BP Bioprocess 2164-5566 Scientific Research Publishing 10.12677/BP.2022.121002 BP-49526 BP20220100000_28300276.pdf 生命科学 E-Cadherin的表达调控及对细胞增殖的影响 Regulation of E-Cadherin Expression and Effects on Cell Proliferation 王 冬杨 2 1 吴 玉青 2 1 应 方莉 2 1 曹 诣斌 2 1 浙江师范大学，化学与生命科学学院，浙江 金华 null 22 03 2022 12 01 10 19 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

E-钙粘蛋白(E-cadherin)主要在上皮细胞膜上表达，发挥细胞间粘附作用并抑制入侵，其在细胞增殖的过程中也扮演着重要角色，主要通过Wnt，Hippo信号通路及Rho家族的小GTPases影响上皮细胞的增殖。E-cadherin在细胞膜上的稳定性和准确的功能通过与连环蛋白(catenin, CAT)形成稳定的复合物来实现。E-cadherin功能缺失在癌症细胞中被发现，其表达失调主要发生在表观遗传学水平。E-cadherin表达水平下降与肿瘤的出现、分化、侵入和运动转移等密切相关。本文主要介绍了E-cadherin对细胞增殖的影响，分析了其在肿瘤发生和发展过程中调节细胞增殖、侵袭和细胞内信号传导的一些分子机制。 E-cadherin is mainly expressed on epithelial cell membranes, plays an intercellular adhesion and inhibits invasion, which also plays an important role in cell proliferation, mainly affecting epithelial cell proliferation through Wnt, Hippo signaling pathways and small GTPases of the Rho family. The stability and accurate function of E-cadherin at the cell membrane is achieved by forming a stable complex with catenin (CAT). Loss of E-cadherin function has been found in cancer cells, and its dysregulation mainly occurs at the epigenetic level. The decreased expression level of E-cadherin is closely related to the emergence, differentiation, invasion and movement metastasis of tumors. This paper mainly introduces the effect of E-cadherin on cell proliferation and analyzes some of the molecular mechanisms by which it regulates cell proliferation, invasion and intracellular signaling during tumorigenesis and development.

 E-Cadherin，CAT，细胞增殖，转录调控，癌症, E-Cadherin CAT Cell Proliferation Transcriptional Regulation Cancer 摘要

E-钙粘蛋白(E-cadherin)主要在上皮细胞膜上表达，发挥细胞间粘附作用并抑制入侵，其在细胞增殖的过程中也扮演着重要角色，主要通过Wnt，Hippo信号通路及Rho家族的小GTPases影响上皮细胞的增殖。E-cadherin在细胞膜上的稳定性和准确的功能通过与连环蛋白(catenin, CAT)形成稳定的复合物来实现。E-cadherin功能缺失在癌症细胞中被发现，其表达失调主要发生在表观遗传学水平。E-cadherin表达水平下降与肿瘤的出现、分化、侵入和运动转移等密切相关。本文主要介绍了E-cadherin对细胞增殖的影响，分析了其在肿瘤发生和发展过程中调节细胞增殖、侵袭和细胞内信号传导的一些分子机制。

 关键词

E-Cadherin，CAT，细胞增殖，转录调控，癌症

 Regulation of E-Cadherin Expression and Effects on Cell Proliferation<sup> </sup>

Dongyang Wong, Yuqing Wu, Fangli Ying, Yibin Cao*

College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua Zhejiang

Received: Feb. 22nd, 2022; accepted: Mar. 15th, 2022; published: Mar. 22nd, 2022

 ABSTRACT

E-cadherin is mainly expressed on epithelial cell membranes, plays an intercellular adhesion and inhibits invasion, which also plays an important role in cell proliferation, mainly affecting epithelial cell proliferation through Wnt, Hippo signaling pathways and small GTPases of the Rho family. The stability and accurate function of E-cadherin at the cell membrane is achieved by forming a stable complex with catenin (CAT). Loss of E-cadherin function has been found in cancer cells, and its dysregulation mainly occurs at the epigenetic level. The decreased expression level of E-cadherin is closely related to the emergence, differentiation, invasion and movement metastasis of tumors. This paper mainly introduces the effect of E-cadherin on cell proliferation and analyzes some of the molecular mechanisms by which it regulates cell proliferation, invasion and intracellular signaling during tumorigenesis and development.

