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Claudins家族靶點(diǎn):CLDN4接踵而至,展示聯(lián)合用藥潛力!

日期:2022-09-26 09:54:20

近期,Nature旗下Cell Death & Disease雜志,一篇標(biāo)題為“TGF-β induces GBM mesenchymal transition through upregulation of CLDN4 and nuclear translocation to activate TNF-α/NF-κB signal pathway”文章首次發(fā)現(xiàn),CLDN4在膠質(zhì)母細(xì)胞瘤(GBM)組織和細(xì)胞中上調(diào),研究提示,CLDN4通過(guò)調(diào)節(jié)TNF-α誘導(dǎo)的NF-κB活性,誘導(dǎo)GBM細(xì)胞的間質(zhì)轉(zhuǎn)化,增強(qiáng)GBM細(xì)胞的遷移能力。進(jìn)一步的實(shí)驗(yàn)數(shù)據(jù)表明,穩(wěn)定敲低CLDN4,可抑制異種移植小鼠膠質(zhì)瘤的生長(zhǎng)和侵襲,且聯(lián)合ITD-1治療,對(duì)小鼠腫瘤的抑制效果更好 [1]。CLDN4作為Claudins家族的重要分子,在各種類型腫瘤中廣泛出現(xiàn)高表達(dá)或表達(dá)缺失。陸續(xù)有研究表明,CLDN4可作為治療腫瘤的特定靶點(diǎn)。令人鼓舞的是,已有多篇文獻(xiàn)報(bào)道將抗CLDN4抗體聯(lián)合治療,可增強(qiáng)抗腫瘤作用。因此,繼CLDN18.2、CLDN9CLDN6等靶點(diǎn)后,CLDN4接踵而至,有望成為Claudins家族腫瘤靶向治療的有效靶點(diǎn),且在聯(lián)合用藥方面展示出潛力。


1. 什么是CLDN4?

緊密連接蛋白4(Claudin 4/CLDN4)屬于Claudins家族的一員,也是緊密連接(Tight Junctions,TJ)的重要連接蛋白之一。Claudins蛋白均由4個(gè)跨膜結(jié)構(gòu)域構(gòu)成,N端和C端均位于細(xì)胞內(nèi)部,C-末端上存在結(jié)合域,可與胞質(zhì)內(nèi)層的蛋白結(jié)合(如:ZO-1),在信號(hào)轉(zhuǎn)導(dǎo)中發(fā)揮重要的作用。細(xì)胞膜外有2個(gè)長(zhǎng)度不等的環(huán)(ECL1和ECL2),它們可以和臨近其他同類型的環(huán)相接觸,構(gòu)成細(xì)胞間的緊密連接(圖1[2]。細(xì)胞外環(huán)是維持緊密連接功能和上皮屏障完整性所必需的。緊密連接是位于上皮細(xì)胞和內(nèi)皮細(xì)胞頂端的細(xì)胞間黏附結(jié)構(gòu)。Claudins作為緊密連接的重要組成部分,可調(diào)節(jié)上皮細(xì)胞通透性及維持細(xì)胞極性等方面發(fā)揮作用。當(dāng)Claudins蛋白發(fā)生變化時(shí),將影響細(xì)胞間的通透性,可引起疾病的發(fā)生 [2, 3]。越來(lái)越多研究揭示CLDN4在癌癥中發(fā)揮著調(diào)控作用,或可作為潛力腫瘤治療靶標(biāo) [4-6]。事實(shí)上,大量證據(jù)已表明Claudins成員在腫瘤免疫治療中扮演重要的角色,且在臨床中具有極大的成藥性。針對(duì)Claudins家族火熱研究靶點(diǎn),可點(diǎn)擊以往Claudins蛋白相關(guān)文章(CLDN6CLDN9;CLDN18.2)。

CLDN4的結(jié)構(gòu)

圖1. CLDN4的結(jié)構(gòu) [2]


2. CLDN4的作用機(jī)制

相關(guān)文獻(xiàn)指出,Claudins參與腫瘤的機(jī)制途徑可能為:1)Claudins異常表達(dá)引起緊密連接紊亂和滲漏,促進(jìn)腫瘤細(xì)胞的轉(zhuǎn)移和侵襲;2)細(xì)胞極性的降低增加腫瘤的營(yíng)養(yǎng)和生長(zhǎng)因子供應(yīng),使腫瘤細(xì)胞的增殖加快;3)細(xì)胞間黏附的減少,會(huì)增加轉(zhuǎn)移風(fēng)險(xiǎn)并促進(jìn)腫瘤的發(fā)展 [7-9]。如今,CLDN4作為常見(jiàn)的腫瘤異常表達(dá)基因,對(duì)其研究仍處于初步階段,其在腫瘤中的信號(hào)調(diào)節(jié)機(jī)制有待深入了解。

