緊密連接蛋白Claudin-3在肝膽疾病中的研究進(jìn)展

0 引言

各種上皮細(xì)胞以及內(nèi)皮細(xì)胞之間的相鄰面主要由細(xì)胞連接構(gòu)成,這些細(xì)胞連接是細(xì)胞旁轉(zhuǎn)運(yùn)的重要組成部分,除了維持細(xì)胞屏障的完整性,還限制分子的細(xì)胞旁路轉(zhuǎn)運(yùn),其主要分為緊密連接(tight junction,TJ)、橋粒、中間連接和縫隙連接等.TJ是主要位于細(xì)胞膜最頂端的連接裝置,在細(xì)胞連接中占主要部分,由3種跨膜蛋白,緊密連接蛋白(Claudins)、閉合蛋白、連接黏附分子以及閉合小環(huán)蛋白ZO-1、ZO-2、ZO-3等組成,其中主要結(jié)構(gòu)為Claudins.肝臟緊密連接主要由Claudin-1、-2、-3、-12和-25組成,其中Claudin-3是肝膽系統(tǒng)中含量最多的緊密連接蛋白

.肝臟Claudin-3的表達(dá)失調(diào)會(huì)導(dǎo)致肝膽系統(tǒng)中的緊密連接破壞,代謝功能、屏障功能、增殖能力和分子傳遞功能受損,與多種肝膽系統(tǒng)疾病的發(fā)生發(fā)展密切相關(guān).本文就Claudin-3在肝膽疾病中的研究進(jìn)展進(jìn)行綜述.

團(tuán)場(chǎng)學(xué)校、幼兒園通過(guò)每周一次的雙語(yǔ)口語(yǔ)學(xué)習(xí)培訓(xùn)、民族團(tuán)結(jié)主題班會(huì)、學(xué)習(xí)傳統(tǒng)文化主題隊(duì)會(huì)等系列活動(dòng)415場(chǎng)次，把民族團(tuán)結(jié)的種子播撒到了孩子幼小的心靈中。醫(yī)院組成醫(yī)療隊(duì)伍遠(yuǎn)赴離團(tuán)場(chǎng)300多公里以外的青河縣，為阿熱勒鄉(xiāng)達(dá)巴特村的村民進(jìn)行免費(fèi)義診。元旦春節(jié)、肉孜節(jié)、古爾邦節(jié)期間，團(tuán)場(chǎng)黨員干部開(kāi)展了“走親戚慶節(jié)日”活動(dòng)。通過(guò)活動(dòng)的開(kāi)展，加深了彼此間的了解與認(rèn)識(shí)，增進(jìn)了彼此間的友誼和感情。

1 緊密連接蛋白Claudin-3的概述

Claudins由Furuse等

于1998年首次發(fā)現(xiàn),相對(duì)分子質(zhì)量20 kDa-34 kDa,是緊密連接中最重要的骨架蛋白,也是緊密連接發(fā)揮維持細(xì)胞屏障完整性功能和限制物質(zhì)運(yùn)輸?shù)囊粋€(gè)關(guān)鍵分子,它的表達(dá)數(shù)量和分布結(jié)構(gòu)的變化直接影響TJ的結(jié)構(gòu)和功能.Claudins蛋白家族是一種至少擁有27個(gè)家族成員的蛋白

,根據(jù)功能的差異可將其分為兩類

:一類與形成屏障功能有關(guān),如Claudin-1、-3、-4和-5等;另一類則與構(gòu)成特定的通道有關(guān),可通過(guò)分子大小及電荷選擇決定物質(zhì)的細(xì)胞旁轉(zhuǎn)運(yùn),如 Claudin-2、-7、-10和-16等.Claudins是一種跨膜蛋白

