修回日期: 2022-05-31
接受日期: 2022-07-26
在线出版日期: 2022-08-08
紧密连接蛋白Claudin-3是紧密连接蛋白家族Claudins的重要成员之一, 是肝胆系统中含量最多的紧密连接蛋白. 在构建肝胆管细胞紧密连接、维持细胞屏障功能和分子传递功能等方面发挥重要的作用. 肝脏Claudin-3的表达失调会导致肝胆系统紧密连接破坏、代谢功能、屏障功能、增殖能力和分子传递功能受损, 与肝脏恶性肿瘤、胆固醇结石、慢性肝病等多种肝胆疾病的发生发展密切相关. 本文就Claudin-3在肝胆疾病中的研究进展进行综述.
核心提要: Claudin-3是机体紧密连接的重要组成部分, 也是肝脏中表达最高的紧密连接蛋白. 本文主要概述了Claudin-3在肝胆恶性肿瘤、胆固醇结石、慢性肝病等多种肝胆疾病中的作用, 在诊断、特异治疗和预后判断等方面有着广泛的应用前景.
引文著录: 许祖知, 费书珂. 紧密连接蛋白Claudin-3在肝胆疾病中的研究进展. 世界华人消化杂志 2022; 30(15): 668-673
Revised: May 31, 2022
Accepted: July 26, 2022
Published online: August 8, 2022
Claudin-3 is an important member of the claudin family of tight junction proteins and is the most abundant tight junction protein in the hepatobiliary system. It plays an important role in building tight junctions of hepatobiliary cells, and maintaining cellular barrier function and molecular delivery function. Dysregulation of hepatic claudin-3 expression leads to disruption of hepatobiliary system junctions, metabolic function, barrier function, proliferation capacity, and molecular delivery function, and is closely related to the development of various hepatobiliary diseases such as hepatic malignancies, cholesterol stones, and chronic liver diseases. In this paper, we review the progress in the research of claudin-3 in hepatobiliary diseases.
- Citation: Xu ZZ, Fei SK. Research progress of tight junction protein claudin-3 in hepatobiliary systemic diseases. Shijie Huaren Xiaohua Zazhi 2022; 30(15): 668-673
- URL: https://www.wjgnet.com/1009-3079/full/v30/i15/668.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i15.668
各种上皮细胞以及内皮细胞之间的相邻面主要由细胞连接构成, 这些细胞连接是细胞旁转运的重要组成部分, 除了维持细胞屏障的完整性, 还限制分子的细胞旁路转运, 其主要分为紧密连接(tight junction, TJ)、桥粒、中间连接和缝隙连接等. TJ是主要位于细胞膜最顶端的连接装置, 在细胞连接中占主要部分, 由3种跨膜蛋白, 紧密连接蛋白(Claudins)、闭合蛋白、连接黏附分子以及闭合小环蛋白ZO-1、ZO-2、ZO-3等组成, 其中主要结构为Claudins. 肝脏紧密连接主要由Claudin-1、-2、-3、-12和-25组成, 其中Claudin-3是肝胆系统中含量最多的紧密连接蛋白[1,2]. 肝脏Claudin-3的表达失调会导致肝胆系统中的紧密连接破坏, 代谢功能、屏障功能、增殖能力和分子传递功能受损, 与多种肝胆系统疾病的发生发展密切相关. 本文就Claudin-3在肝胆疾病中的研究进展进行综述.
