miRNA與肺癌順鉑耐藥相關(guān)性的研究進(jìn)展

陳　力(綜述)　金玉麟　王　琳　時(shí)蒙昆　詹　成(審校)　時(shí)　雨　王　群

(1復(fù)旦大學(xué)附屬中山醫(yī)院胸外科　上海　200032; 2四川大學(xué)華西醫(yī)院骨科　成都　610041)

肺癌發(fā)病率和死亡率均位居惡性腫瘤的首位,嚴(yán)重威脅人類健康。非小細(xì)胞肺癌(non-small cell lung cancer,NSCLC)是肺癌中最主要的類型,占肺癌總數(shù)約85%。我國2015年《非小細(xì)胞肺癌臨床實(shí)踐指南》顯示,以順鉑為基礎(chǔ)的化療方案被推薦用于NSCLC患者。但某些患者對(duì)順鉑具有先天耐藥性還有更多早期敏感的患者在順鉑治療過程中逐漸產(chǎn)生耐藥性。近年來多項(xiàng)研究表明,miRNA在肺癌順鉑耐藥機(jī)制中起著重要的作用,影響著順鉑在細(xì)胞內(nèi)轉(zhuǎn)運(yùn)、細(xì)胞周期、上皮細(xì)胞-間質(zhì)細(xì)胞轉(zhuǎn)化(epithelial mesenchymal transition,EMT)、細(xì)胞凋亡等。我們通過查閱近年來國內(nèi)外有關(guān)miRNA在肺癌順鉑耐藥中作用的相關(guān)文獻(xiàn)(表1),對(duì)其研究進(jìn)展作一綜述。

表1　miRNA在肺癌順鉑敏感性的作用Tab 1　Effects of miRNAs in cisplatin resistance of lung cancer

Resistance or sensitization was the response of cisplatin in cells when the miRNA was up-regulated.

順鉑的抗腫瘤作用機(jī)制順鉑主要是作用于DNA,與DNA形成加合物,限制DNA的解旋,阻礙DNA的復(fù)制,進(jìn)而抑制癌細(xì)胞的分裂,使癌細(xì)胞凋亡和壞死。順鉑進(jìn)入體內(nèi),在低氯環(huán)境中氯解離,形成水合陽離子,主要與DNA等生物大分子結(jié)合形成共價(jià)鍵。DNA上主要的結(jié)合位點(diǎn)是A和G的N7,順鉑在理論上可以和這兩個(gè)位點(diǎn)結(jié)合形成鏈內(nèi)交聯(lián)、鏈間交聯(lián)、DNA-蛋白質(zhì)分子間交聯(lián),從而使DNA鏈局部扭結(jié)或解旋,阻止DNA聚合酶推進(jìn),致使DNA復(fù)制、轉(zhuǎn)錄失敗,造成腫瘤細(xì)胞死亡,其中大部分為鏈內(nèi)交聯(lián),鏈間交聯(lián)的形成不足5%,故順鉑抗腫瘤作用是非特異性的[1]。

miRNA在肺癌順鉑耐藥中的作用

miRNA對(duì)順鉑轉(zhuǎn)運(yùn)的調(diào)節(jié)決定順鉑效果的一個(gè)關(guān)鍵點(diǎn)是順鉑在細(xì)胞內(nèi)的濃度。細(xì)胞大量泵出順鉑,使細(xì)胞內(nèi)順鉑濃度降低,有效作用劑量減少而產(chǎn)生耐藥。ABC轉(zhuǎn)運(yùn)蛋白家族(ATP-binding cassette transporters family)是一組跨膜蛋白,具有ATP結(jié)合區(qū)域的單向底物轉(zhuǎn)運(yùn)泵,以主動(dòng)轉(zhuǎn)運(yùn)方式完成細(xì)胞對(duì)順鉑的跨膜轉(zhuǎn)運(yùn)。Ma等[3]研究發(fā)現(xiàn),在順鉑耐藥的A549細(xì)胞中,miR-106a-5p的表達(dá)量明顯高于普通A549細(xì)胞,而上調(diào)的miR-106a-5p作用于下游因子ABCA1基因,降低ABCA1蛋白的表達(dá)量,使得細(xì)胞內(nèi)順鉑的有效濃度降低而誘導(dǎo)順鉑耐藥。miR-21-5p在腫瘤的發(fā)生發(fā)展過程中扮演重要角色,在不同類型腫瘤中的表達(dá)均出現(xiàn)明顯上升,與腫瘤細(xì)胞的侵襲、增殖、血管生成和耐藥性等生物學(xué)行為相關(guān)。研究表明,沉默肺癌細(xì)胞的miR-21-5p基因可使多藥耐藥1(multiple drug resistance 1,MDR1)基因表達(dá)產(chǎn)物P-糖蛋白(P-glycoprotein,P-gp)降低,而P-gp在腫瘤細(xì)胞中外泵順鉑的作用明確,因此沉默miR-21-5p最終導(dǎo)致肺癌細(xì)胞對(duì)順鉑的敏感性提高[4]。

