50余種miRNA在神經(jīng)膠質(zhì)瘤中的表達(dá)水平及作用靶點

劉太奇，陳思羽，李文德，黃　韌*

(1. 廣東醫(yī)學(xué)院，廣東天然藥物研究與開發(fā)重點實驗室，廣東 湛江　524023；2.廣東省實驗動物監(jiān)測所，廣東省實驗動物重點實驗室，廣州　510663)

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50余種miRNA在神經(jīng)膠質(zhì)瘤中的表達(dá)水平及作用靶點

劉太奇1，陳思羽1，李文德2，黃韌2*

(1. 廣東醫(yī)學(xué)院，廣東天然藥物研究與開發(fā)重點實驗室，廣東 湛江524023；2.廣東省實驗動物監(jiān)測所，廣東省實驗動物重點實驗室，廣州510663)

miRNAs是一類內(nèi)源性的非編碼小分子RNA，它能降解靶mRNAs或阻遏其翻譯過程。在神經(jīng)膠質(zhì)瘤中，有些miRNAs表達(dá)水平是上調(diào)的，而有些則是下調(diào)的；有些miRNAs在腫瘤發(fā)生發(fā)展過程中起促進(jìn)作用，而有些則發(fā)揮著類似抑癌基因的功能。因此，研究神經(jīng)膠質(zhì)瘤中miRNAs的表達(dá)概況，既可以為臨床上膠質(zhì)瘤的早期診斷提供輔助依據(jù)，還可以提供新的治療策略。本文將就miRNAs在膠質(zhì)瘤中表達(dá)水平及作用靶點的研究作一綜述。

神經(jīng)膠質(zhì)瘤；miRNA；靶點

1　miRNA簡介

miRNA是一類長約18～24個核糖核苷酸的內(nèi)源性非編碼小分子RNA。最早由Lee等人[1]于1993年對秀麗隱桿線蟲進(jìn)行突變體遺傳分析時發(fā)現(xiàn)，至今人們在線蟲、果蠅、動植物體內(nèi)已發(fā)現(xiàn)15000多種miRNA，其中有1 921個成熟的miRNA調(diào)控人類約1/3編碼蛋白的基因[2]。成熟的miRNA由原始miRNA轉(zhuǎn)錄本(primary miRNA transcrips, pri-miRNA)經(jīng)核酸酶Drosha剪切形成60～70個核苷酸的發(fā)卡狀miRNA前體(pre-miRNA)。再由Ran-GTP或Exportin 5轉(zhuǎn)運至細(xì)胞質(zhì)，Dicer酶進(jìn)一步將其修飾成約18～24個核苷酸長度的miRNA雙鏈，隨后組裝形成miRNA誘導(dǎo)的沉默復(fù)合體(miRNA-induced scilencing complex, miRISC)。雙鏈miRNA的一條單鏈被降解，另一條單鏈則通過堿基互補配對的方式識別靶mRNA，并根據(jù)互補程度的不同指導(dǎo)沉默復(fù)合體降解靶mRNA或阻遏其翻譯過程[3]。

2　miRNA與膠質(zhì)瘤的相關(guān)性

膠質(zhì)瘤是人類最常見的原發(fā)性腦腫瘤，且有侵襲周圍腦組織的傾向。輕度(I～I(xiàn)I級)膠質(zhì)瘤患者確診后的5年存活率為30%～70%；而膠質(zhì)母細(xì)胞瘤作為侵襲性腫瘤的典型，其瘤體生長快且易迅速滲入周圍組織，患者預(yù)后差，平均存活期僅9～12個月[4]。因此，尋找新的診療策略以改善患者預(yù)后，延長存活期是臨床醫(yī)學(xué)亟待解決的重大問題。

近年來，miRNAs與膠質(zhì)瘤的相關(guān)性研究日益成為生命科學(xué)的一大研究熱點。miRNAs在腫瘤發(fā)生與侵襲、血管生成以及腫瘤細(xì)胞凋亡等過程中扮演著重要角色。一些miRNAs與臨床診斷及放化療抗性密切相關(guān)。此外，它們對于靶向藥物分子的療效具有潛在的影響作用。miRNAs還可能與膠質(zhì)瘤干細(xì)胞的性質(zhì)相關(guān)，由此影響腫瘤的維持與生長[5]。

