修回日期: 2015-11-13
接受日期: 2015-11-23
在线出版日期: 2016-01-08
上皮间质转化(epithelial mesenchymal transition, EMT)参与机体器官或组织纤维化及肿瘤的发生与转移过程, 已成为当前研究的热点之一. 转录因子Snail作为C2H2型的一类锌指蛋白, 主要通过SNAG结构域和共抑制子C端结合蛋白组成转录抑制区域实现对基因表达的抑制, 在EMT过程中发挥重要的调控作用. 近年来大量研究证实, Snail可通过调控肿瘤坏死因子α(tumor necrosis factor α, TNF-α)-核因子κB(nuclear factor κB, NF-κB)-Snail和转化生长因子β1(transforming growth factor β1, TGF-β1)-Smads-Snail这两条途径相关信号蛋白分子的基因表达, 调节信号传导通路, 从而促进肠EMT的发生. 本文拟对转录因子Snail在这两条介导肠EMT途径中的调控作用作一简要概述, 以期对Snail参与调控EMT有更进一步的认识.
核心提示: 本文以Snail调控肠上皮间质转化(epithelial mesenchymal transition, EMT)为切入点, 从肿瘤坏死因子α(tumor necrosis factor α)-核因子κB(nuclear factor κB)-Snail和转化生长因子β1(transforming growth factor β1)-Smads-Snail这两条途径相关信号蛋白分子的基因表达调控进行论述, 认为转录因子Snail以其独特的生物学特性, 在器官/组织纤维化和肿瘤等疾病的EMT进程中扮演着重要的调控角色.
引文著录: 李雨薇, 吴焕淦, 施茵. 转录因子Snail在肠上皮间质转化中的调控作用. 世界华人消化杂志 2016; 24(1): 81-88
Revised: November 13, 2015
Accepted: November 23, 2015
Published online: January 8, 2016
Epithelial-mesenchymal transition (EMT) is involved in many pathological processes such as tissue fibrosis, tumor occurrence and metastasis, which has become one of current research focuses. The transcription factor Snail is a C2H2-type zinc finger protein and has a crucial regulatory role in EMT through the transcription inhibition region, which is composed of SNAG domain and C-terminal binding protein, to inhibit the expression of genes. Recently, numerous studies have confirmed that Snail can promote EMT through the tumor necrosis factor α (TNF-α)-nuclear factor κB (NF-κB)- Snail pathway and transforming growth factor β1 (TGF-β1)-Smads-Snail pathway. This article aims to summarize the regulatory role of Snail in mediating intestinal EMT via the above two
pathways.
- Citation: Li YW, Wu HG, Shi Y. Role of Snail in regulation of intestinal epithelial-mesenchymal transition. Shijie Huaren Xiaohua Zazhi 2016; 24(1): 81-88
- URL: https://www.wjgnet.com/1009-3079/full/v24/i1/81.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i1.81
上皮间质转化(epithelial mesenchymal transition, EMT)是在生理或病理情况下发生的一种细胞迁移过程, 上皮细胞发生极化, 进而导致一系列生物学变化. 在EMT过程中, 上皮细胞会改变其属性, 如细胞极性消失、细胞间连接黏附下降或消失等, 同时获得迁移、侵袭能力和高抗凋亡力, 而呈细长纺锤型的间质细胞, 即通常转化成成纤维细胞和肌纤维母细胞[1]. EMT参与机体的很多生理和病理过程, 在生理方面如胚胎、心脏瓣膜、肌组织的形成, 伤口组织重建与再生等; 在病理方面引起器官或组织纤维化、肿瘤的发生与转移等[2-4]. 一般情况下, 组织炎症的发生, 会促使细胞外间质受各种炎症趋化因子梯度的诱导, 到病变部位进行损伤修复. 而在炎症性肠病中, 由于免疫反应的过度激活, 使肠道发生持续性炎症及组织异常修复的恶性循环, 肠上皮组织在损伤、炎症和细胞因子等作用下被激活, 导致其细胞表型和功能发生改变, 同时上皮细胞的标志物消失, 取而代之的是大量纤维化型间质细胞, 并由此获得产生大量胶原蛋白(Ⅰ、Ⅲ、Ⅳ、Ⅴ型胶原)和纤维连接蛋白等细胞外基质(extracellular matrix, ECM)的能力, 同时这些细胞的迁移和渗透能力也发生了改变, 导致肠EMT的发生, 最终形成肠纤维化[5,6]. 而近年来随着对EMT研究的深入, 日渐发现肿瘤坏死因子α(tumor necrosis factor α, TNF-α)、转化生长因子β1(transforming growth factor β1, TGF-β1)、Wnt、Notch、Hedgehog等介导的通路均可导致EMT的发生[7,8]. 已有学者研究[9,10]发现, 肠EMT的发生主要是通过由TNF-α与TGF-β1所介导的TNF-α-核因子κB(nuclear factor κB, NF-κB)-Snail和TGF-β1-Smads-Snail途径, 而在这两条途径中, 转录因子Snail扮演着关键性的调控角色, 已成为研究EMT的热点. 本文拟对这两条途径中Snail所发挥的调控作用的相关研究文献进行简要概述, 以期对Snail的生物学效应以及在肠EMT途径中的调控机制有更进一步的认识.