Keywords:E-Cadherin, CAT, Cell Proliferation, Transcriptional Regulation, Cancer

Copyright © 2022 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

E-cadherin是一种跨膜糖蛋白，在粘附连接处将上皮细胞连接在一起，维持其正常的形态和极性。在正常上皮组织中E-cadherin高表达，β-catenin在细胞膜上被隔离，阻止其释放到细胞质并进入细胞核 [ 1 ]，阻止了β-catenin与细胞核中DNA结合蛋白家族LEF (淋巴增强因子)/TCF (T细胞因子)的成员结合。因此，Wnt信号通路没有被激活，癌症的发生被阻止 [ 2 ]。已有研究证明，Wnt基因和Wnt信号通路的其他成分可导致癌症 [ 3 ]。同时有研究表明，Hippo信号通路是E-cadherin依赖性抑制增殖所必需的。Hippo信号成分可不依赖于其他细胞间的相互作用调控E-cadherin在细胞表面的亲和性结合，可作为哺乳动物细胞中Hippo信号传导途径的上游调节剂起作用。在多种肿瘤细胞中发现E-cadherin表达水平下降，在此过程中肿瘤细胞发生上皮–间质转化(epithelial-mesenchymal transition, EMT)，以此完成细胞转移。导致癌变的E-cadherin表达失调主要发生在表观遗传学水平。E-cadherin的表达与细胞的侵袭力降低、生长抑制、凋亡、细胞周期阻滞和分化有关。最近有研究表明，E-cadherin在各种癌症中的相关性迅速增加。本文综述了E-cadherin及其下游信号在细胞增殖调节和癌症发生发展中的作用。

 2. E-Cadherin的结构与功能

钙粘蛋白代表了一个独特的单跨膜结构域糖蛋白家族，通过其NH2-末端胞外域的同质相互作用介导钙依赖性的细胞–细胞粘附 [ 4 ]。其中E-钙粘蛋白(E-cadherin)是分布在上皮组织中的钙依赖性单次跨膜糖蛋白，由CDH1基因编码，分子量约为120 kD，基因定位于16q22.1，含有16个外显子和15个内含子，能够编码含884个氨基酸的多肽，在AJ (粘附连接)结构和功能的维持中起主导作用 [ 5 ]，对抑制单个上皮细胞的运动和提供稳态组织结构至关重要。E-cadherin由一个较大的胞外域、一个跨膜区、一个保守的胞内域组成 [ 6 ]。胞外域有5个钙黏蛋白胞外重复结构域(EC1-EC5)，且与钙离子(Ca2+)结合形成刚性线性分子。钙黏蛋白分子在相邻细胞间形成一个拉链状结构，强化了相邻细胞间的粘附作用，参与形成细胞间粘附连接、维持细胞极性和组织完整性(如图1) [ 7 ]。E-cadherin的胞内域和连环蛋白(catenin, CAT)以及actin结合蛋白相互作用，使得cadherin-catenin复合物锚定于actin细胞骨架。其中α-catenin连接E-cadherin与肌动蛋白细胞骨架，部分β-catenin和γ-catenin可以与T细胞因子家族的转录因子结合，并促进其转录活性。通过控制细胞质内β-catenin的数量，E-cadherin可以调节细胞死亡/增殖过程中关键基因如cyclin D1和c-myc的表达 [ 8 ]，在细胞膜上的稳定性和准确的功能通过与细胞质p120ctn [ 9 ] 的结合来实现。

图1. 细胞粘附连接

E-cadherin通过调节Ca2+依赖性细胞之间的黏合，在发育、细胞极化和组织形成等方面来维持上皮表型 [ 10 ]。在发育的早期阶段，细胞保留E-cadherin和粘附连接，并在维持组织稳态、调节上皮细胞通透性和屏障功能中发挥关键。在乳腺癌、胃癌、口腔癌、肝细胞癌和肺癌等肿瘤的研究中发现，E-cadherin表达降低与肿瘤的发生、分化、侵袭、转移和预后密切相关 [ 11 ]。事实上，E-cadherin介导的细胞黏附的去调节是上皮细胞向间质转化(EMT)过程中的一个关键步骤，在这个过程中，接触抑制的丧失与促进细胞增殖与侵袭有关 [ 12 ] [ 13 ]。