在膠質(zhì)瘤中,研究發(fā)現(xiàn)CLDN4/TNFα/NF-κB信號(hào)軸,在膠質(zhì)瘤的生物學(xué)進(jìn)展中起關(guān)鍵作用,揭示CLDN4誘導(dǎo)膠質(zhì)瘤EMT是通過(guò)調(diào)節(jié)TNF-α介導(dǎo)的NF-κB信號(hào)通路(圖2[1]。在卵巢癌中,CLDN4的過(guò)表達(dá),可通過(guò)PI3K/Akt和EMT轉(zhuǎn)錄因子Twist1信號(hào)通路,誘導(dǎo)卵巢癌細(xì)胞EMT [10, 11]。在胰腺癌中,轉(zhuǎn)化生長(zhǎng)因子β(TGF-β)可以負(fù)性調(diào)解CLDN4表達(dá),且高表達(dá)CLDN4可抑制胰腺癌細(xì)胞的侵襲 [12]。在乳腺癌中,CLDN4通過(guò)PAK4-CEBPB-CLDN4軸,促進(jìn)腫瘤細(xì)胞遷移和侵襲 [13]。

另外,在人喉癌Hep-2細(xì)胞中,CLDN4低表達(dá),并初步證實(shí)CLDN4通過(guò)JAK2/STAT3信號(hào)通路,可抑制細(xì)胞增殖 [14]。另有研究認(rèn)為,在喉癌Hep-2細(xì)胞中,DNA甲基化可下調(diào)CLDN4基因,其與MeCP2募集HDAC1有關(guān),進(jìn)一步發(fā)現(xiàn),CLDN4上調(diào)可抑制Hep-2細(xì)胞增殖,并增加細(xì)胞間緊密連接數(shù)目 [15]

CLDN4誘導(dǎo)膠質(zhì)瘤細(xì)胞EMT途徑

圖2. CLDN4誘導(dǎo)膠質(zhì)瘤細(xì)胞EMT途徑 [1]


3. CLDN4在腫瘤中的作用

很多學(xué)者研究發(fā)現(xiàn),CLDN4在多種腫瘤中存在異常表達(dá)現(xiàn)象。尤其在消化道腫瘤,包括食管腫瘤、胃癌、結(jié)腸癌、肝癌、胰腺癌、喉鱗狀細(xì)胞癌等等;以及在生殖系統(tǒng)腫瘤,如卵巢癌、宮頸癌,均有研究顯示CLDN4在這些腫瘤組織中的異常高表達(dá)或低表達(dá)。因此,CLDN4作為常見(jiàn)的腫瘤異常表達(dá)基因,將有著非常重要的潛在應(yīng)用價(jià)值。

3.1 CLDN4與消化道腫瘤

在胰腺癌中,有研究表明,羅格列酮(Rosiglitazone)可通過(guò)抑制MEK-ERK信號(hào)通路,增加CLDN4的表達(dá),從而抑制胰腺癌細(xì)胞的侵襲,認(rèn)為CLDN4是胰腺癌細(xì)胞侵襲和轉(zhuǎn)移表型的潛在抑制劑 [17]。然而,使用cDNA微陣列分析胰腺導(dǎo)管內(nèi)乳頭狀黏液性腫瘤,顯示CLDN4基因上調(diào),提示CLDN4可能參與到早期胰腺癌的形成 [18]。在胃癌中,CLDN4異常高表達(dá),采用CLDN4 siRNA 轉(zhuǎn)染SGC7901胃癌細(xì)胞,發(fā)現(xiàn)細(xì)胞的侵襲能力顯著下降,進(jìn)一步研究發(fā)現(xiàn),敲低CLDN4可增強(qiáng)PI3K和Akt的磷酸化,促進(jìn)胃癌細(xì)胞的增殖、遷移、侵襲,以及降低胃癌細(xì)胞對(duì)化療的敏感性 [19, 20]。

在肝癌中,鋅指蛋白703(ZNF703)能夠與CLDN4啟動(dòng)子結(jié)合,激活CLDN4的表達(dá),誘導(dǎo)EMT從而促進(jìn)腫瘤轉(zhuǎn)移和索拉非尼耐藥 [21]。在喉鱗狀細(xì)胞癌中,CLDN4表達(dá)下調(diào),研究證實(shí)喉癌組織中CLDN4的表達(dá)與MECP-2的表達(dá)相關(guān),進(jìn)一步的研究發(fā)現(xiàn),DNA甲基化轉(zhuǎn)移酶抑制劑(5-aza-dc)作用喉鱗癌細(xì)胞系hep-2后,可上調(diào)CLDN4的表達(dá),并使hep-2細(xì)胞的遷移和侵襲能力下降 [22]。因此,CLDN4或可成為消化道相關(guān)腫瘤診斷的分子標(biāo)志物。

3.2 CLDN4與生殖系統(tǒng)腫瘤

在卵巢癌中,過(guò)表達(dá)CLDN4可促進(jìn)卵巢癌細(xì)胞的EMT進(jìn)程,且高表達(dá)的CLDN4與患者的不良預(yù)后相關(guān) [10, 11]。近期,另有研究揭示CLDN4缺失,可抑制DNA修復(fù),并增加對(duì)PARP抑制劑的敏感性。而高表達(dá)CLDN4的卵巢癌腫瘤細(xì)胞,其對(duì)PARP抑制劑的敏感性降低 [23]。