转录因子Snail是属于Snail基因超家族的第一个成员, 定位于人类染色体20q13.13, Snail基因的转录产物长约2.0 kb[11]. Snail超家族是具有手指状多肽空间的锌指结构域的一类结合功能蛋白. Snail与Snail超家族成员间有着类似的架构, 结构链包括4-6个高度保守的羧基末端区域和高度多变的氨基酸末端区域组成[12,13]. 根据半胱氨酸残基与组氨酸残基的组成比例, 属于2个半胱氨酸和2个组氨酸残基组成的C2H2型的锌指蛋白类, Snail与家族其他调控蛋白的架构及功能特点的差异是由名为中间P-S富集区域所体现, Snail的SNAG结构域和共抑制子C端结合蛋白是转录抑制区域, 可实现对靶基因表达的抑制[14]. Snail包含4个锌指结构域, 各由1个α螺旋、2个β折叠和含有1个DNA连接槽的氨基酸末端区组成, 主要是通过协调锌离子, 来调控基因的表达. 螯合锌离子提供的交叉链接所稳定的α-螺旋结构, 与DNA双螺旋结构, 形成空间构象上的互补, 与DNA启动子(6个碱基CAGGTG结合位点)进行特异性结合, 氨基端嵌于DNA蛋白的凹槽中, 识别特异的DNA序列, 调控基因的转录[15,16].
在低等动物果蝇中胚层的中胚叶组织形成的环节中, 首先发现了Snail超家族的第一个成员Snail. Snail参与的生理性EMT过程, 主要在胚胎期体现.在原肠胚形成中胚层的过程中, 高等动物哺乳类脊椎动物的神经脊形成中占有重要作用[17]. Locascio等[18]与Larue等[19]在中胚层与神经嵴的前体中发现Snail, 其作用是激活上皮细胞转化为间质细胞, 促使神经管的分化与移动. Snail介入细胞上皮间质变化过程, 使上皮细胞分离并迁移, 到含有间质细胞的组织中, 促使EMT发生. Snail主要表达在胚胎分化及含有间质组织的器官, 如: 胎盘及成人的心、肾、肺、肝等, 均需要Snail基因的调控[20]. 他编码264个氨基酸的蛋白质[21]. 在细胞形态学方面, Snail可促使细胞通过增殖、凋亡、周期改变等使细胞形态发生改变. 在细胞运动学方面, Snail可促进神经分化和左右发育不对称等生长发育进程[22]. 近年来研究表明, Snail在器官或组织纤维化、肿瘤等疾病的EMT进程中是关键性的调控因子, Snail可促使上皮标志物的特性消失, 转而表达间质细胞的特性, 由此增强细胞的转移与侵袭能力. Snail可通过Wnt/Snail[23]、TNF-α/Snail[9]、TGF-β1/Snail[7]、Notch/Snail[24]等途径来调节信号传导, 促进EMT过程的发生.
目前研究已发现, Snail参与调控TNF-α、TGF-β1、Wnt、Notch、miRNA等所介导的EMT途径, 而其中由TNF-α、TGF-β1所介导的TNF-α-NF-κB-Snail和TGF-β1-Smads-Snail途径是导致肠EMT的两条主要途径. Snail与这两条途径中的相关信号因子交互作用, 形成调控EMT机制的特殊信号通路.