 3. E-Cadherin与连环蛋白

E-cadherin的胞内肽段与一组称为连环蛋白(catenin, CAT)的细胞骨架蛋白结合，参与细胞信号转导、组织形态发生和胚胎发育等过程。E-cadherin与上皮细胞的连接粘着密切相关，其表达水平的下降是上皮细胞离散的分子基础。β-catenin和γ-catenin以互斥的方式直接与E-cadherin的COOH-末端结构域相互作用，并且这两种蛋白质都与α-catenin相关联，后者将钙粘蛋白复合物连接到肌动蛋白细胞骨架并介导稳定的细胞粘附。β-catenin是上皮细胞中E-cadherin介导的细胞粘附所必需的，与细胞粘附密切相关，它是细胞内可溶性蛋白，基因定位于3p21.3p22染色体上，共有16个外显子，是一种具有多种功能的蛋白质。一方面，β-catenin可与E-cadherin和α-catenin结合形成复合物与细胞骨架相连，稳定细胞连接。因而，当这种结合型β-catenin比例增多时，细胞所具有的黏附功能就会增强。另一方面，胞质中的β-catenin作为Wnt信号通路的关键信号分子，在细胞信号转导通路上与多种T细胞转录因子相互作用调节基因转录，除了其粘附功能外，β-catenin还被发现在胚胎发育和成体组织稳态过程中作为信号传递过程的关键组成部分 [ 14 ]。

p120ctn是另一个连环蛋白家族成员 [ 15 ]，它与E-cadherin的细胞质近膜部分结合并影响E-钙粘蛋白聚集和粘合强度。p120ctn与膜旁结构域结合 [ 16 ] [ 17 ]，对钙粘蛋白的稳定性和转换至关重要。Soto [ 18 ] 等人研究发现p120ctn在乳腺肿瘤细胞的转化生长中具有双重作用。E-cadherin正常表达时p120ctn可稳定E-cadherin复合物并促进其抑瘤功能，有效抑制Ras的激活。当E-cadherin在肿瘤进展过程中丢失时，Ras的负调控被解除，内源性p120ctn通过激活Rac1以及随后的Raf和MEK的磷酸化来诱导转化细胞的生长。

 4. E-Cadherin通过信号通路影响细胞增殖

E-cadherin是主要的钙粘蛋白分子，不仅通过其粘附结合活性，而且通过其信号转导活性调节细胞生长。E-cadherin参与多种信号通路调节细胞增殖、侵袭和细胞内信号传导，包括Wnt信号通过β-catenin、PI3K和MAPK的核定位响应EGF配体和生长因子，以及Hippo信号通路 [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ]。

4.1. E-Cadherin与Wnt/β-Catenin信号途径

Wnt信号通路家族广泛存在无脊椎动物和脊椎动物中，是一类高度保守的信号通路，其对于维持组织发育的内稳态具有重要作用。至今，共有3种类型的Wnt通路被发现。其一是Wnt/β-catenin通路，主要通过β-catenin激活基因转录；其二是Wnt/PCR途径，通过小G蛋白激活JNK来调控细胞骨架重排；其三是Wnt/Ca2+途径，通过释放胞内Wnt/Ca2+来影响细胞粘连和相关基因的表达 [ 24 ]。其中Wnt/β-catenin通路又称经典Wnt通路，是目前研究最为广泛的通路。