,在結(jié)構(gòu)上,Claudins由面向細(xì)胞質(zhì)的N’末端、C’末端,2個(gè)細(xì)胞外環(huán)、4個(gè)跨膜結(jié)構(gòu)域組成,其中面向胞漿的C’末端還含有由80-90個(gè)氨基酸殘基組成的PDZ結(jié)構(gòu)域,它與ZO1、ZO2、ZO3和多PDZ結(jié)構(gòu)域蛋白1(MUPP1)相互作用,這是緊密連接蛋白復(fù)合體與其他多種蛋白的結(jié)合位點(diǎn)

.在該結(jié)構(gòu)域還包含與蛋白質(zhì)翻譯后修飾相關(guān)的氨基酸殘基,如絲氨酸-蘇氨酸磷酸化、酪氨酸磷酸化、小泛素化(sumoylation,SUMO)化和棕櫚?；?這些都可能影響著Claudins的定位和功能

.同時(shí),Claudins調(diào)節(jié)相鄰細(xì)胞的離子選擇性主要是由于Claudins的細(xì)胞外環(huán)所攜帶的氨基酸的帶電性質(zhì),形成電荷選擇性通道

.例如,Claudin-2的過(guò)度表達(dá)顯著增加了上皮細(xì)胞的離子電導(dǎo),形成陽(yáng)離子選擇性的細(xì)胞旁通道

.Claudin-1、-6、-9的細(xì)胞外鏈可能是丙型肝炎病毒的結(jié)合位點(diǎn)

.Claudin-1缺失可能導(dǎo)致罕見(jiàn)的遺傳性疾病(新生兒魚(yú)鱗病)和硬化性膽管炎,由于緊密連接中Claudin-1的缺乏,肝細(xì)胞和膽管細(xì)胞會(huì)出現(xiàn)膽汁的滲漏,這會(huì)導(dǎo)致患者出現(xiàn)膽汁淤積,谷草轉(zhuǎn)氨酶(aspartate transaminase,AST)、谷丙轉(zhuǎn)氨酶(alanine transaminase,ALT)、血清γ-谷氨酰轉(zhuǎn)移酶活性和膽紅素明顯升高

.而Claudin-3作為肝臟中表達(dá)最多的TJ蛋白,主要在肝細(xì)胞和膽管細(xì)胞中表達(dá)

.在先天性膽道閉鎖的小兒患者中,肝臟內(nèi)的Claudin-3含量無(wú)明顯變化,而周圍肝細(xì)胞和肝臟膽管管腔表面的Claudin-3排列明顯紊亂

.因此,Claudin-3在肝細(xì)胞和膽管細(xì)胞屏障功能、分泌功能、物質(zhì)代謝等多個(gè)方面發(fā)揮重要作用,進(jìn)而影響肝臟生理,一旦Claudin-3表達(dá)失調(diào),則會(huì)導(dǎo)致多種肝臟疾病的發(fā)生發(fā)展.

2 緊密連接蛋白Claudin-3的生物學(xué)作用

緊密連接蛋白Claudin-3定位于7q11.23,是參與血腦屏障、腸道屏障、血睪屏障構(gòu)成的重要組成部分

.同時(shí)Claudin-3不僅在人體前列腺、胰腺細(xì)胞、肝細(xì)胞等多種腺細(xì)胞,同時(shí)還在乳腺導(dǎo)管上皮、子宮內(nèi)膜、食管黏膜、肺泡上皮、和膽管上皮細(xì)胞等多種上皮細(xì)胞內(nèi)均有表達(dá)

.Claudin-3是TJ的主要跨膜蛋白之一,是細(xì)胞間黏附功能的結(jié)構(gòu)基礎(chǔ),并在細(xì)胞間的傳輸轉(zhuǎn)運(yùn)中發(fā)揮著重要的接頭作用.除此之外,Claudin-3在維持上皮細(xì)胞極性、基因轉(zhuǎn)錄、抑制腫瘤、細(xì)胞增殖分化、新陳代謝相關(guān)的基因和炎癥免疫反應(yīng)等方面有著重大的作用.上皮TJ蛋白組成的復(fù)雜變化會(huì)影響細(xì)胞極性,如Claudin-3的減少與極性復(fù)合蛋白(partition defective-3,PAR-3)和絲氨酸/蘇氨酸磷酸酶(protein phosphatase-1,PP-1)的定位和表達(dá)改變有關(guān)