TNF-α是肠EMT发生的主要促炎因子, 也是此途径的启动因子. TNF-α激活下游相关因子, 启动骨牌效应的信号传导, NF-κB基因转录, Snail水平上调, 靶向抑制E-cadherin等蛋白, 上皮细胞标志物与间质细胞标志物反向表达, 细胞蛋白结构改变, 肠EMT形成.
TNF-α主要是通过与靶细胞膜上肿瘤坏死因子受体(tumor necrosis factor receptor, TNFR)的结合, 来调节肠上皮细胞的增殖、分化与凋亡. TNFR有TNFR1和TNFR2两个亚型. 其中TNFR1含死亡结构域(death domain, DD), 故其具有强力的细胞凋亡效应, TNF-α与TNFR1胞外受体区特异性结合, 促使抑制蛋白(associated death domain protein, PADD)释放, 并与TNFR1-DD结构域结合成TNFR1/PADD复合体, 诱导一系列反应蛋白, 由此引发其下游信号通路开启细胞凋亡的过程[25]. TNF-α与TNFR2结合后, 一方面加强了TNFR1促使细胞凋亡的作用, 同时激活NF-κB, 启动其下游的信号通路, 并诱导各种靶基因的转录与表达. NF-κB多以无活性三聚体存于胞质中.当此通路受外界因素激活后, 蛋白激酶将IκB激酶复合体(IκB kinase, IKK)的NF-κB磷酸化后NF-κB的抑制蛋白(inhibitor of NF-κB, IκB)被泛素化. NF-κB继续被蛋白酶降解至其核定位点被显露, 同时转移至胞核内, 发挥其对Snail靶基因的调控, 诱导相关基因的转录, 并介导细胞的增殖与分化[26-28]. Bonavida等[29]和Lin等[30]实验证实EMT逆转的循环通路中, Snail是这个循环的关键, 从而调控NF-κB和下游信号启动的分子机制, 细胞中Snail的表达随着NF-κB的活化增加而升高, 最终致使细胞出现EMT, Snail的存在保证了这条通路的循环. Cheon等[31]使用AK-1特定SIRT2抑制剂, 抑制HCT116人类结肠癌细胞发生EMT, 其主要机制是抑制Snail蛋白表达, 具体途径是透过糖原合酶激酶-3β(glycogen synthase kinase 3β, GSK-3β)发生磷酸化, 导致Snail降解, 癌细胞中随着Snail水平下调, 同时NF-κB失活、E-钙黏蛋白水平下调, 出现细胞迁移力和侵袭力的减弱. Flier等[32]发现在2, 4, 6-三硝基苯磺酸诱导的小鼠克罗恩病结肠炎模型中, 肠上皮细胞E-钙黏蛋白(E-cadherin)下调, 发生EMT, 并导致肠纤维化. Bataille等[33]认为β-连环蛋白(β-catenin)从胞膜向胞核转移也是克罗恩病发生EMT的标志之一, 其在克罗恩病并发瘘管形成的过程中, 发现EMT的标志性分子表达发生变化, 即肠道上皮标志物E-cadherin表达下调和间质标志物β-catenin表达上调. Snail表达上调后, 主要与E-cadherin启动子Epal组件的E-box结合, Snail透过锌指DNA结合区域与启动子主架构链上的CANNTG序列结合, 抑制E-cadherin作用[34]. Comijn等[35]与Battle等[36]的研究均发现, Snail的转录抑制功能, 不单是由锌指结构区来体现, 还依赖存在于氨基末端的基序SNAG反式激活区域(Snail Gfi)实现, 无此分子结构的Snail无法对E-cadherin启动子的活性进行抑制. E-cadherin是一种上皮组织的钙黏附蛋白, 通过钙离子泵, 介导Ca2+依赖性细胞间黏附功能, 以此影响细胞的形态、极化、运动和组织形成等作用[37,38]. E-cadherin含有5'-CAGGTG序列的2个E-box结构[39]. Snail与E-cadherin启动子的E-box结合后, 抑制E-cadherin基因转录或使E-cadherin发生甲基化, 使其基因序列呈低表达或不表达[40]. Snail与E-cadherin启动子的编码基因CDH1结合, 从而抑制此基因转录[41]. 周传文等[42]实验证明, Snail可与CDH1结合, 下调E-cadherin的表达, 引起细胞间的极性改变和黏附性下降, 并促进细胞迁移. 该实验结果与首次证明此研究的Cano等[2]的研究结果一致.