Wnt/β-catenin信号通路存在抑制(off)与激活(on)两种状态，β-catenin在其中起关键调节作用。在缺少Wnt配体时，通路处于抑制状态。β-catenin与细胞表面的E-cadherin发生反应，形成稳定复合物并与肌动蛋白联结。进入细胞内部的β-catenin，与APC、axin2、GSK-3β等蛋白形成复合物，继而通过泛素化与磷酸化被降解。细胞核内，转录因子TCF与其抑制蛋白结合，从而抑制目标基因的转录与表达。当Wnt信号存在，Wnt与其受体卷曲蛋白(Frz)特异性结合后，通路被激活。Frz作用于胞质内的蓬乱蛋白(Dishevelled, Dsh或Dvl)，该蛋白抑制GSK-3β活性，阻断β-catenin的降解途径，使细胞内游离的β-catenin含量上升并在核内积累，与T细胞因子/淋巴增强因子复合物(TCF/LEF)家族转录因子形成复合物以激活Wnt靶基因(如c-myc和cyclinD1等)的转录与表达 [ 25 ]。E-cadherin表达水平上升可以引起β-catenin与细胞表面的E-cadherin结合量增多，胞质β-catenin水平降低，最后抑制细胞增殖 [ 26 ] (如图2)。可见E-cadherin的表达水平变化对Wnt/β-catenin途径有调控作用。

图2. E-cadherin与Wnt信号通路

 4.2. E-Cadherin与Hippo信号途径

Hippo信号通路是一种由一系列的激酶组成的细胞传导通路，该通路在调节动物器官大小、限制细胞的增殖以及诱导细胞凋亡等方面发挥着关键性的作用 [ 27 ]。Hippo信号通路由上游调节分子、核心分子和下游效应分子组成，在哺乳动物中，该信号通路主要包括Ste-20样激酶1、大肿瘤抑制因子1以及具有PDZ结合域的转录共活化因子(TAZ)和Yes相关蛋白(YAP)等，其中MST和LATS属于抑癌基因，起抑制细胞过度增殖的作用，而TAZ和YAP属于促癌基因，起促进细胞增殖、抑制细胞凋亡的作用 [ 28 ]。Hippo通路存在活性和失活两种状态，且可被多种异常信号激活。当Hippo信号通路处于活性状态时，MST1/2发生磷酸化后激活LATS1/2，继而磷酸化YAP/TAZ，使其失活被抑制，积聚在细胞质中；当Hippo信号通路处于失活状态时，YAP/TAZ去磷酸化后移至细胞核内作用于目的基因，促进其转录和表达 [ 29 ] (如图3) [ 21 ]。

图3. E-cadherin与Hippo信号通路

研究表明，Hippo信号通路是E-cadherin依赖性接触抑制增殖所必需的。敲低Hippo信号成分或过度表达YAP可抑制E-cadherin在细胞表面的亲和性结合，导致细胞增殖减少，而这并不依赖于其他细胞间的相互作用，说明E-cadherin/catenin复合物也可作为哺乳动物细胞中Hippo信号传导途径的上游调节剂起作用 [ 21 ]。同样，Benham-Pyle等发现E-cadherin胞外功能域的相互交联，通过将YAP1滞留于细胞质，可以阻止静默细胞重新进入细胞周期 [ 30 ]。

 4.3. E-Cadherin 和Rho GTPases

另一类在细胞表面被E-cadherin结合调控的信号分子是Rho家族的小GTPases (Rho, Rac，和Cdc42) [ 31 ]。Rho GTPases以其活性GTP结合形式与调控肌动蛋白聚合、细胞运动和基因表达的靶蛋白相互作用并将其激活，它们在AJs的组装和维护中发挥重要作用，并在生长因子和机械刺激下促进肌动蛋白细胞骨架的重塑 [ 31 ]。转化细胞中这些小GTPases的失调已被证明会干扰Cadherin的功能和促进肿瘤发生。例如，非小细胞肺癌中的E-cadherin表达通过降低RhoA或Cdc42的水平改变细胞增殖和迁移 [ 32 ]。在AJs组装效率低下的Ras转化细胞中，Rac激活剂Tiam1的表达可以恢复AJ组装和上皮形态，减少细胞迁移和侵袭 [ 33 ]。

 5. E-Cadherin的表达调控与癌症发生

除了在细胞间粘附中的作用外，E-cadherin还参与了癌症发生过程中的许多信号通路。由于上皮细胞中E-cadherin的下调导致细胞极性降低，迁移和侵袭特性增加，E-钙粘蛋白的缺失刺激启动上皮-间充质转化(EMT)的活性信号 [ 34 ]。