Claudins由Furuse等[3]于1998年首次发现, 相对分子质量20 kDa-34 kDa, 是紧密连接中最重要的骨架蛋白, 也是紧密连接发挥维持细胞屏障完整性功能和限制物质运输的一个关键分子, 它的表达数量和分布结构的变化直接影响TJ的结构和功能. Claudins蛋白家族是一种至少拥有27个家族成员的蛋白[4], 根据功能的差异可将其分为两类[5]: 一类与形成屏障功能有关, 如Claudin-1、-3、-4和-5等; 另一类则与构成特定的通道有关, 可通过分子大小及电荷选择决定物质的细胞旁转运, 如 Claudin-2、-7、-10和-16等. Claudins是一种跨膜蛋白[6], 在结构上, Claudins由面向细胞质的N'末端、C'末端, 2个细胞外环、4个跨膜结构域组成, 其中面向胞浆的C'末端还含有由80-90个氨基酸残基组成的PDZ结构域, 它与ZO1、ZO2、ZO3和多PDZ结构域蛋白1(MUPP1)相互作用, 这是紧密连接蛋白复合体与其他多种蛋白的结合位点[7-9]. 在该结构域还包含与蛋白质翻译后修饰相关的氨基酸残基, 如丝氨酸-苏氨酸磷酸化、酪氨酸磷酸化、小泛素化(sumoylation, SUMO)化和棕榈酰化等, 这些都可能影响着Claudins的定位和功能[10-14]. 同时, Claudins调节相邻细胞的离子选择性主要是由于Claudins的细胞外环所携带的氨基酸的带电性质, 形成电荷选择性通道[15]. 例如, Claudin-2的过度表达显著增加了上皮细胞的离子电导, 形成阳离子选择性的细胞旁通道[16]. Claudin-1、-6、-9的细胞外链可能是丙型肝炎病毒的结合位点[17]. Claudin-1缺失可能导致罕见的遗传性疾病(新生儿鱼鳞病)和硬化性胆管炎, 由于紧密连接中Claudin-1的缺乏, 肝细胞和胆管细胞会出现胆汁的渗漏, 这会导致患者出现胆汁淤积, 谷草转氨酶(aspartate transaminase, AST)、谷丙转氨酶(alanine transaminase, ALT)、血清γ-谷氨酰转移酶活性和胆红素明显升高[18]. 而Claudin-3作为肝脏中表达最多的TJ蛋白, 主要在肝细胞和胆管细胞中表达[19]. 在先天性胆道闭锁的小儿患者中, 肝脏内的Claudin-3含量无明显变化, 而周围肝细胞和肝脏胆管管腔表面的Claudin-3排列明显紊乱[20]. 因此, Claudin-3在肝细胞和胆管细胞屏障功能、分泌功能、物质代谢等多个方面发挥重要作用, 进而影响肝脏生理, 一旦Claudin-3表达失调, 则会导致多种肝脏疾病的发生发展.
紧密连接蛋白Claudin-3定位于7q11.23, 是参与血脑屏障、肠道屏障、血睾屏障构成的重要组成部分[21]. 同时Claudin-3不仅在人体前列腺、胰腺细胞、肝细胞等多种腺细胞, 同时还在乳腺导管上皮、子宫内膜、食管黏膜、肺泡上皮、和胆管上皮细胞等多种上皮细胞内均有表达[2]. Claudin-3是TJ的主要跨膜蛋白之一, 是细胞间黏附功能的结构基础, 并在细胞间的传输转运中发挥着重要的接头作用. 除此之外, Claudin-3在维持上皮细胞极性、基因转录、抑制肿瘤、细胞增殖分化、新陈代谢相关的基因和炎症免疫反应等方面有着重大的作用. 上皮TJ蛋白组成的复杂变化会影响细胞极性, 如Claudin-3的减少与极性复合蛋白(partition defective-3, PAR-3)和丝氨酸/苏氨酸磷酸酶(protein phosphatase-1, PP-1)的定位和表达改变有关[22]. 有研究表明[23], Claudin-3在不同的肿瘤组织中表达不同, 作用也不尽相同. Claudin-3在乳腺癌、前列腺癌、卵巢癌、胃癌等肿瘤中表达增多, 而在结直肠癌、食管 癌等肿瘤中的表达则下降[24-29]. Claudin-3在胃癌组织中的表达高于癌旁正常组织, 但在胃癌黏膜下侵袭的表面表达较低, 胃癌肿瘤晚期合并远处淋巴转移的患者其Claudin-3表达也低[30]. 在增生期子宫内膜进展成为子宫内膜癌的疾病演变过程中, Claudin-3的表达明显升高, 并且其递增与子宫肌层的浸润密切相关[31]. Claudin-3除了与肿瘤及增殖相关之外, 还与机体的代谢有着密不可分的关系. 在Claudin-3敲除的小鼠, 其脂肪酸、氨基酸以及脂质的代谢相关基因在肝脏的表达显著下调, 而炎症免疫相关基因表达明显上调. Claudin-3的敲除也会降低肝脏内相关胆汁酸代谢基因(Cyp27a1、Ces1b和Akr1c6)的表达[32]. 胆汁酸是脂肪生成的重要调节因子, 胆汁酸代谢改变可能对肝脏能量代谢产生负面影响[33]. 所以, 可以推测胆汁酸组成的改变可能是Claudin-3敲除小鼠脂肪酸、脂质等明显下调的一个重要因素.
