MiRNA介导乳腺癌顺铂耐药的相关机制进展

李兴江， 陈秀， 何蕴藉， 祝灵平， 唐金海

乳腺癌是女性尤其是年龄<45岁的女性群体中最常见的肿瘤疾病[1]，且是女性死亡的主要原因之一[2]。最新数据显示，全球范围内乳腺癌的新发病例约为170万/年，死亡人数约为52万/年[3]。由于早期检测方法和治疗手段的不断发展，近30年来乳腺癌的死亡率明显下降[4]。但对于失去肿瘤切除机会的晚期乳腺癌患者，全身化疗不失为一种选择。顺铂作为非特异性细胞周期药物和细胞毒性药物已广泛用于治疗乳腺癌，它作用于相邻的N-7位鸟嘌呤，形成1、2位链内交联，或DNA与蛋白质交联[5-6]。然而，约50%的乳腺癌患者会发生原发性耐药或产生获得性耐药[7]。获得性耐药是一个多因素的过程，耐药性的产生在一定程度上减弱了治疗效果。miRNA是一类非编码小RNA，它们通过降解mRNA或抑制mRNA的翻译能力而负向调控靶基因的表达[8-11]。现从细胞生存、DNA损伤反应、药物排泄、DNA甲基化、染色质修饰及生物合成几个方面阐述miRNA与乳腺癌对顺铂耐药性产生之间的作用关系。

1 miRNA与细胞生存

Let-7i是一个抑癌miRNA[12-13]，它与乳腺癌细胞对顺铂的药物敏感性呈正相关[14]。Let-7i可以直接作用于多个致癌蛋白如K-ras、H-ras、HMGA2[12，15-19]，并作用多个细胞周期相关基因如CDC25A、CDK6、cyclin D1、cyclin D2和 cyclin D3[20-21]。沉默的K-ras可以抑制NF-κB p65的核转位，促使TPA反应元件(TRE)定位在NRF2基因的外显子1的调控区，进而抑制NRF2基因的转录，最终减弱细胞对顺铂的耐药性[22-23]。NF-κB的活化逆转参与了细胞周期和细胞凋亡的调控[24]。高迁移性蛋白A2(HMGA2)属于结构转录因子HMGA家族，当顺铂引起DNA双链断裂时，HMGA2可以使细胞停滞在sub-G1和G2-M期，引起染色体重构[25]，改变顺铂药效。在MCF-7细胞中[26]，细胞周期相关基因cdk2的激活和细胞分裂进入S期的过程需要CDC25A蛋白的过表达[27-28]。CDC25A是G1特异细胞周期调节因子[29]，能激发p21脱离细胞周期蛋白cyclin E-Cdk2复合物，从而激活cyclin E-Cdk2[30]。cyclin D1蛋白的下调导致细胞停滞在G1期。总的来说，Let-7i通过诱导细胞周期停滞相关mRNA的翻译抑制细胞增殖，促使细胞对顺铂敏感[31]。

体内外研究发现，miR-569可以通过NF-κB信号通路下调TP53INP1的表达增加乳腺癌细胞对顺铂的耐受能力[32-33]。Liang等[34]证实，某些化疗药物可能增强肿瘤细胞的侵袭和转移能力。miR-200b和miR-200c在MCF-7/CDDP耐药细胞中的表达明显低于亲本MCF-7敏感细胞，而miR-200b和miR-200c能够抑制ZEB1/deltaEF1、SIP1/ZEB2。ZEB1和SIP1是抑制E-钙黏连蛋白和上皮间质转化(EMT)的转录因子[35-36]。上皮间质转化是公认的肿瘤侵袭转移机制之一。推测，miR-200b和miR-200c的表达下调可以诱导肿瘤细胞发生侵袭、转移和顺铂耐药。Schwarzenbach等[37]报道，miR-214可作为鉴别乳腺癌与健康正常对照的诊断分子，也可作为乳腺癌淋巴结转移的分子标志物。MiR-214还可通过靶向抑制PTEN/Akt信号通路诱导细胞产生顺铂耐药性和增加细胞的生存率[38]。总之，let-7i、miR-569、miR-200、miR-214主要通过调节细胞的存活能力来调节细胞对顺铂的耐药性。