3　膠質(zhì)瘤中表達(dá)上調(diào)的miRNAs及其作用靶點

Li等[6]通過qRT-PCR實驗證實U251、U87、SHG44和A172四個神經(jīng)膠質(zhì)瘤細(xì)胞系中miR-222含量水平是HA(人星形角質(zhì)細(xì)胞系)的50到150倍，且以U251及U87細(xì)胞中miR-222含量最高。隨后，研究者采用Target Scan在線預(yù)測軟件對miR-222及其潛在靶基因Dickkopf-2 (DKK2，NM_000633) 的3’-UTR端進(jìn)行了靶向預(yù)測分析并選出擬合度最佳的作用靶點(miR-222與DKK2 3’-UTR端可互補配對的堿基序列)。設(shè)計合成并PCR擴(kuò)增含有潛在作用靶點的DKK2 3’-UTR序列及其突變型序列，將其分別與雙熒光素酶報告基因載體連接構(gòu)建重組質(zhì)粒。實驗者采用miR-222的模擬物(mimics)、抑制物(inhibitor)及陰性對照(control)分別與重組質(zhì)粒共轉(zhuǎn)染U251細(xì)胞及U87細(xì)胞，48 h后裂解細(xì)胞并檢測熒光素酶活性，結(jié)果表明miR-222可靶向調(diào)控DKK2的表達(dá)。MTT檢測結(jié)果表明，與對照組相比，轉(zhuǎn)染了miR-222模擬物的膠質(zhì)瘤細(xì)胞存活率升高；而轉(zhuǎn)染了miR-222抑制物的膠質(zhì)瘤細(xì)胞存活率顯著降低。裸鼠異位植瘤實驗發(fā)現(xiàn)對miR-222沉默處理可顯著抑制腫瘤發(fā)生。

Wang等[7]運用qRT-PCR和蛋白印跡等實驗技術(shù)證實β-catenin/TCF4與miR-30a-5p基因啟動區(qū)的兩個位點結(jié)合，從而促進(jìn)miR-30a-5p的生成。miR-30a-5p可通過靶向作用于神經(jīng)細(xì)胞黏附分子(neural cell adhesion molecule, NCAM)3＇UTR的兩個位點，從而抑制NCAM的表達(dá)。由此可知，Wnt/β-catenin信號通路通過miR-30a-5p實現(xiàn)了對NCAM表達(dá)水平的調(diào)控，從而可以調(diào)節(jié)神經(jīng)膠質(zhì)瘤細(xì)胞的生長速率和侵襲活性。Wnt/β-catenin-miR-30a-5p-NCAM這一新型調(diào)節(jié)軸在調(diào)控膠質(zhì)瘤細(xì)胞侵襲活性及腫瘤發(fā)生等方面扮演了重要角色。

外囊泡以外泌體的形式轉(zhuǎn)運胞內(nèi)蛋白或核酸(包括各種miRNAs)來傳遞細(xì)胞間的信息。Rui Shi等[8]檢測了膠質(zhì)瘤復(fù)發(fā)患者腦脊液中腫瘤相關(guān)的miRNAs水平，比較并評估了腦脊液、血清及外泌體中miR-21水平變化對患者預(yù)后的價值。其樣本來源于70位膠質(zhì)瘤(術(shù)后)患者，以腦外傷患者作為非腫瘤對照組。結(jié)果表明，實驗組(膠質(zhì)瘤患者)腦脊液外泌體中miR-21水平顯著高于對照組，然而兩組血清樣本中miR-21水平則無顯著性差異。腦脊液源外泌體中miR-21的含量水平不僅與腫瘤轉(zhuǎn)移有關(guān)，還與腫瘤好發(fā)部位的復(fù)發(fā)幾率有關(guān)。研究者從另外198個膠質(zhì)瘤組織樣本中證實miR-21含量水平與腫瘤診斷分級有關(guān)，且與患者總生存時間的中值呈負(fù)相關(guān)。用慢病毒抑制劑抑制U251細(xì)胞中miR-21的表達(dá)后，其靶基因PTEN、RECK和PDCD4所對應(yīng)的蛋白表達(dá)水平均有提升。由此可知，外泌體中miR-21的含量水平可作為膠質(zhì)瘤診斷和預(yù)后的一項可靠指標(biāo)，特別是用于預(yù)測腫瘤復(fù)發(fā)和轉(zhuǎn)移。神經(jīng)膠質(zhì)瘤中表達(dá)上調(diào)的miRNAs及其作用靶點、miRNA對膠質(zhì)瘤的影響或其在診療中的應(yīng)用詳見表1。