大量研究[1,43-45]证实, Snail与E-cadherin启动子的E-box结合, 影响了整个上皮细胞的基因蛋白表达谱, 下调上皮细胞标志物, 如: 闭锁蛋白、角蛋白、E-钙黏蛋白、层黏蛋白1等等; 上调间质细胞标志物, 如: 成纤维细胞特异性蛋白-1、弹性蛋白、N-钙黏蛋白、纤维连接蛋白、α-平滑肌肌动蛋白、波形蛋白. 被激活后的间质细胞可特异性分泌基质蛋白等细胞因子, 促使合成大量的细胞外基质(主要包括Ⅰ、Ⅱ、Ⅲ、Ⅳ形胶原、蛋白多糖、硫酸软骨素、透明质酸等). 目前的研究均表明, Snail是TNF-α-NF-κB-SNAIL信号通路的中心环节, 其表达水平反馈上游信号因子TNF-α, 使其持续刺激细胞, 再藉由各种上游因子复合物激活NF-κB的活性表达, 由此上调下游核心转录因子, 诱导细胞向EMT发展.
Snail参与调控肠EMT的另一条重要路径, 是由对组织或器官炎症损伤修复的重要细胞因子TGF-β1所介导的EMT途径. TGF-β1主要是刺激此途径下游的各种信号蛋白分子, 对其进行磷酸化或泛素化修饰, 形成各种复合物, 进一步影响该途径相关基因的表达与转录, 并促进其中的关键调控因子Snail蛋白高水平表达, 进而抑制其靶目标E-cadherin表达, 破坏细胞基质黏附力, 最终导致肠EMT形成.
TGF-β1主要是由丝氨酸激酶蛋白结构域、苏氨酸激酶蛋白结构域组成的接受外来信号的胞内区. TGF-β1有Smad和非Smad两种信号途径来表达其生物学效应. 在EMT发生的信号途径中, 主要是以受体激活型Smad为主导[46]. TGF-β1在细胞外受外界因素刺激启动后, 在细胞膜上直接与转化生长因子β1受体2(transforming growth factor β1 receptor 2, TβR2)结合, 或间接透过TβR3与TβR2结合, 形成复合体TGF-β1/TβR2, 同时TβR2出现自身磷酸化活化后, 快速与TβR1结合成性质稳定的异聚体, 此异聚体含有2个跨膜丝氨酸-苏氨酸激酶受体, TβR2激酶使TβR1磷酸化, 再通过丝氨酸激酶、苏氨酸激酶完成胞内外的信号跨膜传导, 激活Smads蛋白(Smad2/3)并磷酸化Smad2、Smad3的C-末端[47-49].
肖永陶等[9]通过体外研究显示, TGF-β1介导的EMT为克罗恩病肠道发生纤维化的发病机制. Meares等[50]观察到TGF-β上调锌指结合蛋白的启动子E-box(ZEB1、ZEB2), 激活通路信号中的RNA进而抑制细胞发生EMT过程. Zhang等[51]藉由葡萄糖调节蛋白78(glucose regulated protein 78, GRP78)研究TGF-β1-Smad2/3通路机制, 证明此通路可使细胞基质黏附力下降, 最终导致EMT发生; 同时也证明TGF-β是此通路信号传导的重要启动因子, Snail与磷酸化的Smad2/3相互作用, 是此通路信号向下游传导信号的关键环节; 活化后的Smad2、Smad3与细胞质中的Smad4结合成异三聚体或四聚体, 并进入细胞核, Snail识别其基因序列形成Snail-Smad3/4转录复合物, 再与Snail所主导的靶目标E-cadherin等启动子区相结合, 抑制这些基因转录, 促使EMT的发生.在实验性小鼠肠炎模型制备当中, 发现TGF-β可通过激活此途径, 其自身也可分泌细胞因子, 直接刺激成纤维细胞分泌ECM, ECM的异常增多与积聚, 最终形成EMT[7]. 有研究表明[52], 克罗恩并发肠瘘患者肠道中的成纤维细胞, 可分泌细胞因子并诱导TGF-β1大量表达, 进而增加Snail转录, 引起EMT的发生. 同时还发现导致克罗恩病肠瘘的原因, 是在瘘道及其周围发生纤维化的组织中, Snail的高表达引发EMT所致. Ozawa等[53]在重组酶系统实验中观察到, 伴随着切除Snail-loxp, E-cadherin和闭锁蛋白表达恢复, N-cadherin和纤维连接蛋白表达缺失, 上皮细胞功能作用正常, Chen等[54]透过对TGF-β/Snail通路的反证实验, 被敲除Snail蛋白的细胞基因, 在TGF-β高水平表达的环境下, 无法加速推进EMT进程.以上研究皆证明通过调控Snail可使其诱导的EMT过程逆转.
