史 敏, 呂建鑫, 潘 波, 王曉軍, 戴璐嫻, 楊曉紅, 付子毅, 謝 暉

(1. 江蘇省揚(yáng)州市婦幼保健院 乳腺科, 江蘇 揚(yáng)州, 225002; 2. 南京市婦幼保健院, 江蘇 南京, 210004)

microRNA(miRNA)是一類長(zhǎng)度約21～25 nt的非編碼RNA, 在轉(zhuǎn)錄后水平調(diào)控靶基因的表達(dá)[1-2]。miRNA的成熟包括在胞核及胞質(zhì)中的加工過(guò)程，在核酸內(nèi)切酶Drosha作用下，miRNA的編碼基因由RNA聚合酶Ⅱ轉(zhuǎn)錄形成具有莖環(huán)結(jié)構(gòu)的RNA由核內(nèi)輸出，經(jīng)Dicer酶加工形成成熟的miRNA，與Argonaute蛋白結(jié)合形成RISC(RNA-induced silencing complex, 基因沉默復(fù)合體)，進(jìn)而調(diào)控靶基因的表達(dá)[3-4]。miRNA與靶基因的3′-UTR區(qū)結(jié)合，導(dǎo)致mRNA降解和/或翻譯抑制，下調(diào)靶蛋白的表達(dá)，從而達(dá)到調(diào)控靶基因表達(dá)的目的[5]。事實(shí)上, miRNA調(diào)節(jié)了約30%的蛋白編碼基因，并參與多種生物學(xué)功能的調(diào)控，包括細(xì)胞增殖、凋亡及分化[6]。因此, miRNA的功能異常與多種人類疾病有關(guān)，包括腫瘤[7]在內(nèi)。近年研究[8]表明, miRNA與多種實(shí)體腫瘤的耐藥性密切相關(guān)。經(jīng)對(duì)乳腺癌細(xì)胞耐藥株及敏感株的研究，證實(shí)多種miRNA對(duì)乳腺癌多藥耐藥具有調(diào)控作用[9-14]。

1 miRNA調(diào)控乳腺癌耐藥的機(jī)制

乳腺癌是女性最常見(jiàn)的惡性腫瘤，全球每年約有1.4億新發(fā)病例，約有46萬(wàn)婦女死于乳腺癌，是導(dǎo)致患癌癥婦女死亡的首要原因[15]。近年來(lái)，我國(guó)女性乳腺癌發(fā)病率逐年顯著遞增，遠(yuǎn)高于其他國(guó)家，并趨于年輕化，嚴(yán)重威脅女性的生命健康和生活質(zhì)量[16]。盡管在過(guò)去20年間，通過(guò)對(duì)疾病篩查的普遍實(shí)施和新的治療方法的發(fā)展，西方國(guó)家的乳腺癌死亡率顯著下降，但對(duì)這些治療方法的耐藥成為越來(lái)越嚴(yán)重的問(wèn)題[17]，據(jù)報(bào)道[18]約有90%的乳腺癌患者最終死于耐藥。乳腺腫瘤對(duì)結(jié)構(gòu)和功能不同的化療藥物均可能產(chǎn)生多藥耐藥(MDR), 明顯影響化療效果。MDR是指腫瘤細(xì)胞在接觸一種抗腫瘤藥物并產(chǎn)生耐藥的同時(shí)，對(duì)結(jié)構(gòu)、功能及殺傷機(jī)制迥異的多種抗腫瘤藥物具有交叉耐藥，是最重要的耐藥形式之一。最新研究[19]表明，MDR已成為乳腺癌治療失敗的關(guān)鍵因素。

Iorio等[20]于2005年首次發(fā)現(xiàn)，miRNA在乳腺癌和正常乳腺組織中表達(dá)存在顯著差異。Ryu等[21]在MCF-710A、MCF-7及MDA-MB-231等不同乳腺癌細(xì)胞株中鑒定出189種表達(dá)明顯異常的miRNA，且這些miRNA均有不同程度的致癌潛能。后續(xù)研究發(fā)現(xiàn)，多種miRNA與乳腺癌耐藥相關(guān), miR-221/222在他莫昔芬耐藥的細(xì)胞中低表達(dá)[22], miR-328在米托蒽醌耐藥的細(xì)胞中低表達(dá)[23], miR-125在紫杉醇耐藥的細(xì)胞中高表達(dá)[24]等等。這些證據(jù)充分說(shuō)明: miRNA的表達(dá)異常是乳腺癌耐藥細(xì)胞的一個(gè)重要特征，與乳腺癌耐藥有著極其密切的關(guān)系。miRNA對(duì)乳腺癌耐藥的調(diào)控機(jī)制十分復(fù)雜，目前并未完全闡明?，F(xiàn)今較明確的機(jī)制主要包括調(diào)節(jié)ABC轉(zhuǎn)運(yùn)蛋白的表達(dá)、調(diào)節(jié)凋亡通路、調(diào)節(jié)藥物代謝酶的表達(dá)及調(diào)節(jié)腫瘤干細(xì)胞的形成等。

