李興江， 陳秀， 何蘊(yùn)藉， 祝靈平， 唐金海

乳腺癌是女性尤其是年齡<45歲的女性群體中最常見的腫瘤疾病[1]，且是女性死亡的主要原因之一[2]。最新數(shù)據(jù)顯示，全球范圍內(nèi)乳腺癌的新發(fā)病例約為170萬/年，死亡人數(shù)約為52萬/年[3]。由于早期檢測方法和治療手段的不斷發(fā)展，近30年來乳腺癌的死亡率明顯下降[4]。但對于失去腫瘤切除機(jī)會的晚期乳腺癌患者，全身化療不失為一種選擇。順鉑作為非特異性細(xì)胞周期藥物和細(xì)胞毒性藥物已廣泛用于治療乳腺癌，它作用于相鄰的N-7位鳥嘌呤，形成1、2位鏈內(nèi)交聯(lián)，或DNA與蛋白質(zhì)交聯(lián)[5-6]。然而，約50%的乳腺癌患者會發(fā)生原發(fā)性耐藥或產(chǎn)生獲得性耐藥[7]。獲得性耐藥是一個(gè)多因素的過程，耐藥性的產(chǎn)生在一定程度上減弱了治療效果。miRNA是一類非編碼小RNA，它們通過降解mRNA或抑制mRNA的翻譯能力而負(fù)向調(diào)控靶基因的表達(dá)[8-11]。現(xiàn)從細(xì)胞生存、DNA損傷反應(yīng)、藥物排泄、DNA甲基化、染色質(zhì)修飾及生物合成幾個(gè)方面闡述miRNA與乳腺癌對順鉑耐藥性產(chǎn)生之間的作用關(guān)系。

1 miRNA與細(xì)胞生存

Let-7i是一個(gè)抑癌miRNA[12-13]，它與乳腺癌細(xì)胞對順鉑的藥物敏感性呈正相關(guān)[14]。Let-7i可以直接作用于多個(gè)致癌蛋白如K-ras、H-ras、HMGA2[12，15-19]，并作用多個(gè)細(xì)胞周期相關(guān)基因如CDC25A、CDK6、cyclin D1、cyclin D2和 cyclin D3[20-21]。沉默的K-ras可以抑制NF-κB p65的核轉(zhuǎn)位，促使TPA反應(yīng)元件(TRE)定位在NRF2基因的外顯子1的調(diào)控區(qū)，進(jìn)而抑制NRF2基因的轉(zhuǎn)錄，最終減弱細(xì)胞對順鉑的耐藥性[22-23]。NF-κB的活化逆轉(zhuǎn)參與了細(xì)胞周期和細(xì)胞凋亡的調(diào)控[24]。高遷移性蛋白A2(HMGA2)屬于結(jié)構(gòu)轉(zhuǎn)錄因子HMGA家族，當(dāng)順鉑引起DNA雙鏈斷裂時(shí)，HMGA2可以使細(xì)胞停滯在sub-G1和G2-M期，引起染色體重構(gòu)[25]，改變順鉑藥效。在MCF-7細(xì)胞中[26]，細(xì)胞周期相關(guān)基因cdk2的激活和細(xì)胞分裂進(jìn)入S期的過程需要CDC25A蛋白的過表達(dá)[27-28]。CDC25A是G1特異細(xì)胞周期調(diào)節(jié)因子[29]，能激發(fā)p21脫離細(xì)胞周期蛋白cyclin E-Cdk2復(fù)合物，從而激活cyclin E-Cdk2[30]。cyclin D1蛋白的下調(diào)導(dǎo)致細(xì)胞停滯在G1期。總的來說，Let-7i通過誘導(dǎo)細(xì)胞周期停滯相關(guān)mRNA的翻譯抑制細(xì)胞增殖，促使細(xì)胞對順鉑敏感[31]。