Snail属于锌指蛋白家族, 因其特殊的锌指结构域, 可由其C-末端的DNA连接凹槽, 与含有特定DNA序列(CAGGTG核心碱基序列)的启动子E-box结合[55]. 而E-cadherin含有两个CAGGTG核心碱基序列的启动子E-box, 故其被认为是Snail的直接靶基因, 而此区域是主要的转录功能被抑制的结合位点[56]. 有研究[57]显示, 克罗恩病在发生EMT时, 对E-cadherin基因的抑制不仅仅是Snail的直接作用, 而且β-catenin发生磷酸化, 降解细胞间的钙黏蛋白与肌动蛋白的复合物, 使E-cadherin功能无法正常表达, 肠上皮细胞发生EMT转化[57]. 在Snail与E-cadherin结合过程中, 不仅仅黏附连接蛋白E-cadherin下调, Snail可以在基因转录和蛋白表达水平、启动子活性等等不同阶段, 对上皮细胞间的连接丧失作用. Snail的这种破坏作用, 可从对E-cadherin之类的黏附连接蛋白, 扩展到对闭合蛋白、封闭蛋白等之类的紧密连接蛋白[14]. Zha等[58]发现Snail可影响肌动蛋白的架构稳定性, 促使细胞迁移与骨架重组. Snail对这些蛋白的抑制机制虽不同, 但其最终均导致上皮细胞的顶-底极性丧失, 细胞间黏附力降低, 桥粒缺失, 细胞骨架破坏或重组, 角蛋白表达下调, 中间丝蛋白、纤维波形蛋白表达上调, 在细胞质中由中间丝建立起新的支撑架构[16,59]. Shirakihara等[56]研究表明, TNF-α-NF-κB-Snail和TGF-β1-Smads-Snail这两条途径的激活, 可促使细胞分离, 细胞伪足形成, 从而获得迁移、侵袭能力, 突破基底膜, 向炎症组织迁移, 导致EMT发生, 出现正常肠黏膜上皮向肠EMT的不可逆的恶性转化, 最终导致肠纤维化的发生.
转录因子Snail在EMT形成途径中的调控机制已日渐受到临床关注, 并有大量的临床与基础研究在展开[60], 目前认为转录因子Snail以其独特的生物学特性, 在器官/组织纤维化和肿瘤等疾病的EMT进程中扮演着重要的调控角色. 本文以Snail调控肠EMT为切入点, 对其在介导肠EMT的TNF-α-NF-κB-Snail和TGF-β1-Smads-Snail这两条途径中的调控机制的研究概况进行简要介绍, 虽然这部分研究工作较少, 尚处于起步阶段, 但随着今后对其调控EMT机制的不断深入研究, 必将会为临床防治肠EMT及肠纤维化提供新的思路和研究方向.
上皮间质转化(epithelial mesenchymal transition, EMT)是在生理或病理情况下发生的一种细胞迁移过程, 上皮细胞发生极化, 进而导致一系列生物学变化. 而在炎症性肠病中, 由于免疫反应的过度激活, 使肠道发生持续性炎症及组织异常修复的恶性循环, 这些细胞的迁移和渗透能力也发生了改变, 导致肠EMT的发生, 最终形成肠纤维化.
王晓娣, 主任医师, 中日友好医院消化内科
近来研究表明, Snail在器官或组织纤维化、肿瘤等疾病的肠EMT进程中是关键性的调控因子, 可使上皮标志物的特性消失, 转而表达间质细胞的特性, 并由此增强细胞的转移与侵袭能力.