1.1 miRNA對(duì)ABC轉(zhuǎn)運(yùn)蛋白的調(diào)節(jié)

乳腺癌患者產(chǎn)生MDR的最主要原因是由藥物外排增加、細(xì)胞內(nèi)藥物濃度下降所致[25]。藥物外排增加受ABC轉(zhuǎn)運(yùn)蛋白調(diào)節(jié)，其在預(yù)后較差的乳腺癌各亞型中均表達(dá)顯著增加[26]。P糖蛋白(P-glycoprotein)是ABC轉(zhuǎn)運(yùn)蛋白中研究最為透徹的與藥物外排有關(guān)的蛋白，與紫杉烷類及蒽環(huán)類化療藥物耐藥密切相關(guān)。P-gp由MDR1基因(ABCB1)編碼，可以轉(zhuǎn)運(yùn)多種分子結(jié)構(gòu)，這即意味著只要對(duì)一種化療藥物耐藥，通常就會(huì)對(duì)多種結(jié)構(gòu)不同的藥物耐藥。研究[11，27]表明，miR-27a、miR-451可能上調(diào)多藥耐藥基因MDR1及其產(chǎn)物P-gp的表達(dá)。另有多項(xiàng)研究顯示，miRNA能以ABC超家族的多個(gè)成員如ABCB、ABCG、ABCC等為靶基因，對(duì)腫瘤細(xì)胞耐藥性進(jìn)行調(diào)控。Pan等[10]研究發(fā)現(xiàn), miR-328在乳腺癌細(xì)胞中與ABCG2的表達(dá)呈負(fù)相關(guān)，耐藥細(xì)胞株MCF-7/MXl00中, miR-328表達(dá)顯著下調(diào)，而ABCG2表達(dá)顯著上調(diào)，導(dǎo)致細(xì)胞對(duì)米托蒽醌耐藥。Zhou等[24]為進(jìn)一步闡明miR-328的調(diào)控機(jī)制，分別檢測(cè)轉(zhuǎn)染miR-328的MCF-7/MXl00細(xì)胞、轉(zhuǎn)染miR-328拮抗劑的MCF-7細(xì)胞以及破壞ABCG2 3′-UTR區(qū)相應(yīng)miR-328反應(yīng)元件(MRE)的MCF-7細(xì)胞等的ABCG2 3′-UTR的熒光素酶活性，發(fā)現(xiàn)其分別下降50%以上、上升100%及上升3倍，這充分證實(shí)miR-328是通過(guò)與ABCG2 3′-UTR區(qū)相應(yīng)的MRE特異性結(jié)合，進(jìn)而負(fù)調(diào)控ABCG2的表達(dá)。之后的研究[9]證實(shí), miR-519c和miR-520h通過(guò)靶向作用于ABCG2 mRNA的3′-UTR區(qū)進(jìn)而調(diào)控其蛋白的表達(dá)。Pelletier等[14]通過(guò)對(duì)乳腺癌患者ABCG2 3′-UTR區(qū)的檢測(cè)，發(fā)現(xiàn)miRNA可干擾其多態(tài)性，增強(qiáng)與3′-UTR區(qū)的結(jié)合作用進(jìn)而影響乳腺癌的MDR。后續(xù)研究還發(fā)現(xiàn)更多的miRNA以類似機(jī)制調(diào)控耐藥相關(guān)蛋白的表達(dá)，如miR-451可負(fù)調(diào)控P-gP[11]、miR-326、miR-345和miR-7等，均可負(fù)調(diào)控多藥耐藥蛋白1(MRPl/ABCC1)[13, 28], 與乳腺癌對(duì)阿霉素、依托泊苷以及順鉑等化療藥物耐藥性的形成密切相關(guān)。miR-200c[29]和miR-298[30]在耐多柔比星乳腺癌細(xì)胞中均低表達(dá)，當(dāng)提高其表達(dá)量時(shí)，可增加乳腺癌細(xì)胞對(duì)多柔比星的敏感性并降低MDR1/ABCB1及P-gP的表達(dá)，從而提高細(xì)胞內(nèi)多柔比星藥物濃度。說(shuō)明miRNA通過(guò)調(diào)節(jié)ABC轉(zhuǎn)運(yùn)蛋白的表達(dá)，從而造成細(xì)胞內(nèi)藥物外排、胞內(nèi)藥物濃度下降而致乳腺癌細(xì)胞耐藥性增強(qiáng)。