體內(nèi)外研究發(fā)現(xiàn)，miR-569可以通過NF-κB信號通路下調(diào)TP53INP1的表達(dá)增加乳腺癌細(xì)胞對順鉑的耐受能力[32-33]。Liang等[34]證實(shí)，某些化療藥物可能增強(qiáng)腫瘤細(xì)胞的侵襲和轉(zhuǎn)移能力。miR-200b和miR-200c在MCF-7/CDDP耐藥細(xì)胞中的表達(dá)明顯低于親本MCF-7敏感細(xì)胞，而miR-200b和miR-200c能夠抑制ZEB1/deltaEF1、SIP1/ZEB2。ZEB1和SIP1是抑制E-鈣黏連蛋白和上皮間質(zhì)轉(zhuǎn)化(EMT)的轉(zhuǎn)錄因子[35-36]。上皮間質(zhì)轉(zhuǎn)化是公認(rèn)的腫瘤侵襲轉(zhuǎn)移機(jī)制之一。推測，miR-200b和miR-200c的表達(dá)下調(diào)可以誘導(dǎo)腫瘤細(xì)胞發(fā)生侵襲、轉(zhuǎn)移和順鉑耐藥。Schwarzenbach等[37]報(bào)道，miR-214可作為鑒別乳腺癌與健康正常對照的診斷分子，也可作為乳腺癌淋巴結(jié)轉(zhuǎn)移的分子標(biāo)志物。MiR-214還可通過靶向抑制PTEN/Akt信號通路誘導(dǎo)細(xì)胞產(chǎn)生順鉑耐藥性和增加細(xì)胞的生存率[38]?？傊?，let-7i、miR-569、miR-200、miR-214主要通過調(diào)節(jié)細(xì)胞的存活能力來調(diào)節(jié)細(xì)胞對順鉑的耐藥性。

2 miRNA與DNA損傷反應(yīng)

大多數(shù)腫瘤可以通過調(diào)節(jié)DNA損傷反應(yīng)克服腫瘤初期的藥物作用，并建立獲得性耐藥性，從而產(chǎn)生了假設(shè)：參與DNA損傷反應(yīng)過程的多個(gè)miRNA與腫瘤化療耐藥性相關(guān)[39]。DNA損傷反應(yīng)包括DNA修復(fù)、細(xì)胞凋亡和細(xì)胞沉默等過程[40]?，F(xiàn)已證明，miR-296-5p和miR-382通過引發(fā)細(xì)胞沉默過程介導(dǎo)腫瘤細(xì)胞的耐藥性。miR-21通過減少53BP1(雙鏈DNA斷裂修復(fù)的分子標(biāo)志物)位點(diǎn)的數(shù)量，增強(qiáng)DNA損傷耐受、改善DNA修復(fù)和藥物清除過程。無獨(dú)有偶，miR-200b和miR-200c能夠通過抑制ZEB1/deltaEF1和SIP1/ZEB2的表達(dá)決定細(xì)胞的上皮表型[35]，而細(xì)胞來源或腫瘤類型是miRNA對DNA損傷產(chǎn)生何種應(yīng)答的內(nèi)在關(guān)鍵因素[41]。上述結(jié)果表明，miRNA家族可以逆轉(zhuǎn)腫瘤細(xì)胞的藥物敏感性。順鉑類抗腫瘤藥物通過激活A(yù)TR和p53基因，減少磷酸化Chk1，引起細(xì)胞凋亡[42]，而在MCF-7細(xì)胞中敲除表達(dá)miR-203的基因能夠逆轉(zhuǎn)對SOCS3的直接抑制，激活p53、p21(WAF1/CIP1)和Bax等基因，誘發(fā)細(xì)胞生長抑制和細(xì)胞凋亡，抑制耐藥[43]。除了miR-203的抗凋亡作用，miR-21也證實(shí)可以調(diào)節(jié)p21的表達(dá)，抑制細(xì)胞凋亡，改變細(xì)胞對順鉑的敏感性[44]。

STAT B屬于轉(zhuǎn)錄因子STAT家族的一員。有研究發(fā)現(xiàn)，miR-134能靶向結(jié)合STAT5B mRNA的3’UTR端[45]，而STAT5B可以誘導(dǎo)HSP90的轉(zhuǎn)錄[46]，使得包括Bcl-2在內(nèi)的致癌蛋白穩(wěn)定表達(dá)[47]，克服腫瘤細(xì)胞的凋亡[48]。推測miR-134可通過STAT5B-Hsp90-Bcl-2的相互作用逆轉(zhuǎn)細(xì)胞對順鉑的耐藥作用。O’Brien等[45]比較乳腺癌組織和癌旁正常組織的miRNA的表達(dá)水平，證實(shí)了miR-134在藥物敏感性中所起的積極作用。

