諸葛春鳳　劉詩權(quán)

廣西醫(yī)科大學(xué)第一附屬醫(yī)院消化科(530021)

上皮-間質(zhì)轉(zhuǎn)化在結(jié)直腸癌中的研究進(jìn)展

諸葛春鳳劉詩權(quán)*

廣西醫(yī)科大學(xué)第一附屬醫(yī)院消化科(530021)

摘要結(jié)直腸癌是常見的惡性腫瘤，侵襲轉(zhuǎn)移是導(dǎo)致患者死亡的主要原因。上皮-間質(zhì)轉(zhuǎn)化(EMT)是上皮細(xì)胞轉(zhuǎn)變?yōu)殚g質(zhì)表型的過程，參與包括結(jié)直腸癌在內(nèi)多種腫瘤的發(fā)生、發(fā)展、侵襲和轉(zhuǎn)移，并與腫瘤化療耐藥密切相關(guān)。EMT的發(fā)生涉及多條信號通路，但其機(jī)制尚未完全闡明。本文就EMT機(jī)制及其在結(jié)直腸癌中的研究進(jìn)展作一綜述。

關(guān)鍵詞上皮-間質(zhì)轉(zhuǎn)化；結(jié)直腸腫瘤；分子機(jī)制；信號通路；抗藥性, 腫瘤

Drug Resistance, Neoplasm

上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition, EMT)指上皮細(xì)胞失去極性，細(xì)胞骨架重塑，轉(zhuǎn)變成具有侵襲轉(zhuǎn)移能力的間質(zhì)樣上皮的現(xiàn)象[1]。EMT分為三種亞型：Ⅰ型EMT與胚胎發(fā)育和器官形成有關(guān)，Ⅱ型EMT與創(chuàng)傷修復(fù)、炎癥和纖維化有關(guān)，Ⅲ型EMT與腫瘤侵襲、轉(zhuǎn)移和凋亡密切相關(guān)[2]。EMT主要表現(xiàn)為上皮表型消失，如上皮細(xì)胞標(biāo)記物E-cadherin、β-catenin等表達(dá)下調(diào)或逐漸消失，并獲得間質(zhì)表型，如間質(zhì)細(xì)胞標(biāo)記物N-cadherin、Vimentin、MMPs等，β-catenin核易位，負(fù)性調(diào)控膜相關(guān)性E-cadherin/β-catenin復(fù)合物的形成，使腫瘤細(xì)胞間黏附能力下降，導(dǎo)致細(xì)胞骨架動力學(xué)改變，從而增強腫瘤細(xì)胞侵襲轉(zhuǎn)移的能力。

一、EMT的概念和特征

1982年Greenburg等[3]研究人晶狀體時發(fā)現(xiàn)，其上皮細(xì)胞在膠原凝膠中發(fā)生形態(tài)的改變，形成偽足，并向間質(zhì)樣細(xì)胞分化，從而提出EMT的概念。Boden國際會議提出：在細(xì)胞形態(tài)學(xué)和侵襲運動方面，可用下列標(biāo)準(zhǔn)來判斷是否發(fā)生EMT：①細(xì)胞極性的喪失，細(xì)胞與細(xì)胞間結(jié)構(gòu)相對松散；②出現(xiàn)紡錘形樣或成纖維樣的形態(tài)；③板狀/絲狀偽足的出現(xiàn)；④侵襲轉(zhuǎn)移增強[4]。

