崔小強(qiáng) 郭愛華 高玉強(qiáng) 戰(zhàn)淑慧
青島大學(xué)醫(yī)學(xué)院附屬青島市市立醫(yī)院消化科(266071)
黏液遍及整個(gè)胃腸道,黏液屏障包含兩層:內(nèi)層黏液具有較薄且難以移動(dòng)、無(wú)菌的特點(diǎn),外層黏液較厚且容易分散、有菌[1-2],細(xì)胞外黏液屏障主要包括3種成分,即分泌型黏蛋白、非特異性抗菌分子以及特異性抗菌免疫球蛋白。分泌型黏蛋白可包括MUC2、MUC5AC、MUC5B、MUC6、MUC19、MUC7[3],在抵御胃腸道致病菌入侵中起有非常重要的作用。但有時(shí)致病菌能破壞細(xì)胞外黏液屏障從而到達(dá)細(xì)胞表面,這時(shí)分布于細(xì)胞表面的黏蛋白能抵御這些微生物的侵襲,包括MUC1、MUC3A、MUC3B、MUC4、MUC12、MUC13、MUC15、MUC16和MUC17[4]。
黏蛋白MUC1是第一個(gè)被發(fā)現(xiàn)的細(xì)胞表面黏蛋白,表達(dá)于多數(shù)腺體和導(dǎo)管上皮細(xì)胞以及部分造血細(xì)胞中。MUC1基因位于染色體1q21,MUC1蛋白由單一的轉(zhuǎn)錄物編碼、翻譯而成,在內(nèi)質(zhì)網(wǎng)內(nèi)自我切割成兩個(gè)亞基,然后插入到內(nèi)質(zhì)網(wǎng)膜中,其N端中的數(shù)目可變串聯(lián)重復(fù)序列(variable number of tandem repeats, VNTR)發(fā)生廣泛N-糖基化,緊接著在高爾基體內(nèi)經(jīng)O-糖基化后轉(zhuǎn)移到細(xì)胞膜表面[5]。
許多致病菌能穿透內(nèi)層黏液并結(jié)合于胃腸道細(xì)胞表面,通過(guò)自身的分泌系統(tǒng)將細(xì)菌蛋白引入胃腸道上皮細(xì)胞,擾亂細(xì)胞正常的生理功能,因此細(xì)菌對(duì)分泌系統(tǒng)的激活至關(guān)重要,許多致病菌能適應(yīng)胃腸道上皮細(xì)胞表面的配體而演變細(xì)胞表面配基。幽門螺桿菌(Helicobacterpylori, Hp)作為胃癌的Ⅰ類致癌原,是慢性活動(dòng)性胃炎、消化性潰瘍、胃黏膜相關(guān)淋巴樣組織(mucosa-associated lymphoid tissue, MALT)淋巴瘤和胃癌的主要致病因素,目前認(rèn)為約70%的胃癌是由Hp感染引起[6]。多項(xiàng)研究證實(shí)黏蛋白MUC1與Hp感染密切相關(guān),可能參與了Hp感染機(jī)制。本文就黏蛋白MUC1與Hp的關(guān)系作一綜述。
McGuckin等[7]的研究檢測(cè)了感染Hp的野生型MUC1小鼠和缺乏MUC1小鼠的Hp定植情況和炎癥水平,結(jié)果顯示感染Hp僅1 d,缺乏MUC1小鼠的胃黏膜Hp定植數(shù)量為野生型MUC1小鼠的5倍,且這種差異至少持續(xù)了2個(gè)月;缺乏MUC1小鼠的胃黏膜更容易發(fā)生嚴(yán)重的慢性胃炎,提示MUC1能抑制Hp密度以及Hp感染導(dǎo)致的慢性炎癥。Every等[8]的研究發(fā)現(xiàn),在體外貓胃螺桿菌能結(jié)合胃上皮細(xì)胞,且缺乏MUC1的胃上皮細(xì)胞黏附的細(xì)菌數(shù)量明顯高于表達(dá)MUC1的胃上皮細(xì)胞,然而缺乏MUC1的小鼠感染貓胃螺桿菌后,MUC1黏蛋白并不會(huì)影響貓胃螺桿菌的定植及其致病過(guò)程,與以往Hp的研究結(jié)果不一致。提示MUC1黏蛋白可抑制貓胃螺桿菌黏附胃上皮細(xì)胞但不抑制感染貓胃螺桿菌后的定植和致病。Zhang等[9]通過(guò)Boyden Chambers系統(tǒng)發(fā)現(xiàn)MUC1在感染Hp的胃腸上皮細(xì)胞中的表達(dá)下調(diào),黏膜通透性增強(qiáng);提示Hp感染可能抑制MUC1的表達(dá),直接導(dǎo)致黏膜屏障的嚴(yán)重?fù)p傷。Navabi等[10]報(bào)道無(wú)論在Hp定植早期還是慢性感染期,Hp感染均可降低黏蛋白的生產(chǎn)率、分泌速度以及黏膜中MUC1黏蛋白水平。Radziejewska等[11]采用蛋白質(zhì)印跡法檢測(cè)了Hp根除治療對(duì)胃炎患者胃液中MUC1黏蛋白的影響,結(jié)果顯示治療前幾乎所有患者胃液中MUC1黏蛋白含量較低,而治療末期所有患者胃液中MUC1黏蛋白含量均升高。Radziejewska等[12]的研究采用酶聯(lián)免疫吸附測(cè)定(enzyme linked immunosorbent assay, ELISA)法檢測(cè)了13例胃液標(biāo)本中MUC1黏蛋白的表達(dá)及其與Hp的黏附情況,結(jié)果顯示所有胃液標(biāo)本中均含有MUC1黏蛋白,且Hp均與MUC1黏蛋白相黏附。Park等[13]的研究認(rèn)為過(guò)氧化物酶體增殖物激活受體(PPAR)γ可促進(jìn)AGS胃癌細(xì)胞中MUC1黏蛋白的表達(dá),從而抑制Hp感染導(dǎo)致的白細(xì)胞介素(IL)-8的產(chǎn)生。上述研究均證實(shí)Hp感染與MUC1黏蛋白關(guān)系密切,提示MUC1黏蛋白參與Hp感染,但具體機(jī)制仍未完全明確。