.有研究表明

,Claudin-3在不同的腫瘤組織中表達(dá)不同,作用也不盡相同.Claudin-3在乳腺癌、前列腺癌、卵巢癌、胃癌等腫瘤中表達(dá)增多,而在結(jié)直腸癌、食管 癌等腫瘤中的表達(dá)則下降

.Claudin-3在胃癌組織中的表達(dá)高于癌旁正常組織,但在胃癌黏膜下侵襲的表面表達(dá)較低,胃癌腫瘤晚期合并遠(yuǎn)處淋巴轉(zhuǎn)移的患者其Claudin-3表達(dá)也低

.在增生期子宮內(nèi)膜進(jìn)展成為子宮內(nèi)膜癌的疾病演變過(guò)程中,Claudin-3的表達(dá)明顯升高,并且其遞增與子宮肌層的浸潤(rùn)密切相關(guān)

.Claudin-3除了與腫瘤及增殖相關(guān)之外,還與機(jī)體的代謝有著密不可分的關(guān)系.在Claudin-3敲除的小鼠,其脂肪酸、氨基酸以及脂質(zhì)的代謝相關(guān)基因在肝臟的表達(dá)顯著下調(diào),而炎癥免疫相關(guān)基因表達(dá)明顯上調(diào).Claudin-3的敲除也會(huì)降低肝臟內(nèi)相關(guān)膽汁酸代謝基因(Cyp27a1、Ces1b和Akr1c6)的表達(dá)

.膽汁酸是脂肪生成的重要調(diào)節(jié)因子,膽汁酸代謝改變可能對(duì)肝臟能量代謝產(chǎn)生負(fù)面影響

.所以,可以推測(cè)膽汁酸組成的改變可能是Claudin-3敲除小鼠脂肪酸、脂質(zhì)等明顯下調(diào)的一個(gè)重要因素.

3 緊密連接蛋白Claudin-3與肝膽疾病

3.1 Claudin-3與肝膽系統(tǒng)惡性腫瘤 肝膽系統(tǒng)惡性腫瘤主要包括原發(fā)性肝癌(hepatocellular carcinoma,HCC)、膽管癌(cholangiocarcinoma,CCA)等,其中HCC是肝內(nèi)最常見(jiàn)的惡性腫瘤,其在我國(guó)的發(fā)病率以及死亡率居高不下

.目前HCC患者術(shù)后5年生存率僅為30%左右,這主要與HCC的高侵襲性和高轉(zhuǎn)移率密切相關(guān)

.E-鈣粘蛋白(E-cadherin)的缺失是上皮-間質(zhì)轉(zhuǎn)化(epithelialmesenchymal transition,EMT)的標(biāo)志,通過(guò)EMT,腫瘤細(xì)胞獲得了突破基底膜侵入周圍組織或轉(zhuǎn)移到遠(yuǎn)處器官的能力

.Lin等

的研究表明,抑制Claudin-3表達(dá)可以促進(jìn)腫瘤體內(nèi)生長(zhǎng),其中Claudin-3可能通過(guò)維持E-cadherin的表達(dá)和限制β-連環(huán)蛋白(β-catenin)信號(hào)轉(zhuǎn)導(dǎo),介導(dǎo)了與體內(nèi)其他細(xì)胞的相互作用,從而抑制了生長(zhǎng)和轉(zhuǎn)移潛能.Che等