二、EMT參與結(jié)直腸癌的分子機(jī)制

1. 上皮細(xì)胞表型的維持：上皮標(biāo)志分子主要包括黏附蛋白E-cadherin、β-catenin和Occludin等，其中E-cadherin是腫瘤侵襲轉(zhuǎn)移的關(guān)鍵分子事件。E-cadherin可招募細(xì)胞質(zhì)中的β-catenin，形成E-cadherin/β-catenin復(fù)合物，參與細(xì)胞間連接[5]。E-cadherin還可通過β-catenin與肌動蛋白纖維相連，形成穩(wěn)定的細(xì)胞間連接。腫瘤細(xì)胞的分化依賴于E-cadherin，分化較好的癌細(xì)胞株中，E-cadherin表達(dá)接近正常狀態(tài)，而在未分化或低分化癌中的表達(dá)減弱或不表達(dá)。E-cadherin受多種生長因子(EGF、FGF/HGF、TGF-β等)和轉(zhuǎn)錄因子(Snail/slug、Zeb1/2、Smad、Twist)調(diào)控，這些因子作用于E-cadherin啟動子E盒，抑制其轉(zhuǎn)錄和表達(dá)[6-7]。細(xì)胞內(nèi)E-cadherin是黏附連接和上皮完整性的主要組件，低表達(dá)和缺失均會引起細(xì)胞間黏附力減弱，運動能力增強，從而引起腫瘤細(xì)胞侵襲轉(zhuǎn)移。Ding等[8]發(fā)現(xiàn)E-cadherin表達(dá)缺失常見于進(jìn)展型結(jié)腸癌，因此結(jié)腸癌中E-cadherin表達(dá)減少或缺失可能常伴有遠(yuǎn)處轉(zhuǎn)移，且患者預(yù)后差。E-cadherin基因可通過沉默甲基化啟動序列完成轉(zhuǎn)錄水平的調(diào)節(jié)[9]。Brabletz等[10]發(fā)現(xiàn)抑制E-cadherin的表達(dá)，誘導(dǎo)β-catenin核易位可增強結(jié)直腸癌細(xì)胞的侵襲能力，且E-cadherin低表達(dá)與結(jié)直腸癌發(fā)生遠(yuǎn)處轉(zhuǎn)移有關(guān)。由此可見，E-cadherin可作為評估結(jié)直腸癌浸潤、擴(kuò)散和細(xì)胞分化程度等的一項檢測指標(biāo)。

2. 間質(zhì)表型標(biāo)記物：Vimentin為間葉細(xì)胞中的細(xì)胞骨架蛋白，在正常上皮細(xì)胞中不表達(dá)，僅見于腫瘤間質(zhì)，因此Vimentin可作為細(xì)胞EMT的重要標(biāo)志。大量研究已證實Vimentin在多種惡性腫瘤(如肺癌、胃癌、結(jié)腸癌、前列腺癌等)中表達(dá)，且與腫瘤細(xì)胞的分化、侵襲和轉(zhuǎn)移密切相關(guān)[11]。但即使同一腫瘤，不同細(xì)胞株中Vimentin表達(dá)亦不相同，如Vimentin在結(jié)腸癌細(xì)胞株SW480中高表達(dá)，而在其他細(xì)胞株(HT-29、SW948、RKO)中甚至不表達(dá)。研究[12]發(fā)現(xiàn)干擾Vimentin mRNA下調(diào)其表達(dá)，對于SW480結(jié)腸癌細(xì)胞的黏附特性無影響，細(xì)胞劃痕實驗和侵襲實驗顯示細(xì)胞遷移、侵襲能力顯著下降。邵書先等[13]的研究發(fā)現(xiàn)結(jié)直腸癌組織中Vimentin基因的甲基化率增高，但與患者的性別、年齡、腫瘤部位、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移和TNM分期均無關(guān)，說明Vimentin基因甲基化檢測可能對診斷早期結(jié)直腸癌具有重要意義。

3. p53基因：p53為調(diào)控結(jié)腸癌EMT發(fā)生的關(guān)鍵分子，能調(diào)控侵襲性腫瘤中與轉(zhuǎn)移有關(guān)的基因。在p21不存在的情況下，p53從野生型向突變型轉(zhuǎn)變，抑制E-cadherin表達(dá)并上調(diào)Slug和Zeb-1表達(dá)，后者是抑制E-cadherin表達(dá)的轉(zhuǎn)錄因子，從而促進(jìn)EMT的發(fā)生。突變型p53對E-cadherin的抑制作用主要是通過結(jié)合E-cadherin近端啟動子區(qū)E盒，激活Hedgehog-GLI信號通路，從而增強結(jié)腸癌細(xì)胞侵襲、遷移和增殖的能力[14]。Chanrion等[15]的NICD/p53-/-小鼠模型研究證實p53缺失可抑制miRNAs表達(dá)，從而激活Notch和Wnt信號通路，而這些通路又可負(fù)性調(diào)控p53和miRNAs表達(dá)，形成一個循環(huán)通路，上調(diào)EMT相關(guān)轉(zhuǎn)錄因子的表達(dá)，最終導(dǎo)致EMT。