在宮頸癌中,當(dāng)細(xì)胞連接破壞后,與正常鱗狀上皮相比,宮頸癌組織中CLDN4表達(dá)明顯上調(diào)。當(dāng)宮頸癌前病變?cè)絿?yán)重,組織表達(dá)的CLDN4水平則隨之上升。CLDN4蛋白表達(dá)強(qiáng)度與宮頸癌前病變的程度密切相關(guān),提示CLDN4的高表達(dá)可能會(huì)促進(jìn)宮頸癌的發(fā)生 [24]。此外,高危型人乳頭瘤病毒(HR-HPV)聯(lián)合CLDN4檢測(cè)能夠提高宮頸癌前病變?cè)\斷的特異性。HR-HPV已被證實(shí)為宮頸癌及宮頸癌前病變的重要治病因素。因此,CLDN4或可作為診斷卵巢癌和宮頸癌前病變的重要手段。

3.3 CLDN4與其它腫瘤

在前列腺癌中,在表達(dá)CLDN4的小鼠前列腺癌異種移植模型中,注射產(chǎn)氣莢膜梭菌腸毒素(clostridium perfringens enterotoxin, CPE)可顯著抑制腫瘤的生長(zhǎng)。CPE是人食物中毒及胃腸疾病的重要致病因子。CLDN3和CLDN4作為CPE的受體,CPE與受體特異性結(jié)合后,可通過(guò)胞膜穿透作用使細(xì)胞溶解壞死。研究表明,CPE的細(xì)胞毒性僅限于CLDN3和CLDN4高表達(dá)的癌細(xì)胞,并呈劑量依賴性 [25--27]。因此,在CLDN3和CLDN4高表達(dá)的癌組織中,整合CPE治療,使其能結(jié)合特異CLDN受體,將使化療藥物具有腫瘤特異性,從而增強(qiáng)化療效果。

在膠質(zhì)瘤中,基于TCGA數(shù)據(jù)集進(jìn)行Kaplan-Meier的分析表明,CLDN4的表達(dá)與OS和DFS呈負(fù)相關(guān)。進(jìn)一步發(fā)現(xiàn),CLDN4能夠調(diào)節(jié)TNF-α誘導(dǎo)的NF-κB活性。破壞CLDN4/TNFα/NF-κB信號(hào)軸的功能,可能是治療惡性膠質(zhì)瘤患者的一種新策略 [1]。在三陰性乳腺癌中,CLDN4表達(dá)高于非三陰性乳腺癌,通過(guò)小鼠模型,使用CLDN4細(xì)胞外結(jié)構(gòu)域抗體(4D3)可削弱乳腺癌細(xì)胞緊密連接的屏障功能,增強(qiáng)紫杉醇(Paclitaxel)的抗癌作用 [28]。在膀胱癌中,在皮下腫瘤和肺轉(zhuǎn)移的小鼠模型中,聯(lián)合CLDN4抗體(4D3)治療可增強(qiáng)順鉑(Cisplatin)抑制腫瘤生長(zhǎng)的效果 [29]。


4. CLDN4的臨床研究前景

大量研究已證明CLDN家族是一類具有重要研究?jī)r(jià)值的細(xì)胞表面蛋白質(zhì)分子,發(fā)揮著重要的屏障作用。CLDN蛋白在腫瘤細(xì)胞表面存在的異常表達(dá),和多種腫瘤的發(fā)生發(fā)展有關(guān)。當(dāng)前,CLDN4蛋白在細(xì)胞增殖、遷移和侵襲中的作用有了越來(lái)越多的新見(jiàn)解,大量證據(jù)顯示CLDN4的異常表達(dá)能影響腫瘤的侵襲和轉(zhuǎn)移能力。尤其是在高表達(dá)CLDN4的腫瘤中,CLDN4有望作為腫瘤的標(biāo)志物和治療靶點(diǎn)。日益增多的證據(jù)表明,聯(lián)合抗CLDN4抗體治療,具有潛在的應(yīng)用前景,能增強(qiáng)現(xiàn)有藥物的作用效果。隨著CLDN家族領(lǐng)域研究的不斷深入,相信越來(lái)越多CLDN蛋白作用將為更多疾病的診斷治療提供新思路。

為鼎力協(xié)助科研和藥企人員針對(duì)CLDN4在機(jī)體功能調(diào)節(jié)方面,以及CLDN4在腫瘤中的臨床應(yīng)用研究,CUSABIO推出CLDN4活性蛋白(Code: CSB-MP005506HU)產(chǎn)品,助力您在CLDN4機(jī)制方面的研究或其潛在臨床價(jià)值的探索。

Recombinant Human Claudin-4(CLDN4)-VLPs (Active)

High Specifity Validated by Western Blot

The high specifity was validated by western blot. CSB-MP005506HU is detected by Mouse anti-6*His monoclonal antibody.

Excellent Bioactivity Validated by Functional ELISA

Immobilized Human CLDN4 at 5 μg/ml can bind Anti-CLDN4 recombinant antibody (CSB-RA005506MA1HU), the EC50 is 29.56-50.75 ng/mL.


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