1.2 miRNA對(duì)細(xì)胞凋亡通路的調(diào)控

細(xì)胞抗凋亡能力的提高是腫瘤細(xì)胞多藥耐藥產(chǎn)生的重要機(jī)制之一[31]?？鼓[瘤藥物通過(guò)介導(dǎo)內(nèi)源性或外源性凋亡反應(yīng)而使腫瘤細(xì)胞死亡。miRNA可通過(guò)調(diào)控凋亡通路相關(guān)蛋白表達(dá)，進(jìn)而影響乳腺癌細(xì)胞對(duì)化療藥物的敏感性。Bcl-2是重要的抗凋亡蛋白，其表達(dá)水平與乳腺癌耐藥細(xì)胞中相關(guān)的miRNA表達(dá)水平密切相關(guān)。Cittelly等[32]研究發(fā)現(xiàn)，Bcl-2的表達(dá)水平與miR-15a、miR-16的表達(dá)水平在MCF-7/HER2Δ16細(xì)胞中呈負(fù)相關(guān)，通過(guò)分別轉(zhuǎn)染miR-15a和miR-16后, Bcl-2的表達(dá)水平顯著降低，細(xì)胞對(duì)他莫昔芬的敏感性顯著增強(qiáng)；而通過(guò)沉默miR-15a和miR-16, 使Bcl-2的表達(dá)顯著增加，細(xì)胞的抗凋亡能力及對(duì)他莫昔芬的耐藥性均顯著增強(qiáng)，提示miR-15a、miR-16通過(guò)下調(diào)Bcl-2的表達(dá)，進(jìn)而調(diào)控乳腺癌細(xì)胞MCF-7/HER2Δ16耐藥性的形成。另有研究[34]證實(shí)，miR-125b、miR-221、miR-222和miR-923在耐紫杉醇乳腺癌細(xì)胞中高表達(dá)，并發(fā)現(xiàn)miR-125b與Bcl-2的表達(dá)水平呈正相關(guān)，均高表達(dá)，其機(jī)制為miR-125b通過(guò)抑制促凋亡基因Bak1(Bcl-2 antagonist killer 1)的表達(dá)致細(xì)胞內(nèi)Bak1的表達(dá)水平顯著降低，Bak1對(duì)Bcl-2的拮抗作用顯著降低，Bcl-2表達(dá)水平上調(diào)，細(xì)胞抗凋亡能力增加，對(duì)紫杉醇耐藥性增加。Ru等[33]發(fā)現(xiàn)miR-203可直接負(fù)調(diào)控細(xì)胞因子信號(hào)抑制因子3(SOCS3)的表達(dá)，進(jìn)而降低了p53、p21、Bax等促凋亡蛋白的表達(dá)，使藥物介導(dǎo)的細(xì)胞凋亡作用明顯受抑制，引起乳腺癌細(xì)胞對(duì)順鉑的耐藥；而敲除乳腺癌細(xì)胞miR-203基因后，其對(duì)順鉑的敏感性顯著增加。而Kong等[34]的研究證實(shí)，miR-155通過(guò)調(diào)控轉(zhuǎn)錄因子FOX03a的表達(dá)使乳腺癌細(xì)胞對(duì)紫杉醇及多柔比星耐藥，而FOX03a的下游靶點(diǎn)均參與了細(xì)胞凋亡進(jìn)程。Gong等[35]研究證實(shí), miR-21表達(dá)上調(diào)使乳腺癌細(xì)胞對(duì)曲妥珠單抗治療耐藥，進(jìn)一步研究證實(shí)其使同源性磷酸酶-張力蛋白基因(phosphatase and tensin homolog, PTEN)表達(dá)缺失，從而導(dǎo)致了腫瘤細(xì)胞的凋亡受抑制。以上研究均表明，在乳腺癌細(xì)胞中，miRNA可以通過(guò)調(diào)控細(xì)胞凋亡而介導(dǎo)乳腺癌細(xì)胞耐藥，這可能也是乳腺癌耐藥性形成的重要原因之一。

1.3 miRNA與藥物代謝酶

藥物代謝加快與乳腺癌患者對(duì)治療反應(yīng)減弱關(guān)系密切[36]。細(xì)胞色素P450(CYP450)酶家族是催化藥物代謝反應(yīng)的關(guān)鍵酶，超過(guò)80%的臨床常用藥物是經(jīng)由CYP450代謝清除的。miRNA可以通過(guò)負(fù)調(diào)控藥物代謝酶CYP450家族中的CYP3A4、CYP1B1等成員的表達(dá)，進(jìn)而調(diào)控乳腺癌的耐藥性。Tsuchiya等[37]在乳腺癌細(xì)胞MCF-7中證實(shí)miR-27b在轉(zhuǎn)錄后水平調(diào)節(jié)CYP1B1的表達(dá)，同時(shí)通過(guò)對(duì)24位乳腺癌患者癌組織及鄰近非癌組織的研究發(fā)現(xiàn), miR-27b在乳腺癌組織中低表達(dá)，并伴隨CYP1B1蛋白的顯著高表達(dá)。另有研究證實(shí), miR-27b[38]、miR-148a[39]抑制CYP3A4的表達(dá)。而CYP1B1[40]、CYP3A4[41]是乳腺癌對(duì)多西他賽耐藥的預(yù)測(cè)因子, CYP1B1、CYP3A4陽(yáng)性乳腺癌對(duì)多西他賽的敏感性較陰性者顯著降低。而這些miRNA在乳腺癌耐藥細(xì)胞中均表達(dá)明顯降低，致CYP3A4、CYP1B1等表達(dá)增加，細(xì)胞內(nèi)化療藥物迅速代謝，難以維持胞內(nèi)有效濃度，進(jìn)而引起細(xì)胞耐藥。