4. miRNAs：miRNAs是一類新發(fā)現(xiàn)的內(nèi)源性非編碼單鏈小分子RNA，通過結(jié)合靶基因mRNA的3’端非翻譯區(qū)而負(fù)向調(diào)控蛋白翻譯。研究[16]表明miRNAs可通過介導(dǎo)EMT參與結(jié)直腸癌的侵襲轉(zhuǎn)移。目前發(fā)現(xiàn)抑制EMT的miRNAs包括miR-200家族、miR-132、miR-28、miR-428等；促進(jìn)EMT的miRNAs包括miR-21、miR-31、miR-214、miR-29a-3p等。Zheng等[17]證實有轉(zhuǎn)移的結(jié)直腸癌組織中miR-132低表達(dá)，并誘導(dǎo)結(jié)直腸癌細(xì)胞發(fā)生EMT。有報道[18]發(fā)現(xiàn)，miR-30b在結(jié)直腸癌中表達(dá)下調(diào)，可上調(diào)Snail表達(dá)，并抑制Snail下游基因E-cadherin表達(dá)、促進(jìn)Vimentin表達(dá)，進(jìn)而誘導(dǎo)EMT，增強結(jié)直腸癌的侵襲遷移能力。Cai等[19]發(fā)現(xiàn)TGF-β誘導(dǎo)結(jié)腸癌細(xì)胞HT-29發(fā)生EMT，miR-22、miR-200b表達(dá)下調(diào)；miR-22缺失對EMT無影響，敲除miR-200b發(fā)現(xiàn)EMT間質(zhì)標(biāo)記物N-cadherin、Vimentin和Twist1表達(dá)增加，E-cadherin表達(dá)減少。Hur等[20]發(fā)現(xiàn)miR-200c可抑制EMT的發(fā)生，上調(diào)E-cadherin表達(dá)并下調(diào)Vimentin表達(dá)，從而抑制結(jié)直腸癌細(xì)胞轉(zhuǎn)移。有研究[21]發(fā)現(xiàn)，miR-139-5p在結(jié)腸癌中作為抑癌基因發(fā)揮生物學(xué)功能。miR-29a-3p和miR-21-5p在結(jié)直腸癌和腺瘤中均高表達(dá)[22]。Cottonham等[23]發(fā)現(xiàn)miR-21與miR-31共同作用，通過抑制TIAM1表達(dá)而增強結(jié)腸癌細(xì)胞遷移和侵襲能力。隨著研究的不斷深入，miRNAs有望成為區(qū)分結(jié)直腸癌類型的指標(biāo)以及結(jié)直腸癌治療的靶點。

三、EMT參與結(jié)直腸癌的相關(guān)信號通路

EMT的發(fā)生由細(xì)胞內(nèi)信號轉(zhuǎn)導(dǎo)通路精確調(diào)控，細(xì)胞外信號與細(xì)胞膜上相關(guān)受體結(jié)合將信號傳至細(xì)胞內(nèi)，激活細(xì)胞內(nèi)核轉(zhuǎn)錄因子，調(diào)控相關(guān)基因表達(dá)。