肝胆系统恶性肿瘤主要包括原发性肝癌(hepatocellular carcinoma, HCC)、胆管癌(cholangiocarcinoma, CCA)等, 其中HCC是肝内最常见的恶性肿瘤, 其在我国的发病率以及死亡率居高不下[34]. 目前HCC患者术后5年生存率仅为30%左右, 这主要与HCC 的高侵袭性和高转移率密切相关[35]. E-钙粘蛋白(E-cadherin)的缺失是上皮-间质转化(epithelial-mesenchymal transition, EMT)的标志, 通过EMT, 肿瘤细胞获得了突破基底膜侵入周围组织或转移到远处器官的能力[36,37]. Lin等[38]的研究表明, 抑制Claudin-3表达可以促进肿瘤体内生长, 其中Claudin-3可能通过维持E-cadherin的表达和限制β-连环蛋白(β-catenin)信号转导, 介导了与体内其他细胞的相互作用, 从而抑制了生长和转移潜能. Che等[39]研究表明, Claudin-3能够抑制Wnt/β-catenin途径, 进而抑制肿瘤细胞的上皮转移. Jiang等[40]研究表明, Claudin-3能够通过下调糖原合成酶激酶3B(glycogen synthase kinase 3B, GSK3B)、钙黏蛋白相关蛋白(catenin beta1, CTNNB1)、锌指家族转录抑制因子2(snail family transcriptional repressor 2, SNAI2)和血管钙黏蛋白(cadherin-2, CDH2)的表达, 使Wnt/β-catenin-EMT转移轴失活, 从而显著抑制肝癌的转移. 基质金属蛋白酶2(matrix metalloproteinase-2, MMP-2)是基质金属蛋白家族中的重要一员, 其可能通过降解肿瘤细胞周围的细胞外基质, 从而促进肿瘤的深层浸润, 这其实本质上就是EMT过程[41]. 李娟[42]等通过临床病例对照研究发现, 与肿瘤周边正常的肝组织相比, HCC组织中Claudin-3阳性表达率降低, MMP-2阳性表达率升高, HCC组织中Claudin-3与MMP-2呈负相关, 这可能是因为HCC组织中的MMP-2的表达升高, 使上皮组织细胞外基质降解、上皮表型丢失, 导致Claudin-3下降, 最终促进HCC的EMT过程及肿瘤浸润. Bodnar等[43]的研究表明, HCC患者Claudin-3的表达与肿瘤的临床分期密切相关, 表明Claudin-3影响了HCC患者的细胞稳定性及肿瘤的演进过程. Claudin-3在HCC组织中的异常表达和分布, 有望成为靶向治疗HCC的新方向. 同时, 既往有研究表明Claudin-3与CCA同样密切相关, Németh[44]等通过研究发现, CCA患者Claudin-3的表达明显降低. 最近, 在Ikeda[45]等的研究中发现, CCA患者组的胆汁细胞外小泡(extracellular vesicles, EVS)中的Claudin-3较结石组相比显著升高, 其敏感性为87.5%, 特异性为87.5%, AUC值为0.945(95%可信区间: 0.84-1). 这表明了人胆汁来源的EVS中的Claudin-3可能是胆管癌的一种新的生物标志物, 具有重大的临床意义.
胆囊结石是消化系统常见的一种疾病, 其主要分为胆固醇结石(cholesterol gallstone disease, GSD)、胆色素结石和磷酸盐结石等. 既往的研究表明, 胆固醇的过饱和为GSD的主要原因, 在GSD形成的过程中, 胆固醇结石核心发现的磷酸钙沉淀也促进了GSD的形成[46]. Tanaka等[47]研究表明, Claudin-3在小鼠的GSD的形成中起着重要的作用. Claudin-3特异性敲除会明显增加小鼠的胆汁流量, 稀释胆汁中胆固醇、磷脂、胆汁酸、胆红素的浓度, 其主要通过增加肝上皮细胞TJ对水的细胞旁通透性. 同时, Claudin-3的缺乏会影响小鼠肝胆管上皮中磷酸根离子(PO43-)的细胞旁转运, 同时增加胆汁中钙离子(Ca2+)的浓度, 导致磷酸钙核心形成, 诱发GSD形成. Claudin-3敲除的小鼠会自发的形成黑色的磷酸盐结石, 用红外吸收分光光度法分析胆结石的成分发现其超过98%为磷酸钙的组成[47]. 在高胆固醇致石饮食的饲养条件下, Claudin-3特异性敲除的小鼠形成的胆囊结石, 主要成分同样为过饱和的胆固醇结晶形成的胆固醇结石, 但是通过红外吸收分光光度法分析发现结石核心仍为磷酸钙沉淀[47]. 所以, Claudin-3影响着GSD的形成, 同时Claudin-3在小鼠肝脏中的表达随着年龄的增加而逐渐降低, 这有助于我们更好地理解GSD的发病率与年龄之间的关系[48].