Lindén等[6]通過(guò)體外Hp和胃上皮細(xì)胞聯(lián)合培養(yǎng)認(rèn)為MUC1黏蛋白參與Hp感染的機(jī)制可能為:①M(fèi)UC1黏蛋白以“誘餌”的形式限制Hp黏附細(xì)胞表面:當(dāng)Hp結(jié)合黏蛋白時(shí),黏蛋白的細(xì)胞外區(qū)域隨之脫落。②Hp主要針對(duì)MUC1黏蛋白表達(dá)兩種主要的細(xì)菌表面配基唾液酸結(jié)合黏附素(sialic acid-binding adhesin, SabA)和血型相關(guān)抗原結(jié)合黏附素(blood group antigen-binding adhesin, BabA),而當(dāng)Hp缺乏這兩種表面配基時(shí)MUC1黏蛋白以“空間阻位”的方式阻止Hp黏附細(xì)胞表面。SabA與Lewis b、H type 1抗原有親和力,BabA結(jié)合sialyl Lewis x結(jié)構(gòu)[14-15],MUC1黏蛋白的Lewis b、H type 1抗原和sialyl Lewis x結(jié)構(gòu)可能參與了Hp與MUC1黏蛋白的結(jié)合過(guò)程[16-17]。Guang等[18]的研究結(jié)果發(fā)現(xiàn)感染Hp后的胃癌細(xì)胞可增加MUC1 mRNA和蛋白表達(dá)水平,并增加MUC1基因啟動(dòng)子的活性,Hp可增強(qiáng)STAT3和MUC1本身與含有STAT3結(jié)合位點(diǎn)的MUC1基因啟動(dòng)子的結(jié)合能力,同時(shí)可降低MUC1基因啟動(dòng)子中鄰近STAT3結(jié)合位點(diǎn)區(qū)域的CpG島甲基化。提示Hp可能通過(guò)STAT3和CpG島低甲基化來(lái)調(diào)節(jié)MUC1的表達(dá)。
MUC1的基因多態(tài)性被證實(shí)與Hp感染后胃炎和胃癌的發(fā)展緊密相關(guān)[19-21],為黏蛋白在慢性Hp感染中的重要性提供了有力依據(jù)。為評(píng)估MUC1黏蛋白VNTR差異性對(duì)Hp黏附胃細(xì)胞能力的影響,Costa等[22]通過(guò)以ELISA為基礎(chǔ)的黏附分析法檢測(cè)不同Hp菌株對(duì)能表達(dá)不同VNTR長(zhǎng)度的重組MUC1的胃癌細(xì)胞的黏附能力,結(jié)果顯示Hp菌株對(duì)帶有更大MUC1 VNTR域的胃細(xì)胞的黏附能力更強(qiáng),提示MUC1黏蛋白的差異可決定Hp菌株定植胃黏膜細(xì)胞的能力,且細(xì)菌黏附細(xì)胞的程度取決于MUC1 VNTR域的大小。但Zhang等[23]的研究則發(fā)現(xiàn),在中國(guó)西北地區(qū)漢族人群中MUC1常見基因多態(tài)性與Hp感染和非賁門胃癌的發(fā)生風(fēng)險(xiǎn)并無(wú)明顯相關(guān)性。
此外,Hp常位于胃淺層黏膜,而在深層少見,深層黏膜的胃黏液細(xì)胞分泌一種特殊的糖蛋白O-連接寡聚糖,其能抑制Hp細(xì)胞壁中膽固醇-α-D-吡喃葡萄糖苷(cholesteryl-alpha-D-glucopyranoside, CGL)的合成,具有抗Hp的活性,這些O-連接寡聚糖末端含有α-GlcNAc(alpha1,4-linked N-acetylglucosamine)[24]。Karasawa等[25]設(shè)計(jì)了A4gnt-/-小鼠,這種小鼠完全缺乏胃腺黏蛋白α-GlcNAc的表達(dá),結(jié)果顯示在無(wú)Hp感染的情況下,α-GlcNAc的缺失通過(guò)炎癥相關(guān)途徑觸發(fā)胃癌的發(fā)生,因此認(rèn)為末端含有α-GlcNAc的胃腺黏蛋白可通過(guò)抑制Hp感染和抑制炎癥相關(guān)途徑來(lái)預(yù)防胃癌的發(fā)生。
綜上所述,MUC1黏蛋白作為細(xì)胞表面黏液屏障中的一種重要成員,與Hp關(guān)系密切,參與了Hp的感染機(jī)制,但具體機(jī)制仍需未來(lái)研究進(jìn)一步探索,而胃黏液中的其他黏蛋白也可能有抑制Hp感染和腫瘤相關(guān)炎癥途徑的作用,因此在未來(lái)的研究中需進(jìn)一步引起關(guān)注。
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