上述miRNAs，如miR-222、miR-30a-5p、miR-21等在神經(jīng)膠質(zhì)瘤中的表達(dá)水平較正常腦組織是上調(diào)的，在腫瘤發(fā)生發(fā)展過程中起到了一定程度的促進(jìn)作用。若患者血清或腦脊液中出現(xiàn)上述miRNAs表達(dá)水平升高，則可為臨床上膠質(zhì)瘤的確診提供輔助依據(jù)。在治療過程中，可考慮靶向?qū)朐擃恗iRNAs的抑制劑，使其表達(dá)水平趨于正常，從而改善患者預(yù)后。

表1　膠質(zhì)瘤中表達(dá)上調(diào)的miRNAs及其靶點

4　膠質(zhì)瘤中表達(dá)下調(diào)的miRNAs及其作用靶點

在人的U251細(xì)胞中，miR-125b是最早被發(fā)現(xiàn)表達(dá)水平下調(diào)的miRNA之一。提高其含量水平時，細(xì)胞周期調(diào)節(jié)蛋白CDK6和CDC25A的表達(dá)受到抑制，導(dǎo)致膠質(zhì)瘤細(xì)胞周期停滯在G1/S期，從而抑制膠質(zhì)瘤細(xì)胞的增殖[18, 19]。另有文獻(xiàn)報道[20]，在CD133陽性的膠質(zhì)瘤干細(xì)胞(glioma stem cells, GSCs )中，miR-125b的下調(diào)會引起E2F2蛋白表達(dá)的升高，從而調(diào)節(jié)腫瘤干細(xì)胞的新陳代謝及分化。Shi等[18]發(fā)現(xiàn)miR-125b對CD133陽性的GSCs侵襲活性的抑制是通過調(diào)節(jié)MMP-2、MMP-9及其相應(yīng)的抑制物RECK、TIMP3的表達(dá)水平來實現(xiàn)的。miR-128可靶向調(diào)節(jié)癌癥相關(guān)的受體酪氨酸激酶，如EGFR和PDGFR[21, 22]。近來有研究表明[21]，伴隨著組蛋白甲基化(H3K27me)和Akt磷酸化，miR-128會出現(xiàn)過表達(dá)。此外，Bmil作為一種干細(xì)胞生物標(biāo)志物同時又是癌基因，受miR-128靶向調(diào)控[22]。p70S6K1是mTOR下游的一個關(guān)鍵靶點，在膠質(zhì)瘤血管生成過程中起到了重要重用。若提高miR-128水平，可抑制p70S6K1的活性及其下游信號分子如HIF-1和VEGF的表達(dá)，從而減緩細(xì)胞增殖、腫瘤生長及血管生成[23]。另有文獻(xiàn)報道[24]，轉(zhuǎn)錄因子E2F3亦是miR-128的作用靶點。

通用抗癌基因p53在GSCs中，也與MicroRNAs有關(guān)聯(lián)。與野生型p53膠質(zhì)瘤相比較，突變型p53膠質(zhì)瘤中，miR-34a的表達(dá)是下調(diào)的[25]。轉(zhuǎn)染了miR-34a的膠質(zhì)瘤細(xì)胞，其生存、增殖及侵襲活力均會受到抑制。膠質(zhì)瘤異種移植后的體內(nèi)實驗表明，miR-34a可抑制腫瘤生長并誘導(dǎo)GSCs分化[25, 26]。此外，最近一項研究[27]證實，miR-34a可通過調(diào)控Akt和Wnt信號通路來抑制GSCs的增殖及腫瘤生長。在GSCs中，miR-34a還可靶向調(diào)控一些癌基因，如c-Met, Notch-1及Notch-2[26]。miR-34家族的其它成員，如miR-34c-3p和miR-34c-5p，也能影響膠質(zhì)瘤細(xì)胞的增殖及侵襲活力[9]。神經(jīng)膠質(zhì)瘤中表達(dá)上調(diào)的miRNAs及其作用靶點、miRNA對膠質(zhì)瘤的影響或其在診療中的應(yīng)用詳見表2：