1. TGF-β/Smad：在腫瘤發(fā)生、發(fā)展過程中，TGF-β發(fā)揮了初期腫瘤抑制以及中后期腫瘤促進(jìn)的雙向作用[24]。近年發(fā)現(xiàn)TGF-β為EMT的重要誘導(dǎo)因素，通過Smad和非Smad信號通路對EMT進(jìn)行調(diào)節(jié)。TGF-β誘導(dǎo)EMT發(fā)生的過程為：TGF-β結(jié)合腫瘤細(xì)胞膜上的TGF-βⅡ型受體(TβRⅡ)，通過TβRⅡ激酶使TGF-βⅠ型受體(TβRⅠ)磷酸化，激活下游Smad2/3并使其磷酸化，磷酸化的R-Smad脫離受體與胞內(nèi)Smad4結(jié)合形成三聚體，進(jìn)入細(xì)胞核后直接與目的基因結(jié)合，從而調(diào)節(jié)目的基因的表達(dá)[25]。Smad4在TGF-β誘導(dǎo)的EMT中發(fā)揮重要作用。有研究[26]顯示Smad4作為抑癌基因能上調(diào)E-cadherin表達(dá)，加強結(jié)腸癌SW480細(xì)胞的細(xì)胞間連接。Smad4缺失或突變導(dǎo)致結(jié)腸癌患者預(yù)后差并增加結(jié)腸癌遠(yuǎn)處轉(zhuǎn)移的機(jī)會。抑制性Smad(如Smad6/7)能減弱TGF-β信號通路，抑制EMT的發(fā)展。然而，Halder等[27]發(fā)現(xiàn)，Smad7等位基因與結(jié)直腸癌的發(fā)生有關(guān)，并能抑制Smad信號通路從而促進(jìn)結(jié)直腸癌肝轉(zhuǎn)移。最近研究發(fā)現(xiàn)，早期結(jié)腸癌細(xì)胞中，TGF-β/Smad能上調(diào)NDRG2表達(dá)，誘導(dǎo)細(xì)胞凋亡，而Sp1在該信號通路中起關(guān)鍵作用；晚期結(jié)腸癌中，Sp1發(fā)生突變或甲基化則抑制TGF-β/Smad信號通路對NDRG2的轉(zhuǎn)錄激活而誘導(dǎo)結(jié)腸癌細(xì)胞EMT的發(fā)生[24]。

2. Src/FAK：FAK是一種重要的非受體蛋白酪氨酸激酶，其分子氨基端含有與整合素β亞單位、細(xì)胞骨架蛋白和信號轉(zhuǎn)導(dǎo)蛋白結(jié)合的位點，為cadherin和integrin介導(dǎo)的黏附通路的調(diào)節(jié)介質(zhì)。Src/FAK信號通路可引起E-cadherin的胞吞作用，促進(jìn)EMT的發(fā)生。采用shRNA技術(shù)敲除結(jié)腸癌SW480細(xì)胞FAK基因，并將該細(xì)胞植入裸鼠體內(nèi)成瘤，結(jié)果顯示瘤體明顯減小[28]。Canel等[29]的研究發(fā)現(xiàn)，F(xiàn)AK抑制劑PF-562,271可抑制腫瘤細(xì)胞的擴(kuò)散和轉(zhuǎn)移。近期一項結(jié)腸癌研究[30]中，高表達(dá)GRP78可通過激活FAK信號通路引起DLD1細(xì)胞偽足的形成而發(fā)生EMT。因此，干擾FAK有望成為治療結(jié)腸癌的新靶點。

3. NF-κB：NF-κB信號通路的活化受多種信號分子和多條信號通路的調(diào)控，IKK/IκB/NF-κB為激活NF-κB的關(guān)鍵環(huán)節(jié)。正常細(xì)胞中，NF-κB亞基與I-κBα、β或γ結(jié)合，以非活性形式存在于胞質(zhì)中。受到刺激后通過激活I(lǐng)KK，磷酸化IκB，活化NF-κB并轉(zhuǎn)移至細(xì)胞核，調(diào)節(jié)下游基因的表達(dá)[31]。細(xì)胞間黏附分子1(ICAM-1)是NF-κB信號通路中調(diào)節(jié)細(xì)胞間聯(lián)系的重要分子，有研究[32]將HK-2細(xì)胞與單核細(xì)胞共培養(yǎng)，激活NF-κB信號通路，上調(diào)ICAM-1表達(dá)，從而誘導(dǎo)了EMT。鞘氨醇激酶1(SphK1)可激活ERK和NF-κB通路，上調(diào)結(jié)腸癌細(xì)胞HT-29中MMP-2、MMP-9和uPA的表達(dá)和分泌[33]，從而促進(jìn)腫瘤侵襲和轉(zhuǎn)移。缺氧/復(fù)氧可誘導(dǎo)結(jié)腸癌細(xì)胞株EMT的發(fā)生，其機(jī)制可能與激活NF-κB信號通路有關(guān)[34]。還有研究[35]發(fā)現(xiàn)TNF-α可活化NF-κB，促進(jìn)結(jié)腸癌細(xì)胞EMT的發(fā)生，并增強細(xì)胞侵襲遷移能力。