2 miRNA与DNA损伤反应

大多数肿瘤可以通过调节DNA损伤反应克服肿瘤初期的药物作用，并建立获得性耐药性，从而产生了假设：参与DNA损伤反应过程的多个miRNA与肿瘤化疗耐药性相关[39]。DNA损伤反应包括DNA修复、细胞凋亡和细胞沉默等过程[40]。现已证明，miR-296-5p和miR-382通过引发细胞沉默过程介导肿瘤细胞的耐药性。miR-21通过减少53BP1(双链DNA断裂修复的分子标志物)位点的数量，增强DNA损伤耐受、改善DNA修复和药物清除过程。无独有偶，miR-200b和miR-200c能够通过抑制ZEB1/deltaEF1和SIP1/ZEB2的表达决定细胞的上皮表型[35]，而细胞来源或肿瘤类型是miRNA对DNA损伤产生何种应答的内在关键因素[41]。上述结果表明，miRNA家族可以逆转肿瘤细胞的药物敏感性。顺铂类抗肿瘤药物通过激活ATR和p53基因，减少磷酸化Chk1，引起细胞凋亡[42]，而在MCF-7细胞中敲除表达miR-203的基因能够逆转对SOCS3的直接抑制，激活p53、p21(WAF1/CIP1)和Bax等基因，诱发细胞生长抑制和细胞凋亡，抑制耐药[43]。除了miR-203的抗凋亡作用，miR-21也证实可以调节p21的表达，抑制细胞凋亡，改变细胞对顺铂的敏感性[44]。

STAT B属于转录因子STAT家族的一员。有研究发现，miR-134能靶向结合STAT5B mRNA的3’UTR端[45]，而STAT5B可以诱导HSP90的转录[46]，使得包括Bcl-2在内的致癌蛋白稳定表达[47]，克服肿瘤细胞的凋亡[48]。推测miR-134可通过STAT5B-Hsp90-Bcl-2的相互作用逆转细胞对顺铂的耐药作用。O’Brien等[45]比较乳腺癌组织和癌旁正常组织的miRNA的表达水平，证实了miR-134在药物敏感性中所起的积极作用。

BRCA1作为一种肿瘤抑制蛋白，在DNA损伤修复和细胞周期中不同蛋白质复合体的相互作用中起核心作用[49]。MCF-7细胞中，miR-218和miR-200可在转录水平上调节BRCA1表达[50]，MDA-MB-231细胞中，miR-638靶向作用于BRCA1的3’-UTR端[51]。由于顺铂耐药性很大程度上归因于BRCA1介导的DNA损伤[52]，所以在体外研究中利用miRNA下调BRCA1的表达能够减弱DNA修复的有效性，从而增加乳腺癌细胞对顺铂治疗的敏感性。综上所述，miR-296-5p、miR-382、miR-21、miR-200、miR-203和miR-134通过影响DDR(如细胞沉默，DNA修复和细胞凋亡)，miR-218、miR-200和miR-638通过作用于BRCA1来调节细胞对顺铂的效应。

3 miRNA与药物排泄

多药耐药相关蛋白(MRP)家族属于ATP结合(ABC)转运蛋白， MRP1和MRP2通过转运顺铂-S-谷胱甘肽连接复合物至细胞外来提高乳腺癌细胞对顺铂的耐药性[53-54]。Negoro等[55]证实，MRP1和MRP2在耐药性产生的机制中发挥着重大作用，MRP1和MRP2的表达水平在顺铂耐药的细胞株中明显上调。Pogribny等[56]提出，miR-345和miR-7可以靶向结合人类MRP1(Abcc1)基因的3’-UTR端，miR-489在MCF-7/CDDP耐药细胞中可能靶向结合MRP2基因。miR-345、miR-7和miR-489主要通过抑制MRP1和MRP2参与到顺铂耐药性产生的过程中。