研究表明,Claudin-3能夠抑制Wnt/β-catenin途徑,進(jìn)而抑制腫瘤細(xì)胞的上皮轉(zhuǎn)移.Jiang等

研究表明,Claudin-3能夠通過(guò)下調(diào)糖原合成酶激酶3B(glycogen synthase kinase 3B,GSK3B)、鈣黏蛋白相關(guān)蛋白(catenin beta1,CTNNB1)、鋅指家族轉(zhuǎn)錄抑制因子2(snail family transcriptional repressor 2,SNAI2)和血管鈣黏蛋白(cadherin-2,CDH2)的表達(dá),使Wnt/β-catenin-EMT轉(zhuǎn)移軸失活,從而顯著抑制肝癌的轉(zhuǎn)移.基質(zhì)金屬蛋白酶2(matrix metalloproteinase-2,MMP-2)是基質(zhì)金屬蛋白家族中的重要一員,其可能通過(guò)降解腫瘤細(xì)胞周圍的細(xì)胞外基質(zhì),從而促進(jìn)腫瘤的深層浸潤(rùn),這其實(shí)本質(zhì)上就是EMT過(guò)程

.李娟

等通過(guò)臨床病例對(duì)照研究發(fā)現(xiàn),與腫瘤周邊正常的肝組織相比,HCC 組織中Claudin-3陽(yáng)性表達(dá)率降低,MMP-2陽(yáng)性表達(dá)率升高,HCC組織中Claudin-3與MMP-2呈負(fù)相關(guān),這可能是因?yàn)镠CC組織中的MMP-2的表達(dá)升高,使上皮組織細(xì)胞外基質(zhì)降解、上皮表型丟失,導(dǎo)致Claudin-3下降,最終促進(jìn)HCC的EMT過(guò)程及腫瘤浸潤(rùn).Bodnar等

的研究表明,HCC患者Claudin-3的表達(dá)與腫瘤的臨床分期密切相關(guān),表明Claudin-3影響了HCC患者的細(xì)胞穩(wěn)定性及腫瘤的演進(jìn)過(guò)程.Claudin-3在HCC組織中的異常表達(dá)和分布,有望成為靶向治療HCC的新方向.同時(shí),既往有研究表明Claudin-3與CCA同樣密切相關(guān),Németh

等通過(guò)研究發(fā)現(xiàn),CCA患者Claudin-3的表達(dá)明顯降低.最近,在Ikeda

等的研究中發(fā)現(xiàn),CCA患者組的膽汁細(xì)胞外小泡(extracellular vesicles,EVS)中的Claudin-3較結(jié)石組相比顯著升高,其敏感性為87.5%,特異性為87.5%,AUC值為0.945(95%可信區(qū)間:0.84-1).這表明了人膽汁來(lái)源的EVS中的Claudin-3可能是膽管癌的一種新的生物標(biāo)志物,具有重大的臨床意義.

治療結(jié)束后，觀察組患者治療總有效率為92.9%，對(duì)照組患者治療總有效率為67.9%，觀察組患者治療總有效率顯著高于對(duì)照組，數(shù)據(jù)間比較；差異有統(tǒng)計(jì)學(xué)意義（P＜0.05）。見(jiàn)表1。

賽前，省聯(lián)社黨委副書(shū)記殷青作了熱情洋溢的致辭。經(jīng)過(guò)激烈角逐，最終昆明代表隊(duì)榮獲一等獎(jiǎng)，科技結(jié)算中心代表隊(duì)、曲靖代表隊(duì)、文山代表隊(duì)榮獲二等獎(jiǎng)，玉溪代表隊(duì)、楚雄代表隊(duì)、保山代表隊(duì)、昭通代表隊(duì)、臨滄代表隊(duì)榮獲三等獎(jiǎng)，版納、德宏、大理、麗江、怒江、普洱、紅河、迪慶、省聯(lián)社機(jī)關(guān)獲優(yōu)秀組織獎(jiǎng)。

3.2 Claudin-3與膽固醇結(jié)石 膽囊結(jié)石是消化系統(tǒng)常見(jiàn)的一種疾病,其主要分為膽固醇結(jié)石(cholesterol gallstone disease,GSD)、膽色素結(jié)石和磷酸鹽結(jié)石等.既往的研究表明,膽固醇的過(guò)飽和為GSD的主要原因,在GSD形成的過(guò)程中,膽固醇結(jié)石核心發(fā)現(xiàn)的磷酸鈣沉淀也促進(jìn)了GSD的形成