BRCA1作為一種腫瘤抑制蛋白，在DNA損傷修復(fù)和細(xì)胞周期中不同蛋白質(zhì)復(fù)合體的相互作用中起核心作用[49]。MCF-7細(xì)胞中，miR-218和miR-200可在轉(zhuǎn)錄水平上調(diào)節(jié)BRCA1表達(dá)[50]，MDA-MB-231細(xì)胞中，miR-638靶向作用于BRCA1的3’-UTR端[51]。由于順鉑耐藥性很大程度上歸因于BRCA1介導(dǎo)的DNA損傷[52]，所以在體外研究中利用miRNA下調(diào)BRCA1的表達(dá)能夠減弱DNA修復(fù)的有效性，從而增加乳腺癌細(xì)胞對順鉑治療的敏感性。綜上所述，miR-296-5p、miR-382、miR-21、miR-200、miR-203和miR-134通過影響DDR(如細(xì)胞沉默，DNA修復(fù)和細(xì)胞凋亡)，miR-218、miR-200和miR-638通過作用于BRCA1來調(diào)節(jié)細(xì)胞對順鉑的效應(yīng)。

3 miRNA與藥物排泄

多藥耐藥相關(guān)蛋白(MRP)家族屬于ATP結(jié)合(ABC)轉(zhuǎn)運(yùn)蛋白， MRP1和MRP2通過轉(zhuǎn)運(yùn)順鉑-S-谷胱甘肽連接復(fù)合物至細(xì)胞外來提高乳腺癌細(xì)胞對順鉑的耐藥性[53-54]。Negoro等[55]證實(shí)，MRP1和MRP2在耐藥性產(chǎn)生的機(jī)制中發(fā)揮著重大作用，MRP1和MRP2的表達(dá)水平在順鉑耐藥的細(xì)胞株中明顯上調(diào)。Pogribny等[56]提出，miR-345和miR-7可以靶向結(jié)合人類MRP1(Abcc1)基因的3’-UTR端，miR-489在MCF-7/CDDP耐藥細(xì)胞中可能靶向結(jié)合MRP2基因。miR-345、miR-7和miR-489主要通過抑制MRP1和MRP2參與到順鉑耐藥性產(chǎn)生的過程中。

4 miRNA與DNA甲基化

DNA甲基轉(zhuǎn)移酶(DNMT)-3A和DNMT-3B是形成DNA甲基化的兩個(gè)關(guān)鍵酶，它們在肺癌細(xì)胞中表達(dá)上調(diào)并與肺癌的預(yù)后負(fù)相關(guān)。Fabbri等[57]發(fā)現(xiàn)，miR-29家族(miR-29a、miR-29b和miR-29c)能靶向結(jié)合DNMT-3A和DNMT-3B的3’-UTRs端，恢復(fù)FHIT和WWOX等甲基化沉默抑制基因的功能。FHIT基因是一個(gè)抑癌基因，其缺失會誘發(fā)乳腺癌的發(fā)生。Su等[58]用薈萃分析法預(yù)測出侵襲性乳腺癌的甲基化FHIT基因增加，表明該甲基化基因可以作為診斷分子標(biāo)志物和腫瘤治療的藥物靶點(diǎn)。WWOX基因包含了染色體脆性位點(diǎn)FRA16D，沉默WWOX的表達(dá)最終將影響ErbB4、AP-2γ、SMAD3、WBP2等轉(zhuǎn)錄因子的活性，并導(dǎo)致乳腺癌的發(fā)生、發(fā)展和耐藥性產(chǎn)生[59]。因此，miR-29家族的高表達(dá)能維持正常的DNA甲基化水平，并同時(shí)在體內(nèi)外條件下抑制腫瘤的發(fā)生。此外，miR-132直接抑制甲基化CpG結(jié)合蛋白2(MeCP2)的表達(dá)。MeCP2屬于甲基化CpG結(jié)合蛋白(MBD)家族，具有選擇性地識別甲基化DNA和重塑染色質(zhì)的功能[60]。在細(xì)胞中阻斷miR-132的抑制作用后，MeCP2的表達(dá)水平顯著增加[61]。Pogribny等[56]的研究佐證了前期的研究結(jié)果：MCF-7/CDDP耐藥細(xì)胞中的DNMT3A以及MeCP2的表達(dá)均受到明顯的抑制。因此，miR-29s和miR-132對鉑類藥物化療療效的作用受到DNA甲基化水平的影響。

