糖基转移酶的调节导致靶蛋白的聚糖模式发生改变,引起的相关蛋白功能的改变可能利于肿瘤细胞发生转移.因此,更好地了解肿瘤中异常糖链修饰的机制将有利于开发聚糖作为肿瘤生物标志物或抗肿瘤药物设计和合成的靶点.

Table 1 Glycosyltransferases associated with tumor metastasis 表 1 肿瘤转移相关的糖基转移酶
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中国科学院生物物理研究所和中国生物物理学会共同主办
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文章信息

陈茜茜, 王立萍, 余雯静, 王涵玉, 汪淑晶, 张嘉宁
CHEN Xi-Xi, WANG Li-Ping, YU Wen-Jing, WANG Han-Yu, WANG Shu-Jing, ZHANG Jia-Ning
糖基转移酶超家族在肿瘤转移中的作用
The Role of Glycosyltransferase Superfamily in Tumor Metastasis
生物化学与生物物理进展, 2017, 44(10): 877-887
Progress in Biochemistry and Biophysics, 2017, 44(10): 877-887
http://dx.doi.org/10.16476/j.pibb.2017.0314

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收稿日期: 2017-07-27
接受日期: 2017-09-15

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