miR-125b、miR-34a等miRNAs在神經(jīng)膠質(zhì)瘤中的表達(dá)水平較正常腦組織是下調(diào)的，在腫瘤發(fā)生發(fā)展過程中起到了一定程度的抑制作用。若患者血清或腦脊液中出現(xiàn)上述miRNAs表達(dá)水平降低，則可為臨床上膠質(zhì)瘤的確診提供輔助依據(jù)。在治療過程中，可考慮靶向?qū)朐擃恗iRNAs或其靶蛋白的抑制劑，使其表達(dá)水平趨于正常，從而改善患者預(yù)后。

表2　膠質(zhì)瘤中表達(dá)下調(diào)的miRNAs及其靶點

5　展望

膠質(zhì)瘤患者在接受傳統(tǒng)的手術(shù)切除、放療及化療后，其預(yù)后仍然較差，因而尋找新的早期診斷指標(biāo)或治療靶標(biāo)勢在必行。在神經(jīng)膠質(zhì)瘤組織中，不同的miRNAs，表達(dá)水平及作用靶點亦有不同。將miRNAs作為神經(jīng)膠質(zhì)瘤早期診斷的生物標(biāo)志物，以miRNAs及其抑制物為基礎(chǔ)的療法，引起眾多研究者的關(guān)注。但如前文所述，miRNAs具有復(fù)雜的網(wǎng)絡(luò)作用機制，將具體的某種miRNA作為早期診斷指標(biāo)或治療靶標(biāo)時，有必要闡明其在腫瘤微環(huán)境中的具體生物學(xué)功能。且無論是腫瘤干細(xì)胞還是其后分化形成的腫瘤細(xì)胞，miRNAs都需要借助傳遞系統(tǒng)以到達(dá)其分子靶標(biāo)。因此，miRNAs在膠質(zhì)瘤臨床應(yīng)用的另一挑戰(zhàn)在于透過血腦屏障和其它胞外基質(zhì)組分以到達(dá)腫瘤組織，從而發(fā)揮其相應(yīng)的生物學(xué)功能。

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Expression levels and targets of more than fifty miRNAs in glioma

LIU Tai-qi1, CHEN Si-yu1, LI Wen-de2，HUANG Ren2*

(1. Guangdong Key Laboratory for Research and Development of Natural Drugs，Guangdong Medical College，Zhanjiang 524023, China; 2. Key Laboratory of Guangdong Laboratory Animals，Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510663 )

miRNAs are a class of small endogenous RNAs that degrade target mRNAs or repress their translation process. Several miRNAs in glioma are up-regulated, while some others down-regulated. Some miRNAs promote tumorigenesis; some others, however, play a similar function of tumor suppressor genes. Therefore, studies on the expression profiles of miRNAs in glioma may afford auxiliary basis for early clinical diagnosis and novel srtategies for therapy of glioma. This paper will review on researches about the expression levels of miRNAs and their targets in glioma.

Glioma; miRNA; Target

抗腫瘤藥物評價公共服務(wù)平臺的建立(2015A040404026)。

劉太奇(1990-)，女，碩士在讀，研究方向： 小分子RNA與神經(jīng)膠質(zhì)瘤。E-mail： 1214298640@qq.com。

黃韌(1959-)，男，研究員，研究方向： 實驗動物學(xué)。E-mail： 1649405216@qq.com。

研究進(jìn)展

R-33

A

1671-7856(2016)07-0079-06

10.3969.j.issn.1671-7856.2016.07.014

2016-03-22