.Tanaka等

研究表明,Claudin-3在小鼠的GSD的形成中起著重要的作用.Claudin-3特異性敲除會(huì)明顯增加小鼠的膽汁流量,稀釋膽汁中膽固醇、磷脂、膽汁酸、膽紅素的濃度,其主要通過(guò)增加肝上皮細(xì)胞TJ對(duì)水的細(xì)胞旁通透性.同時(shí),Claudin-3的缺乏會(huì)影響小鼠肝膽管上皮中磷酸根離子(PO

)的細(xì)胞旁轉(zhuǎn)運(yùn),同時(shí)增加膽汁中鈣離子(Ca

)的濃度,導(dǎo)致磷酸鈣核心形成,誘發(fā)GSD形成.Claudin-3敲除的小鼠會(huì)自發(fā)的形成黑色的磷酸鹽結(jié)石,用紅外吸收分光光度法分析膽結(jié)石的成分發(fā)現(xiàn)其超過(guò)98%為磷酸鈣的組成

.在高膽固醇致石飲食的飼養(yǎng)條件下,Claudin-3特異性敲除的小鼠形成的膽囊結(jié)石,主要成分同樣為過(guò)飽和的膽固醇結(jié)晶形成的膽固醇結(jié)石,但是通過(guò)紅外吸收分光光度法分析發(fā)現(xiàn)結(jié)石核心仍為磷酸鈣沉淀

.所以,Claudin-3影響著GSD的形成,同時(shí)Claudin-3在小鼠肝臟中的表達(dá)隨著年齡的增加而逐漸降低,這有助于我們更好地理解GSD的發(fā)病率與年齡之間的關(guān)系

.

3.3 Claudin-3與肝部分切除術(shù)后 在臨床診治中,部分肝內(nèi)外膽管結(jié)石的患者以及原發(fā)性肝癌患者,行肝臟部分切除手術(shù)(partial hepatectomy,PHX)是有必要的

.除了術(shù)中的精細(xì)操作,術(shù)前患者的肝功能情況、以及患者的基礎(chǔ)身體條件之外,肝臟部分切除術(shù)后肝功能的恢復(fù)以及殘肝的再生對(duì)于患者的恢復(fù)同樣也起著至關(guān)重要的作用.Claudin-3是識(shí)別肝干細(xì)胞的標(biāo)志物之一,Claudin-3在肝細(xì)胞增殖再生中的起著不可或缺的作用

.Zhang

等研究表面,層粘連蛋白α-3(laminin alpha-3)和血小板反應(yīng)蛋白-1(thrombospondin-1)通過(guò)影響Claudin-3來(lái)改變局部組織微環(huán)境,促進(jìn)患病肝臟的再生.Ando等

研究表明,PHX術(shù)后的大鼠,在機(jī)械應(yīng)力作用下,肝細(xì)胞和Kupffer細(xì)胞立即釋放細(xì)胞外ATP,促進(jìn)肝再生.這表明在行PHX術(shù)后,肝臟的增殖能力會(huì)代償性的升高,其增殖分?jǐn)?shù)會(huì)明顯升高.Baier等

的研究表明,野生小鼠在肝臟部分切除(PHX)后,Claudin-3mRNA和蛋白的表達(dá)在術(shù)后3-6 h后下降,并在24 h后開(kāi)始高于初始水平.而Claudin-3敲除的小鼠行PHX術(shù)后,相比于正常野生型PHX小鼠,其增殖指數(shù)(Ki67)明顯降低.在PHX小鼠中,與細(xì)胞分裂、細(xì)胞周期調(diào)節(jié)、膽固醇合成和葡萄糖代謝相關(guān)的基因在Claudin-3敲除小鼠肝中的表達(dá)水平較低,而與晝夜節(jié)律、代謝負(fù)調(diào)控、脂質(zhì)分解代謝、鈣離子結(jié)合以及其他相關(guān)基因的表達(dá)上調(diào).所以,在肝再生以及再生肝代謝調(diào)節(jié)中,Claudin-3起著重要的作用

.針對(duì)Claudin-3這一靶點(diǎn)治療,可能成為肝部分切除患者術(shù)后恢復(fù)治療的一個(gè)非常重要的治療方式.