5 miRNAs與線粒體

線粒體凋亡作為細(xì)胞凋亡的重要途徑廣泛應(yīng)用于腫瘤的治療中，線粒體凋亡受Bcl-2家族蛋白的調(diào)控，包括促凋亡成員(Bak，Bax，Bim，BNIP3等)和抗凋亡成員(Bcl-2，Mcl-1，Bcl- XL，Bcl-w等)[62]。在體外實(shí)驗(yàn)中，抑制miR-221的表達(dá)會增加順鉑對乳腺癌細(xì)胞的細(xì)胞毒性，研究發(fā)現(xiàn)敲除了miR-221后，Bim、Bax及Bak表達(dá)上調(diào)，推測miR-221通過靶向抑制Bim-Bax/Bak軸誘導(dǎo)細(xì)胞產(chǎn)生順鉑耐藥[63]。MiR-944通過抑制BNIP3的表達(dá)導(dǎo)致順鉑耐藥,用順鉑處理抑制了miR-944的MCF-7細(xì)胞，BNIP3高表達(dá)，線粒體膜電位降低，細(xì)胞中caspase-3被激活，從而逆轉(zhuǎn)耐藥[64]。Kohno等[65]發(fā)現(xiàn)，在特定的腫瘤細(xì)胞中，線粒體轉(zhuǎn)錄因子A(mtTFA)的表達(dá)水平取決于線粒體基因組的特點(diǎn)和順鉑藥物的使用。MtTFA被發(fā)現(xiàn)與腫瘤細(xì)胞的存活、凋亡、增殖密切相關(guān)。在乳腺癌細(xì)胞中，miR-200a的高表達(dá)抑制mtTFA的轉(zhuǎn)錄和翻譯，并能減少線粒體DNA的拷貝數(shù)，從而減弱細(xì)胞增殖和抑制順鉑耐藥性的產(chǎn)生[62]。而miR-199a-3p通過下調(diào)線粒體轉(zhuǎn)錄因子A的表達(dá)可促進(jìn)乳腺癌細(xì)胞對順鉑的敏感性[62]。

6 miRNA生物合成途徑的調(diào)控

已證實(shí)miRNA能夠在耐藥機(jī)制中發(fā)揮重要的調(diào)控作用。因此，中斷部分miRNA的生物合成途徑勢必會引起細(xì)胞耐藥性的變化。Dicer酶是雙核酸酶RNaseⅢ家族的一個(gè)成員，在miRNA成熟過程的第2階段起調(diào)節(jié)作用[63]。miRNA自身對miRNA的生物合成途徑具有負(fù)反饋的作用，使得不同功能的miRNA之間相互制約、相互作用。Chan等[64]經(jīng)過研究證實(shí)，miR-31能夠靶向結(jié)合Dicer酶，抑制miRNA的生物合成過程，在一定程度上增強(qiáng)細(xì)胞對藥物的敏感性。Martello等[66]發(fā)現(xiàn)，miR-103和miR-107可以在乳腺癌細(xì)胞中通過靶向結(jié)合Dicer酶而抑制miRNA的生物合成，參與乳腺癌細(xì)胞的耐藥相關(guān)機(jī)制。雖然Dicer酶的調(diào)節(jié)機(jī)制很復(fù)雜，但是通過miRNA的生物合成途徑調(diào)節(jié)耐藥性這一機(jī)制已經(jīng)得到充分的證實(shí)。

7 結(jié)語

鉑類藥物是廣泛用于乳腺癌治療的二線方案， miRNA家族可作用于一系列編碼基因，調(diào)節(jié)細(xì)胞的分化、增殖、凋亡、侵襲、遷移、上皮間質(zhì)轉(zhuǎn)化(EMT)過程和增強(qiáng)絲裂原活化蛋白激酶(MAPK)信號通路，來改變mRNA的表達(dá)，逆轉(zhuǎn)對順鉑的耐藥性。這一現(xiàn)象指明了乳腺癌治療可能新方向。然而，miRNA誘導(dǎo)耐藥形成的相關(guān)微環(huán)境變化的研究只有少量報(bào)道，miRNA的相互作用是否存在其他途徑仍未知，將miRNA的靶向治療應(yīng)用于乳腺癌的治療策略中具有一定的挑戰(zhàn)性。

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