在胚胎发育过程中，E-cadherin的表达早在两个细胞阶段就开始了 [ 35 ]，在卵裂球的粘附和早期胚胎的致密化中起着重要作用 [ 36 ]，如果缺乏E-cadherin胚胎不能极化、致密和形成滋养外胚层上皮 [ 2 ]。桑椹胚致密化是由E-cadherin介导的丝状伪足粘附和肌球蛋白诱导的其对邻近卵裂球的牵引引起的 [ 37 ]。在胚泡形成过程中，这种E-cadherin介导的粘附被原蛋白转化酶7 (PC7)和相关的PCs、Furin和Pace4调节 [ 38 ]。

E-cadherin基因的可逆和不可逆丢失在癌症的进展中都很重要。已知启动子超甲基化会导致许多基因的转录下调，包括E-cadherin基因 [ 39 ]。这一发现表明E-cadherin启动子可以部分甲基化。一般来说，E-cadherin启动子片段的甲基化图谱包含未甲基化或部分甲基化的CpG岛。据报道，通过转录沉默改变E-cadherin的表达也会导致E-cadherin的表达降低 [ 40 ]。这种转录沉默是由一类锌指结合蛋白介导的，这些蛋白靶向E-cadherin的启动子区域并抑制其表达。据报道，锌指转录因子如Snail/Slug在晚期癌症中过度表达 [ 41 ]，这些转录因子在上皮–间质转化(EMT)过程中的胚胎发育中非常重要，此时的E-cadherin表达丢失。

5.1. 通过启动子高甲基化和组蛋白尾部修饰实现转录去调控

启动子超甲基化是将甲基添加到胞嘧啶核苷酸的第五个碳上以生成5-甲基-胞嘧啶的过程，该过程经常发生在肿瘤抑制基因启动子区域中致密CpG二核苷酸区域。已知启动子超甲基化会导致许多基因的转录下调，包括E-cadherin基因 [ 39 ]。这一发现表明E-cadherin启动子可以部分甲基化。一般来说，E-cadherin启动子片段的甲基化图谱包含未甲基化或部分甲基化的CpG岛。有报道称，丙型肝炎病毒和EB病毒等外部病原体分别诱导肝细胞和鼻咽癌中E-cadherin启动子的高甲基化 [ 42 ] [ 43 ]。因此，通过启动子去甲基化激活E-cadherin转录表达可能是一种理想的肿瘤治疗方法。saRNAs可诱导组蛋白去甲基化，导致转录基因激活。有研究发现saRNA可通过上调人类膀胱癌细胞中的p21WAF1⁄CIP1(p21)和E-cadherin来抑制细胞增殖和活力 [ 44 ] [ 45 ] [ 46 ]。

组蛋白突出的N-末端和C-末端也可以进行翻译后修饰(PTM)，为各种共价组蛋白修饰提供空间，这些修饰包括甲基化、乙酰化、磷酸化和磺酰化等 [ 47 ]。组蛋白尾部翻译后修饰压缩(异染色质)或松散(常染色质)染色质结构，分别引起基因的抑制或激活 [ 48 ] [ 49 ]。这些组蛋白PTMs的失调与E-cadherin阻遏物的表达相结合，有致癌作用。异常上调的E-cadherin抑制因子Snail通过乳腺癌中组蛋白H3上第9位赖氨酸甲基化(H3K9me3)介导E-cadherin启动子的甲基化，抑制其表达 [ 50 ]。ZEB1和ZEB2，另两种E-cadherin抑制因子，可募集组蛋白去乙酰化酶(HDAC)，诱导组蛋白去乙酰化 [ 51 ]。表明E-cadherin的抑制是通过其抑制因子与启动子区域的结合，导致异染色质的表观遗传变化，从而阻止其转录。