肖永陶等通过体外研究显示, 转化生长因子β1(transforming growth factor β1, TGF-β1)介导的EMT为克罗恩病肠道发生纤维化的发病机制. 证明此通路可使细胞基质黏附力下降, 最终导致EMT发生; 同时也证明TGF-β1是此信号通路传导的重要启动因子.
本文以Snail调控肠EMT为切入点, 对其在介导肠EMT的肿瘤坏死因子α(tumor necrosis factor α, TNF-α)-核因子κB(nuclear factor κB, NF-κB)-Snail和TGF-β1-Smads-Snail这两条途径中的调控机制的研究概况进行简要介绍, 随着今后对其调控EMT机制的不断深入研究, 必将会为临床防治肠EMT及肠纤维化方面提供新的思路和研究方向.
转录因子Snail在EMT形成途径中的调控机制已日渐受到临床关注, 并有大量的临床与基础研究在展开, 目前认为转录因子Snail以其独特的生物学特性, 在器官/组织纤维化和肿瘤等疾病的EMT进程中扮演着重要的调控角色, 开展Snail的这方面研究将在今后防治器官/组织纤维化和肿瘤等疾病上具有广阔的应用前景.
本文作者对目前热点研究的EMT进行了综述, 为临床防治肠EMT及肠纤维化的研究提供新的思路和研究方向.
编辑:郭鹏 电编: 都珍珍
| 1. | Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420-1428. [PubMed] [DOI] |
| 2. | Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76-83. [PubMed] |
| 3. | Matsuzaki S, Darcha C. Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. Hum Reprod. 2012;27:712-721. [PubMed] [DOI] |
| 4. | Rönsch K, Jägle S, Rose K, Seidl M, Baumgartner F, Freihen V, Yousaf A, Metzger E, Lassmann S, Schüle R. SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer. Mol Oncol. 2015;9:335-354. [PubMed] [DOI] |
| 5. | Sipos F, Galamb O. Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon. World J Gastroenterol. 2012;18:601-608. [PubMed] [DOI] |
| 6. | Li H, Wang Z, Zhang W, Qian K, Xu W, Zhang S. Fbxw7 regulates tumor apoptosis, growth arrest and the epithelial-to-mesenchymal transition in part through the RhoA signaling pathway in gastric cancer. Cancer Lett. 2015; Oct 13. [Epub ahead of print]. [PubMed] [DOI] |
| 8. | Algeri M, Conforti A, Pitisci A, Starc N, Tomao L, Bernardo ME, Locatelli F. Mesenchymal stromal cells and chronic inflammatory bowel disease. Immunol Lett. 2015; Jul 10. [Epub ahead of print]. [PubMed] [DOI] |
| 10. | Motomura Y, Khan WI, El-Sharkawy RT, Verma-Gandhu M, Verdu EF, Gauldie J, Collins SM. Induction of a fibrogenic response in mouse colon by overexpression of monocyte chemoattractant protein 1. Gut. 2006;55:662-670. [PubMed] |
| 11. | Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3:155-166. [PubMed] |
| 12. | Berg JM, Shi Y. The galvanization of biology: a growing appreciation for the roles of zinc. Science. 1996;271:1081-1085. [PubMed] |
| 14. | Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003;116:1959-1967. [PubMed] |
| 15. | Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B, Barsky SH. ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene. 2010;29:1451-1462. [PubMed] [DOI] |
| 16. | Pérez-Mancera PA, González-Herrero I, Pérez-Caro M, Gutiérrez-Cianca N, Flores T, Gutiérrez-Adán A, Pintado B, Sánchez-Martín M, Sánchez-García I. SLUG in cancer development. Oncogene. 2005;24:3073-3082. [PubMed] |
| 17. | Fritzenwanker JH, Saina M, Technau U. Analysis of forkhead and snail expression reveals epithelial-mesenchymal transitions during embryonic and larval development of Nematostella vectensis. Dev Biol. 2004;275:389-402. [PubMed] |
| 18. | Locascio A, Vega S, de Frutos CA, Manzanares M, Nieto MA. Biological potential of a functional human SNAIL retrogene. J Biol Chem. 2002;277:38803-38809. [PubMed] |
| 19. | Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene. 2005;24:7443-7454. [PubMed] |
| 20. | Boutet A, Esteban MA, Maxwell PH, Nieto MA. Reactivation of Snail genes in renal fibrosis and carcinomas: a process of reversed embryogenesis? Cell Cycle. 2007;6:638-642. [PubMed] |
| 21. | Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15:117-134. [PubMed] [DOI] |