在临床诊治中, 部分肝内外胆管结石的患者以及原发性肝癌患者, 行肝脏部分切除手术(partial hepatectomy, PHX)是有必要的[49]. 除了术中的精细操作, 术前患者的肝功能情况、以及患者的基础身体条件之外, 肝脏部分切除术后肝功能的恢复以及残肝的再生对于患者的恢复同样也起着至关重要的作用. Claudin-3是识别肝干细胞的标志物之一, Claudin-3在肝细胞增殖再生中的起着不可或缺的作用[50]. Zhang[51]等研究表面, 层粘连蛋白α-3(laminin alpha-3)和血小板反应蛋白-1(thrombospondin-1)通过影响Claudin-3来改变局部组织微环境, 促进患病肝脏的再生. Ando等[52]研究表明, PHX术后的大鼠, 在机械应力作用下, 肝细胞和Kupffer细胞立即释放细胞外ATP, 促进肝再生. 这表明在行PHX术后, 肝脏的增殖能力会代偿性的升高, 其增殖分数会明显升高. Baier等[32]的研究表明, 野生小鼠在肝脏部分切除(PHX)后, Claudin-3mRNA和蛋白的表达在术后3-6 h后下降, 并在24 h后开始高于初始水平. 而Claudin-3敲除的小鼠行PHX术后, 相比于正常野生型PHX小鼠, 其增殖指数(Ki67)明显降低. 在PHX小鼠中, 与细胞分裂、细胞周期调节、胆固醇合成和葡萄糖代谢相关的基因在Claudin-3敲除小鼠肝中的表达水平较低, 而与昼夜节律、代谢负调控、脂质分解代谢、钙离子结合以及其他相关基因的表达上调. 所以, 在肝再生以及再生肝代谢调节中, Claudin-3起着重要的作用[32]. 针对Claudin-3这一靶点治疗, 可能成为肝部分切除患者术后恢复治疗的一个非常重要的治疗方式.
慢性肝病主要是由于一种或者多种病因, 长期、反复刺激导致肝脏引起的, 其中包括以肝脏弥漫性纤维化、假小叶和再生结节形成为组织学特征的肝硬化(liver cirrhosis, LC), 以肝功能不全、全身炎性反应综合征、免疫麻痹为临床特征的慢加急性肝衰竭(acute-on-chronic liver failure, ACLF)等. 肝硬化在我国最常见的病因为慢性乙型病毒性肝炎. 在肝硬化的疾病演变过程中, 门脉高压、免疫功能的异常和肠黏膜屏障功能障碍会导致肠道细菌内毒素入血, 导致肠源性内毒素血症(intestinal endotoxemia, IETM), 肠道细菌易位进入腹腔, 导致自发性腹膜炎等. 同时, 肠道屏障功能还与多种慢性肝病密切相关, 例如非酒精性脂肪肝(nonalcoholic steatosis hepatitis, NASH)[53]. Claudin-3缺失被认为是紧密连接断裂和肠通透性(intestinal permeability, IP)改变的标志[54,55], 血浆Claudin-3浓度升高提示肠上皮屏障功能障碍[56-58]. Wang的研究表明[59], 包括代偿期LC、失代偿性LC、LC导致的肠源性内毒素血症、ACLF等慢性肝病患者血浆Claudin-3水平均升高, 且与血浆内毒素水平呈正相关. 肠道黏膜的通透性与血浆Claudin-3的水平密切相关, 肠道黏膜的损伤会导致血浆Claudin-3的水平升高, 最终可能导致IETM的发生. 总之, 血浆Claudin-3, 是这各种肝病患者肠黏膜通透性的标志物. 临床干预保护肠道机械屏障免受损伤可能会减少IETM造成的损伤, 应该作为肝病的治疗方法进行研究.
目前的研究发现Claudin-3在维持机体正常屏障、代谢、增殖等功能中发挥重要作用. 一旦Claudin-3的表达出现异常, 则可能导致多种疾病的发生发展, 尤其是在肝胆系统相关疾病. 本文主要介绍了Claudin-3在原发性肝癌、胆固醇结石、慢性肝病肠道菌群失调等疾病中的致病机制, 胆管癌中的生物标志物作用, 以及对肝部分切除术后增殖代谢影响, 这表明研究Claudin-3与肝胆系统疾病发生、发展的过程密切相关, 在诊断、特异治疗和预后判断等方面有着广泛的应用前景. 对Claudin-3的表达情况和其调节因子对肝胆系统其他疾病的作用机制的深入探索, 寻找或设计与其特异性结合的靶向因子, 干扰细胞表型从而达到治疗目的, 有待进一步研究和探讨.
学科分类: 胃肠病学和肝病学
手稿来源地: 湖南省
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科学编辑:张砚梁 制作编辑:张砚梁
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