3.4 Claudin-3與慢性肝病 慢性肝病主要是由于一種或者多種病因,長(zhǎng)期、反復(fù)刺激導(dǎo)致肝臟引起的,其中包括以肝臟彌漫性纖維化、假小葉和再生結(jié)節(jié)形成為組織學(xué)特征的肝硬化(liver cirrhosis,LC),以肝功能不全、全身炎性反應(yīng)綜合征、免疫麻痹為臨床特征的慢加急性肝衰竭(acute-on-chronic liver failure,ACLF)等.肝硬化在我國(guó)最常見(jiàn)的病因?yàn)槁砸倚筒《拘愿窝?在肝硬化的疾病演變過(guò)程中,門脈高壓、免疫功能的異常和腸黏膜屏障功能障礙會(huì)導(dǎo)致腸道細(xì)菌內(nèi)毒素入血,導(dǎo)致腸源性內(nèi)毒素血癥(intestinal endotoxemia,IETM),腸道細(xì)菌易位進(jìn)入腹腔,導(dǎo)致自發(fā)性腹膜炎等.同時(shí),腸道屏障功能還與多種慢性肝病密切相關(guān),例如非酒精性脂肪肝(nonalcoholic steatosis hepatitis,NASH)

.Claudin-3缺失被認(rèn)為是緊密連接斷裂和腸通透性(intestinal permeability,IP)改變的標(biāo)志

,血漿Claudin-3濃度升高提示腸上皮屏障功能障礙

.Wang的研究表明

,包括代償期LC、失代償性LC、LC導(dǎo)致的腸源性內(nèi)毒素血癥、ACLF等慢性肝病患者血漿Claudin-3水平均升高,且與血漿內(nèi)毒素水平呈正相關(guān).腸道黏膜的通透性與血漿Claudin-3的水平密切相關(guān),腸道黏膜的損傷會(huì)導(dǎo)致血漿Claudin-3的水平升高,最終可能導(dǎo)致IETM的發(fā)生.總之,血漿Claudin-3,是這各種肝病患者腸黏膜通透性的標(biāo)志物.臨床干預(yù)保護(hù)腸道機(jī)械屏障免受損傷可能會(huì)減少IETM造成的損傷,應(yīng)該作為肝病的治療方法進(jìn)行研究.

4 結(jié)論

目前的研究發(fā)現(xiàn)Claudin-3在維持機(jī)體正常屏障、代謝、增殖等功能中發(fā)揮重要作用.一旦Claudin-3的表達(dá)出現(xiàn)異常,則可能導(dǎo)致多種疾病的發(fā)生發(fā)展,尤其是在肝膽系統(tǒng)相關(guān)疾病.本文主要介紹了Claudin-3在原發(fā)性肝癌、膽固醇結(jié)石、慢性肝病腸道菌群失調(diào)等疾病中的致病機(jī)制,膽管癌中的生物標(biāo)志物作用,以及對(duì)肝部分切除術(shù)后增殖代謝影響,這表明研究Claudin-3與肝膽系統(tǒng)疾病發(fā)生、發(fā)展的過(guò)程密切相關(guān),在診斷、特異治療和預(yù)后判斷等方面有著廣泛的應(yīng)用前景.對(duì)Claudin-3的表達(dá)情況和其調(diào)節(jié)因子對(duì)肝膽系統(tǒng)其他疾病的作用機(jī)制的深入探索,尋找或設(shè)計(jì)與其特異性結(jié)合的靶向因子,干擾細(xì)胞表型從而達(dá)到治療目的,有待進(jìn)一步研究和探討.

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