銅轉(zhuǎn)運(yùn)P型三磷酸腺苷ATP7A和ATP7B是一對(duì)同源異構(gòu)體,組織分布不同,是目前公認(rèn)的促使鉑類藥物流出細(xì)胞的轉(zhuǎn)運(yùn)蛋白,ATP7A 和ATP7B 蛋白在順鉑耐藥的細(xì)胞中明顯高表達(dá)[5-6]。Song等[7]研究發(fā)現(xiàn),miR-495-3p可靶向下調(diào)ATP7A,使細(xì)胞內(nèi)順鉑的有效濃度上升,從而致使細(xì)胞對(duì)順鉑的敏感性增強(qiáng)。

miRNA對(duì)細(xì)胞周期的調(diào)節(jié)周期蛋白依賴性蛋白激酶(cyclin-dependent kinases,CDK)是一組絲氨酸/蘇氨酸蛋白激酶,和周期蛋白cyclin協(xié)同作用,是細(xì)胞周期調(diào)控中的重要因子。Cyclin E是G1期的周期蛋白,cyclin E與CDK2結(jié)合在G1期末發(fā)揮作用,促進(jìn)細(xì)胞進(jìn)入S期。Cyclin E-Cdk2在腫瘤細(xì)胞中的表達(dá)量常高于正常細(xì)胞,可能與其高表達(dá)促進(jìn)腫瘤發(fā)生發(fā)展相關(guān)。miR-25-3p是一個(gè)在NSCLC和小細(xì)胞肺癌中都高表達(dá)的致癌基因。Zhao等[8]在小細(xì)胞肺癌細(xì)胞和腫瘤組織中發(fā)現(xiàn)miR-25-3p表達(dá)量增高,在H510A細(xì)胞中下調(diào)miR-25-3p的表達(dá)可以降低腫瘤細(xì)胞對(duì)順鉑的耐藥性,同時(shí)降低其生長速度和侵襲能力。究其原因主要是下調(diào)miR-25-3p能導(dǎo)致下游因子cdk2和Cyclin E的表達(dá)量降低,從而誘導(dǎo)G1期細(xì)胞阻滯。另有研究表明,在NSCLC中,miR-25-3p也可以作用于CDC42基因,通過下調(diào)miR-25-3p能上調(diào)CDC42基因的表達(dá)導(dǎo)致G1期細(xì)胞阻滯,從而增強(qiáng)腫瘤細(xì)胞對(duì)順鉑的敏感性[9]。

Yang等[10]在研究順鉑耐藥的NSCLC細(xì)胞中證實(shí)miRNA有抑制細(xì)胞周期G1/S期轉(zhuǎn)換的作用。上調(diào)miR-26a-5p可以靶向抑制高遷移率族蛋白A2(high mobility group A2,HMGA2),從而抑制轉(zhuǎn)錄因子E2F1的活化,減弱E2F1促進(jìn)細(xì)胞周期G1/S轉(zhuǎn)換的功能,從而增強(qiáng)肺癌細(xì)胞對(duì)順鉑的敏感性。Zhang等[11]通過熒光定量PCR和Western blot分析發(fā)現(xiàn)NSCLC組織中miR-107表達(dá)與正常組織明顯不同。人工合成的miR-107激活劑作用于順鉑耐藥A549細(xì)胞后,CDK8表達(dá)下降,對(duì)順鉑的敏感性增加。該研究表明miR-107可以作為NSCLC順鉑化療的新型調(diào)節(jié)劑。