四、EMT與結(jié)直腸癌的化療耐藥相關(guān)

結(jié)直腸癌發(fā)生侵襲、轉(zhuǎn)移是患者死亡的主要原因。許多結(jié)直腸癌患者早期并無明顯癥狀，就診時因癌細(xì)胞通過血行或淋巴轉(zhuǎn)移等因素失去了最佳手術(shù)治療時機(jī)，化放療為主要的治療途徑。目前結(jié)直腸癌的化療藥物包括阿霉素、奧沙利鉑、吉西他濱等，隨著分子靶向藥物的問世，如EGFR抑制劑(西妥昔單抗)等為結(jié)腸癌治療帶來新的希望，但上述藥物均易發(fā)生耐藥性。EMT參與了結(jié)直腸癌化療藥物耐藥的發(fā)生。研究[36]發(fā)現(xiàn)阿霉素耐藥的結(jié)腸癌細(xì)胞中TGF-β信號通路起關(guān)鍵作用，抑制TGF-β能逆轉(zhuǎn)EMT，從而增強結(jié)腸癌細(xì)胞HCT116對阿霉素的敏感性。有研究[37]發(fā)現(xiàn)奧沙利鉑耐藥的結(jié)直腸癌細(xì)胞株呈長梭形、極性喪失、細(xì)胞分離、偽足形成，免疫熒光檢測發(fā)現(xiàn)E-cadherin表達(dá)下調(diào)或缺失、Vimentin表達(dá)上調(diào)。Hoshino等[38]發(fā)現(xiàn)Snail可提高結(jié)腸癌細(xì)胞對5-Fu耐藥性且結(jié)腸癌細(xì)胞株可見EMT的發(fā)生。

五、展望

EMT的發(fā)生涉及多種轉(zhuǎn)錄因子和信號通路，形成一個復(fù)雜的網(wǎng)絡(luò)結(jié)構(gòu)，在包括結(jié)直腸癌在內(nèi)的腫瘤發(fā)生和侵襲轉(zhuǎn)移中發(fā)揮重要作用。大量研究發(fā)現(xiàn)，EMT與腫瘤侵襲轉(zhuǎn)移和化療耐藥密切相關(guān)，因此明確EMT發(fā)生機(jī)制以及研究治療方法至關(guān)重要。靶向治療是目前研究的熱點，具有療效確切、不良反應(yīng)小的優(yōu)點，但目前尚未研制出完善的EMT靶向藥物。因此，需更深入探索腫瘤尤其是結(jié)直腸癌EMT的發(fā)生機(jī)制，為結(jié)直腸癌的治療提供理論依據(jù)和突破口。

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(2015-07-01收稿；2015-08-14修回)

Advances in Research on Epithelial-mesenchymal Transition in Colorectal Cancer

ZHUGEChunfeng,LIUShiquan.

DepartmentofDigestiveDiseases,theFirstAffiliatedHospitalofGuangxiMedicalUniversity,Nanning(530021)

Correspondence to: LIU Shiquan, Email: poempower@163.com

AbstractColorectal cancer is a common malignant tumor, and invasion and metastasis are the major causes of death. Epithelial-mesenchymal transition (EMT) occurs along with transition from epithelial phenotype to mesenchymal phenotype. EMT is involved in the genesis, development, invasion and metastasis of various tumors including colorectal cancer. EMT is closely associated with chemotherapy resistance of tumors. Various signaling pathways are involved in the pathogenesis of EMT and its mechanism is not fully clear. This article reviewed the molecular mechanism and role of EMT in colorectal cancer.

Key wordsEpithelial-Mesenchymal Transition;Colorectal Neoplasms;Molecular Mechanism;Signal Pathway;

DOI:10.3969/j.issn.1008-7125.2016.05.013

*本文通信作者， Email: poempower@163.com