| 22. | Vetter G, Le Béchec A, Muller J, Muller A, Moes M, Yatskou M, Al Tanoury Z, Poch O, Vallar L, Friederich E. Time-resolved analysis of transcriptional events during SNAI1-triggered epithelial to mesenchymal transition. Biochem Biophys Res Commun. 2009;385:485-491. [PubMed] [DOI] |
| 23. | Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004;6:931-940. [PubMed] |
| 24. | Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A. 2008;105:6392-6397. [PubMed] [DOI] |
| 25. | He KL, Ting AT. A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. Mol Cell Biol. 2002;22:6034-6045. [PubMed] |
| 26. | Abraham E. Nuclear factor-kappaB and its role in sepsis-associated organ failure. J Infect Dis. 2003;187 Suppl 2:S364-S369. [PubMed] |
| 27. | Berndt U, Bartsch S, Philipsen L, Danese S, Wiedenmann B, Dignass AU, Hämmerle M, Sturm A. Proteomic analysis of the inflamed intestinal mucosa reveals distinctive immune response profiles in Crohn's disease and ulcerative colitis. J Immunol. 2007;179:295-304. [PubMed] |
| 28. | Zheng H, Shen M, Zha YL, Li W, Wei Y, Blanco MA, Ren G, Zhou T, Storz P, Wang HY. PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis. Cancer Cell. 2014;26:358-373. [PubMed] [DOI] |
| 29. | Bonavida B, Baritaki S. Dual role of NO donors in the reversal of tumor cell resistance and EMT: Downregulation of the NF-κB/Snail/YY1/RKIP circuitry. Nitric Oxide. 2011;24:1-7. [PubMed] [DOI] |
| 30. | Lin CY, Tsai PH, Kandaswami CC, Chang GD, Cheng CH, Huang CJ, Lee PP, Hwang JJ, Lee MT. Role of tissue transglutaminase 2 in the acquisition of a mesenchymal-like phenotype in highly invasive A431 tumor cells. Mol Cancer. 2011;10:87. [PubMed] [DOI] |
| 31. | Cheon MG, Kim W, Choi M, Kim JE. AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells. Cancer Lett. 2015;356:637-645. [PubMed] [DOI] |
| 32. | Flier SN, Tanjore H, Kokkotou EG, Sugimoto H, Zeisberg M, Kalluri R. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J Biol Chem. 2010;285:20202-20212. [PubMed] [DOI] |
| 33. | Bataille F, Rohrmeier C, Bates R, Weber A, Rieder F, Brenmoehl J, Strauch U, Farkas S, Fürst A, Hofstädter F. Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn's disease. Inflamm Bowel Dis. 2008;14:1514-1527. [PubMed] [DOI] |
| 34. | Cheng CW, Wu PE, Yu JC, Huang CS, Yue CT, Wu CW, Shen CY. Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene. Oncogene. 2001;20:3814-3823. [PubMed] |
| 35. | Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001;7:1267-1278. [PubMed] |
| 36. | Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84-89. [PubMed] |
| 37. | Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68:3645-3654. [PubMed] [DOI] |
| 38. | Ray ME, Mehra R, Sandler HM, Daignault S, Shah RB. E-cadherin protein expression predicts prostate cancer salvage radiotherapy outcomes. J Urol. 2006;176:1409-1414; discussion 1414. [PubMed] |
| 39. | Rodrigo I, Cato AC, Cano A. Regulation of E-cadherin gene expression during tumor progression: the role of a new Ets-binding site and the E-pal element. Exp Cell Res. 1999;248:358-371. [PubMed] |
| 41. | Olmeda D, Jordá M, Peinado H, Fabra A, Cano A. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene. 2007;26:1862-1874. [PubMed] |
| 42. | 周 传文, 李 倩君. 锌指转录因子snai1高表达质粒构建和稳定株的筛选. 中国组织工程研究与临床康复. 2010;14:7687-7690. |
| 43. | Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178-196. [PubMed] [DOI] |