miRNA對(duì)EMT的調(diào)節(jié)通過EMT,上皮細(xì)胞失去細(xì)胞極性以及與基底膜連接等上皮表型,獲得了具有較高遷移與侵襲、抗凋亡和降解細(xì)胞外基質(zhì)等能力的間質(zhì)表型。EMT是上皮細(xì)胞來源的惡性腫瘤細(xì)胞獲得遷移和侵襲能力的重要生物學(xué)過程[12]。EMT的特點(diǎn)是使細(xì)胞喪失黏附能力,降低上皮標(biāo)志物的表達(dá),提高間質(zhì)性標(biāo)志物的表達(dá)水平,導(dǎo)致細(xì)胞對(duì)細(xì)胞毒藥物和凋亡調(diào)節(jié)產(chǎn)生耐受。EMT是NSCLC細(xì)胞對(duì)順鉑產(chǎn)生耐藥的重要原因之一[13]。轉(zhuǎn)化生長因子β(transforming growth factor β,TGF-β)是EMT最主要的誘導(dǎo)因子之一,在胚胎發(fā)育、腫瘤轉(zhuǎn)移和纖維化等不同生物學(xué)過程中調(diào)節(jié)EMT的發(fā)生和發(fā)展。Jiang等[14]研究發(fā)現(xiàn),在耐順鉑的NSCLC細(xì)胞中上調(diào)miR-17-5p、miR-20a-5p及miR-20b-5p,能靶向抑制TGF-β信號(hào)通路中的TGF-βR2,從而增強(qiáng)腫瘤細(xì)胞對(duì)順鉑的敏感性并減弱腫瘤細(xì)胞的轉(zhuǎn)移和侵襲能力。miR-15b-5p可以在體內(nèi)外肺腺癌細(xì)胞中靶向作用于脂酰乙醇胺結(jié)合蛋白4(phosphatidylethanolamine-binding protein 4,PEBP4)基因,下調(diào)PEBP4可以調(diào)節(jié)EMT過程,從而導(dǎo)致順鉑耐藥性增強(qiáng)[15]。Li等[16]發(fā)現(xiàn)miR-181a-5p在耐藥和敏感的A549細(xì)胞中表達(dá)差異顯著,將miR-181a-5p的激活劑和抑制劑作用于順鉑耐藥的A549細(xì)胞后,細(xì)胞的轉(zhuǎn)移能力、侵襲性以及EMT相關(guān)基因的表達(dá)量明顯不同。該研究表明,上調(diào)miR-181a-5p將靶向作用于抑癌基因PTEN,使其表達(dá)量下降,導(dǎo)致肺腺癌細(xì)胞對(duì)順鉑耐藥性增強(qiáng)。

miRNA對(duì)細(xì)胞凋亡的調(diào)節(jié)細(xì)胞凋亡是細(xì)胞內(nèi)部有組織的程序性死亡過程,激活細(xì)胞膜表面的死亡受體(外源性途徑),或通過以線粒體為中心的胞內(nèi)事件(內(nèi)源性途徑),均可誘導(dǎo)凋亡。目前研究表明,多種機(jī)制導(dǎo)致腫瘤細(xì)胞對(duì)順鉑誘導(dǎo)的細(xì)胞內(nèi)部或外部損傷不敏感,出現(xiàn)凋亡缺陷,此時(shí)順鉑不足以激活腫瘤細(xì)胞的死亡信號(hào),因而導(dǎo)致肺癌細(xì)胞對(duì)順鉑的耐藥性產(chǎn)生。

在細(xì)胞凋亡過程中,Bcl-2家族成員起著至關(guān)重要的作用。Bcl-2家族可以分為兩大類,一類是抗凋亡的,主要有Bcl-2、Bcl-XL、Bcl-W、Mcl-1、CED9等,另一類是促細(xì)胞死亡的,主要有Bax、Bak、Bcl-XS、Bad、Bik、Bid等。Bcl-2蛋白被認(rèn)為是NSCLC的預(yù)后影響因子[17]。Cao等[18]通過利用MTT比色法、實(shí)時(shí)熒光定量PCR和Western blot研究順鉑耐藥的A549細(xì)胞的生存能力及miR-192-5p和bcl-2的表達(dá)水平時(shí)發(fā)現(xiàn),順鉑耐藥的A549細(xì)胞中miR-192-5p的表達(dá)水平明顯低于正常細(xì)胞,miR-192-5p主要作用于Bcl-2,抑制miR-192-5p使Bcl-2蛋白表達(dá)量明顯增高,導(dǎo)致細(xì)胞凋亡受阻,從而產(chǎn)生耐藥性。有研究表明,下調(diào)A549細(xì)胞中miR-155-5p表達(dá),可導(dǎo)致促凋亡蛋白Bax的表達(dá)量增加,導(dǎo)致順鉑誘導(dǎo)的A549細(xì)胞的凋亡作用增強(qiáng),順鉑敏感性增強(qiáng)[19]。還有報(bào)道,miR-196a-5p、miR-363-5p通過調(diào)節(jié)Bcl-2家族蛋白的表達(dá)量,調(diào)控順鉑誘導(dǎo)的細(xì)胞凋亡,從而影響順鉑化療的作用[20-21]。