 5.2. 通过抑制因子解除转录调控

通过转录沉默也会导致E-cadherin的表达降低 [ 40 ]。这种转录沉默是由一类锌指结合蛋白介导的，这些锌指转录因子靶向E-cadherin的启动子区域并抑制其表达，位于CDH1启动子中的两个保守的E-box元件是必不可少的，因为大多数E-cadherin抑制因子，如 Snail1、Snail2/Slug、Twist、ZEB1和ZEB2与之结合并发挥抑制作用 [ 52 ] [ 53 ]。这个过程通过诱导EMT途径及促进肿瘤存活和耐药性来诱导癌症发生 [ 40 ]。另一方面，FOXA2将辅助抑制因子TLE3募集到ZEB2的启动子，而转录因子KLF4与ZEB2竞争启动子结合位点，ZEB2的表达水平必须超过KLF4，才能打破平衡，使CDH1受到抑制 [ 54 ] [ 55 ]。此外，继发性转移瘤的肿瘤物理微环境也通过缺氧激活的低氧诱导因子-1 (HIF-1)、过氧化物酶体增殖物激活的受体-γ (PPAR-γ)以及转录激活因子(Grhl3 and Hnf4α)与增强子区域结合增加而上调E-cadherin的转录 [ 56 ]。

 5.3. 通过MicroRNAs进行转录后调控

转录后水平的基因调控主要以miRNAs的作用为特征，miRNAs是由20~22个核苷酸(nt)组成的短非编码RNA，通过将它们的种子序列(5’端2-8nt)与常位于靶mRNA的3’端非翻译区的互补列配对，这种配对导致靶mRNA的降解和/或翻译过程的抑制。E-cadherin也属于miRNAs的复杂调控范围。通常，上调E-cadherin的miRNAs可维持细胞的上皮状态，阻碍EMT过程并抑制细胞的侵袭。有研究发现，miRNA-26a可通过抑制E-cadherin的抑制因子来阻止EMT过程 [ 57 ]。相反，靶向阳性EMT调节因子的miRNAs下调时，会促进细胞的EMT过程、侵袭性和致瘤性。例如，ZEB1抑制miR-200并去阻遏其靶标V-Crk禽肉瘤病毒CT10癌基因同源物的表达，激活细胞外基质依赖性β1-整联蛋白/粘着斑激酶信号通路，从而促进肺癌细胞的侵袭和转移 [ 58 ]。

E-cadherin调节性miRNA也可根据肿瘤类型和环境充当致癌或肿瘤抑制性调节实体。例如，在食管鳞状上皮癌细胞中，miRNA-9的过表达下调E-cadherin的表达，刺激β-cadherin核易位，随后启动EMT过程，从而增强或诱导转移 [ 59 ]。相反，miRNA-9通过NF-κB1-Snail1途径阻碍E-cadherin抑制因子Snail1的表达以上调E-cadherin的表达，抑制黑色素瘤癌症的进展 [ 60 ]。

 6. 总结与展望

综上所述，E-cadherin不仅是物理上将上皮细胞结合在一起的粘附蛋白，也是一种调节细胞播散、分化、周期进展及命运(生长/死亡)的分子。E-cadherin通过Wnt，Hippo信号通路及Rho家族的小GTPases在细胞增殖调节中起重要作用，这些过程是否协同工作，以及怎样防止该途径被抑制仍有待解决。同时E-cadherin是一种肿瘤抑制蛋白，在调节多种生理功能方面起着至关重要的作用，这些功能的失调可能导致癌症的发生。在一些癌症中，E-cadherin表达的缺失几乎总是促使肿瘤细胞通过EMT转化为侵袭性更强、分化程度更低的状态。检测E-cadherin的表达及基因的异常对于癌症的临床诊断、预后和治疗是一个很有希望的应用。E-cadherin是单一的生物标记物，与其它关键分子结合是否能提高其在癌症诊断和预后方面的敏感性和特异性，还有待研究，这些领域的进展带来了新的机遇和挑战，许多问题有待解决，很多东西仍需要学习。

 文章引用

王冬杨,吴玉青,应方莉,曹诣斌. E-Cadherin的表达调控及对细胞增殖的影响 Regulation of E-Cadherin Expression and Effects on Cell Proliferation[J]. 生物过程, 2022, 12(01): 10-19. https://doi.org/10.12677/BP.2022.121002

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