| 44. | Triolo D, Dina G, Taveggia C, Vaccari I, Porrello E, Rivellini C, Domi T, La Marca R, Cerri F, Bolino A. Vimentin regulates peripheral nerve myelination. Development. 2012;139:1359-1367. [PubMed] [DOI] |
| 45. | Cao YW, Wan GX, Sun JP, Cui XB, Hu JM, Liang WH, Zheng YQ, Li WQ, Li F. Implications of the Notch1-Snail/Slug-epithelial to mesenchymal transition axis for lymph node metastasis in infiltrating ductal carcinoma. Kaohsiung J Med Sci. 2015;31:70-76. [PubMed] [DOI] |
| 46. | Massagué J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-791. [PubMed] |
| 47. | Ben-David H, Aruna BV, Seger R, Sela M, Mozes E. A 50-kDa ERK-like protein is up-regulated by a dual altered peptide ligand that suppresses myasthenia gravis-associated responses. Proc Natl Acad Sci U S A. 2006;103:18232-18237. [PubMed] |
| 48. | Yang YC, Piek E, Zavadil J, Liang D, Xie D, Heyer J, Pavlidis P, Kucherlapati R, Roberts AB, Böttinger EP. Hierarchical model of gene regulation by transforming growth factor beta. Proc Natl Acad Sci U S A. 2003;100:10269-10274. [PubMed] |
| 49. | Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666-681. [PubMed] [DOI] |
| 50. | Meares GP, Jope RS. Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis. J Biol Chem. 2007;282:16989-17001. [PubMed] |
| 51. | Zhang L, Li Z, Fan Y, Li H, Li Z, Li Y. Overexpressed GRP78 affects EMT and cell-matrix adhesion via autocrine TGF-β/Smad2/3 signaling. Int J Biochem Cell Biol. 2015;64:202-211. [PubMed] [DOI] |
| 52. | Sullivan DE, Ferris M, Pociask D, Brody AR. Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal-regulated kinase pathway. Am J Respir Cell Mol Biol. 2005;32:342-349. [PubMed] |
| 53. | Ozawa M, Kobayashi W. Reversibility of the Snail-induced epithelial-mesenchymal transition revealed by the Cre-loxP system. Biochem Biophys Res Commun. 2015;458:608-613. [PubMed] [DOI] |
| 54. | Chen XH, Liu ZC, Zhang G, Wei W, Wang XX, Wang H, Ke HP, Zhang F, Wang HS, Cai SH. TGF-β and EGF induced HLA-I downregulation is associated with epithelial-mesenchymal transition (EMT) through upregulation of snail in prostate cancer cells. Mol Immunol. 2015;65:34-42. [PubMed] [DOI] |
| 55. | Twigg SR, Wilkie AO. Characterisation of the human snail (SNAI1) gene and exclusion as a major disease gene in craniosynostosis. Hum Genet. 1999;105:320-326. [PubMed] |
| 56. | Shirakihara T, Saitoh M, Miyazono K. Differential regulation of epithelial and mesenchymal markers by deltaEF1 proteins in epithelial mesenchymal transition induced by TGF-beta. Mol Biol Cell. 2007;18:3533-3544. [PubMed] |
| 57. | Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol. 2005;6:622-634. [PubMed] |
| 58. | Zha YH, Mei YW, Mao L, He JF, Yin T, Zhang L, Wang QS. [The advantages for Snail expression to promote cell migration and induce actin reorganization and to protect against the serum-deprivation-triggered apoptosis of bone marrow stem cells]. Shengwu Gongcheng Xuebao. 2007;23:645-651. [PubMed] |
| 59. | Humtsoe JO, Koya E, Pham E, Aramoto T, Zuo J, Ishikawa T, Kramer RH. Transcriptional profiling identifies upregulated genes following induction of epithelial-mesenchymal transition in squamous carcinoma cells. Exp Cell Res. 2012;318:379-390. [PubMed] [DOI] |
| 60. | Rodansky ES, Johnson LA, Huang S, Spence JR, Higgins PD. Intestinal organoids: a model of intestinal fibrosis for evaluating anti-fibrotic drugs. Exp Mol Pathol. 2015;98:346-351. [PubMed] [DOI] |