4 miRNA与DNA甲基化

DNA甲基转移酶(DNMT)-3A和DNMT-3B是形成DNA甲基化的两个关键酶，它们在肺癌细胞中表达上调并与肺癌的预后负相关。Fabbri等[57]发现，miR-29家族(miR-29a、miR-29b和miR-29c)能靶向结合DNMT-3A和DNMT-3B的3’-UTRs端，恢复FHIT和WWOX等甲基化沉默抑制基因的功能。FHIT基因是一个抑癌基因，其缺失会诱发乳腺癌的发生。Su等[58]用荟萃分析法预测出侵袭性乳腺癌的甲基化FHIT基因增加，表明该甲基化基因可以作为诊断分子标志物和肿瘤治疗的药物靶点。WWOX基因包含了染色体脆性位点FRA16D，沉默WWOX的表达最终将影响ErbB4、AP-2γ、SMAD3、WBP2等转录因子的活性，并导致乳腺癌的发生、发展和耐药性产生[59]。因此，miR-29家族的高表达能维持正常的DNA甲基化水平，并同时在体内外条件下抑制肿瘤的发生。此外，miR-132直接抑制甲基化CpG结合蛋白2(MeCP2)的表达。MeCP2属于甲基化CpG结合蛋白(MBD)家族，具有选择性地识别甲基化DNA和重塑染色质的功能[60]。在细胞中阻断miR-132的抑制作用后，MeCP2的表达水平显著增加[61]。Pogribny等[56]的研究佐证了前期的研究结果：MCF-7/CDDP耐药细胞中的DNMT3A以及MeCP2的表达均受到明显的抑制。因此，miR-29s和miR-132对铂类药物化疗疗效的作用受到DNA甲基化水平的影响。

5 miRNAs与线粒体

线粒体凋亡作为细胞凋亡的重要途径广泛应用于肿瘤的治疗中，线粒体凋亡受Bcl-2家族蛋白的调控，包括促凋亡成员(Bak，Bax，Bim，BNIP3等)和抗凋亡成员(Bcl-2，Mcl-1，Bcl- XL，Bcl-w等)[62]。在体外实验中，抑制miR-221的表达会增加顺铂对乳腺癌细胞的细胞毒性，研究发现敲除了miR-221后，Bim、Bax及Bak表达上调，推测miR-221通过靶向抑制Bim-Bax/Bak轴诱导细胞产生顺铂耐药[63]。MiR-944通过抑制BNIP3的表达导致顺铂耐药,用顺铂处理抑制了miR-944的MCF-7细胞，BNIP3高表达，线粒体膜电位降低，细胞中caspase-3被激活，从而逆转耐药[64]。Kohno等[65]发现，在特定的肿瘤细胞中，线粒体转录因子A(mtTFA)的表达水平取决于线粒体基因组的特点和顺铂药物的使用。MtTFA被发现与肿瘤细胞的存活、凋亡、增殖密切相关。在乳腺癌细胞中，miR-200a的高表达抑制mtTFA的转录和翻译，并能减少线粒体DNA的拷贝数，从而减弱细胞增殖和抑制顺铂耐药性的产生[62]。而miR-199a-3p通过下调线粒体转录因子A的表达可促进乳腺癌细胞对顺铂的敏感性[62]。

6 miRNA生物合成途径的调控

已证实miRNA能够在耐药机制中发挥重要的调控作用。因此，中断部分miRNA的生物合成途径势必会引起细胞耐药性的变化。Dicer酶是双核酸酶RNaseⅢ家族的一个成员，在miRNA成熟过程的第2阶段起调节作用[63]。miRNA自身对miRNA的生物合成途径具有负反馈的作用，使得不同功能的miRNA之间相互制约、相互作用。Chan等[64]经过研究证实，miR-31能够靶向结合Dicer酶，抑制miRNA的生物合成过程，在一定程度上增强细胞对药物的敏感性。Martello等[66]发现，miR-103和miR-107可以在乳腺癌细胞中通过靶向结合Dicer酶而抑制miRNA的生物合成，参与乳腺癌细胞的耐药相关机制。虽然Dicer酶的调节机制很复杂，但是通过miRNA的生物合成途径调节耐药性这一机制已经得到充分的证实。

7 结语

铂类药物是广泛用于乳腺癌治疗的二线方案， miRNA家族可作用于一系列编码基因，调节细胞的分化、增殖、凋亡、侵袭、迁移、上皮间质转化(EMT)过程和增强丝裂原活化蛋白激酶(MAPK)信号通路，来改变mRNA的表达，逆转对顺铂的耐药性。这一现象指明了乳腺癌治疗可能新方向。然而，miRNA诱导耐药形成的相关微环境变化的研究只有少量报道，miRNA的相互作用是否存在其他途径仍未知，将miRNA的靶向治疗应用于乳腺癌的治疗策略中具有一定的挑战性。

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