1.4 miRNA與乳腺癌干細(xì)胞

目前，乳腺癌干細(xì)胞(BCSC)的耐藥性已得到普遍的證實(shí)。而miRNA的異常表達(dá)能誘導(dǎo)BCSC的形成、有助于干細(xì)胞特性的維持，可能是BCSC耐藥性形成過(guò)程中的重要的調(diào)控因子。Shimono[42]和Iliopoulos[43]等研究均發(fā)現(xiàn)，miR-200家族在BCSC中表達(dá)水平顯著下降，而miR-200b的表達(dá)上調(diào)會(huì)阻斷BCSC的形成并干擾其特性的維持，從而顯著增強(qiáng)化療藥物對(duì)腫瘤生長(zhǎng)的抑制作用; miR-200b在細(xì)胞內(nèi)的表達(dá)水平下降則能顯著誘導(dǎo)BCSC的形成。miR-128[44]在耐藥性乳腺癌初始細(xì)胞中表達(dá)水平顯著下降，導(dǎo)致Bmi-1及ABCC5過(guò)表達(dá)，而顯示干細(xì)胞特性，并可抑制阿霉素介導(dǎo)的細(xì)胞凋亡和DNA損傷作用，產(chǎn)生耐藥；當(dāng)上調(diào)BCSC中miR-128的表達(dá)水平時(shí)，能夠顯著逆轉(zhuǎn)BCSC對(duì)阿霉素的耐藥性。而B(niǎo)mi-1過(guò)表達(dá)的細(xì)胞具有明顯的干細(xì)胞特性，并證明對(duì)順鉑及培美曲塞耐藥[45]。

2 miRNA在乳腺癌耐藥中的應(yīng)用前景

2.1 miRNA與乳腺癌耐藥的預(yù)測(cè)

如果能夠利用miRNA的檢測(cè)進(jìn)行乳腺癌的診斷及其耐藥性的分析，對(duì)于乳腺癌的臨床治療具有重要意義。Zhu等[46]發(fā)現(xiàn)，幾乎所有體液中均可以檢測(cè)到miR-16、miR-145和miR-155的表達(dá)。而Lodes等[47]更進(jìn)一步證實(shí)，在1mL血漿中即可獲得足夠的可供檢測(cè)的miRNA，同時(shí)可用于判斷是正常組織還是腫瘤組織。這些充分說(shuō)明外周血液中miRNA表達(dá)譜的檢測(cè)對(duì)乳腺癌的診斷及耐藥性的預(yù)測(cè)是有可能實(shí)現(xiàn)的。

2.2 miRNA與乳腺癌耐藥的治療

乳腺癌細(xì)胞耐藥性的形成與細(xì)胞內(nèi)miRNA的異常表達(dá)密切相關(guān)，通過(guò)改變腫瘤細(xì)胞內(nèi)相關(guān)miRNA的表達(dá)水平，逆轉(zhuǎn)乳腺癌的耐藥性是一種潛在的治療策略。誘導(dǎo)miRNA的再表達(dá)，多采用引入合成的短雙鏈RNA分子(即miRNA模擬物)的方式，在臨床前期動(dòng)物實(shí)驗(yàn)中，以病毒、脂質(zhì)體及靶向納米顆粒為載體的轉(zhuǎn)染顯示了良好的作用及耐受性[48]。Kim等[49]將含有miR-145的腺病毒轉(zhuǎn)入人乳腺癌細(xì)胞株和乳腺癌小鼠模型體內(nèi)，發(fā)現(xiàn)能有效抑制乳腺癌細(xì)胞生長(zhǎng)，并且Ad-miR-145與5-Fu聯(lián)合使用療效明顯高于單獨(dú)使用時(shí)的療效。Bourguignon等[50]采用特異性的anti-miR-21序列沉默MCF-7細(xì)胞內(nèi)過(guò)表達(dá)的miR-2l后，能有效阻斷HA-CD44介導(dǎo)的腫瘤細(xì)胞抗凋亡、耐藥等行為的形成。

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