核苷酸切除修復(fù)(nucleotide excision repair,NER)是清除DNA結(jié)合的順鉑加合物和修復(fù)DNA損傷的最主要方式。研究表明,切除修復(fù)交叉互補(bǔ)基因-1 ( excision repair cross complementing gene 1,ERCC1)由于其較強(qiáng)的損傷識(shí)別與修復(fù)能力被認(rèn)為是NER途徑的關(guān)鍵因子。研究表明,上調(diào)miR-138-5p能顯著降低ERCC1的表達(dá)量,減弱DNA損傷修復(fù)功能,增強(qiáng)順鉑誘導(dǎo)的凋亡作用,導(dǎo)致細(xì)胞對(duì)順鉑的敏感性增強(qiáng)[22]。

miRNA在肺癌順鉑耐藥中的其他作用順鉑進(jìn)入細(xì)胞之后,易與含硫的分子結(jié)合,如谷胱甘肽(glutathione,GSH)、金屬硫蛋白(metallothionein,MT)等。細(xì)胞內(nèi)富含的大量GSH與順鉑結(jié)合后,可使順鉑停留在細(xì)胞質(zhì)而不能進(jìn)入細(xì)胞核與其靶點(diǎn)DNA作用,從而降低順鉑的毒性。GSH不僅可以和順鉑共價(jià)結(jié)合,這種作用還能被谷胱甘肽-S-轉(zhuǎn)移酶(glutathione-s-transferase,GST)所催化。有研究發(fā)現(xiàn),耐藥的A549/DDP細(xì)胞中GSTP1的表達(dá)水平是正常A549細(xì)胞的2.7倍,而miR-513a-3p的表達(dá)水平卻是正常細(xì)胞的34%。該研究表明,GSTP1受miR-513a-3p靶向調(diào)控。上調(diào)miR-513a-3p能降低GSTP1的表達(dá),從而減弱細(xì)胞對(duì)順鉑的解毒作用,使順鉑的敏感性增強(qiáng)[23]。因此,在順鉑化療的肺癌中miRNA對(duì)GST及GSH的調(diào)控作用是導(dǎo)致順鉑耐藥重要途徑之一。

此外,當(dāng)接觸化療藥物后,細(xì)胞自噬可及時(shí)清除細(xì)胞內(nèi)的有害物質(zhì),并提供應(yīng)急的底物和能量為修復(fù)損傷贏得時(shí)間和條件,從而保護(hù)腫瘤細(xì)胞免于發(fā)生壞死或調(diào)亡,以維持腫瘤細(xì)胞的持續(xù)生存[24]。研究發(fā)現(xiàn),在依托泊苷和順鉑聯(lián)合化療的H446耐藥細(xì)胞中,miR-24-3p的表達(dá)量明顯降低,而細(xì)胞自噬現(xiàn)象更加活躍。進(jìn)一步研究表明,下調(diào)miR-24-3p是通過靶向上調(diào)自噬相關(guān)基因4A(autophagy associated gene 4A,ATG4A)的表達(dá),導(dǎo)致自噬作用增強(qiáng),從而降低化療藥物的敏感性[25]。

結(jié)語順鉑在抗腫瘤藥中屬于研發(fā)較早、臨床應(yīng)用較成熟的一種藥物,但內(nèi)在的和獲得性的耐藥性限制了順鉑在臨床上的應(yīng)用。目前miRNA在肺癌順鉑耐藥性中的研究尚處于起步階段。正常情況下,細(xì)胞內(nèi)各種蛋白的水平通過miRNA的精細(xì)調(diào)節(jié)網(wǎng)絡(luò)維持在平衡狀態(tài)。miRNA的多態(tài)性及異常表達(dá)可導(dǎo)致肺癌細(xì)胞耐藥相關(guān)通路的基因表達(dá)水平及腫瘤細(xì)胞周期發(fā)生改變,從而打破原有的平衡,進(jìn)而改變肺癌細(xì)胞對(duì)順鉑的敏感性,導(dǎo)致耐藥現(xiàn)象。隨著對(duì)miRNA與肺癌順鉑耐藥性的研究不斷深入,以期尋求新的治療策略來克服肺癌順鉑耐藥性,對(duì)肺癌的臨床治療具有重大的意義。

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