50余种miRNA在神经胶质瘤中的表达水平及作用靶点

刘太奇，陈思羽，李文德，黄　韧*

(1. 广东医学院，广东天然药物研究与开发重点实验室，广东 湛江　524023；2.广东省实验动物监测所，广东省实验动物重点实验室，广州　510663)



50余种miRNA在神经胶质瘤中的表达水平及作用靶点

刘太奇1，陈思羽1，李文德2，黄韧2*

(1. 广东医学院，广东天然药物研究与开发重点实验室，广东 湛江524023；2.广东省实验动物监测所，广东省实验动物重点实验室，广州510663)

miRNAs是一类内源性的非编码小分子RNA，它能降解靶mRNAs或阻遏其翻译过程。在神经胶质瘤中，有些miRNAs表达水平是上调的，而有些则是下调的；有些miRNAs在肿瘤发生发展过程中起促进作用，而有些则发挥着类似抑癌基因的功能。因此，研究神经胶质瘤中miRNAs的表达概况，既可以为临床上胶质瘤的早期诊断提供辅助依据，还可以提供新的治疗策略。本文将就miRNAs在胶质瘤中表达水平及作用靶点的研究作一综述。

神经胶质瘤；miRNA；靶点

1　miRNA简介

miRNA是一类长约18～24个核糖核苷酸的内源性非编码小分子RNA。最早由Lee等人[1]于1993年对秀丽隐杆线虫进行突变体遗传分析时发现，至今人们在线虫、果蝇、动植物体内已发现15000多种miRNA，其中有1 921个成熟的miRNA调控人类约1/3编码蛋白的基因[2]。成熟的miRNA由原始miRNA转录本(primary miRNA transcrips, pri-miRNA)经核酸酶Drosha剪切形成60～70个核苷酸的发卡状miRNA前体(pre-miRNA)。再由Ran-GTP或Exportin 5转运至细胞质，Dicer酶进一步将其修饰成约18～24个核苷酸长度的miRNA双链，随后组装形成miRNA诱导的沉默复合体(miRNA-induced scilencing complex, miRISC)。双链miRNA的一条单链被降解，另一条单链则通过碱基互补配对的方式识别靶mRNA，并根据互补程度的不同指导沉默复合体降解靶mRNA或阻遏其翻译过程[3]。

2　miRNA与胶质瘤的相关性

胶质瘤是人类最常见的原发性脑肿瘤，且有侵袭周围脑组织的倾向。轻度(I～II级)胶质瘤患者确诊后的5年存活率为30%～70%；而胶质母细胞瘤作为侵袭性肿瘤的典型，其瘤体生长快且易迅速渗入周围组织，患者预后差，平均存活期仅9～12个月[4]。因此，寻找新的诊疗策略以改善患者预后，延长存活期是临床医学亟待解决的重大问题。

近年来，miRNAs与胶质瘤的相关性研究日益成为生命科学的一大研究热点。miRNAs在肿瘤发生与侵袭、血管生成以及肿瘤细胞凋亡等过程中扮演着重要角色。一些miRNAs与临床诊断及放化疗抗性密切相关。此外，它们对于靶向药物分子的疗效具有潜在的影响作用。miRNAs还可能与胶质瘤干细胞的性质相关，由此影响肿瘤的维持与生长[5]。

3　胶质瘤中表达上调的miRNAs及其作用靶点

Li等[6]通过qRT-PCR实验证实U251、U87、SHG44和A172四个神经胶质瘤细胞系中miR-222含量水平是HA(人星形角质细胞系)的50到150倍，且以U251及U87细胞中miR-222含量最高。随后，研究者采用Target Scan在线预测软件对miR-222及其潜在靶基因Dickkopf-2 (DKK2，NM_000633) 的3’-UTR端进行了靶向预测分析并选出拟合度最佳的作用靶点(miR-222与DKK2 3’-UTR端可互补配对的碱基序列)。设计合成并PCR扩增含有潜在作用靶点的DKK2 3’-UTR序列及其突变型序列，将其分别与双荧光素酶报告基因载体连接构建重组质粒。实验者采用miR-222的模拟物(mimics)、抑制物(inhibitor)及阴性对照(control)分别与重组质粒共转染U251细胞及U87细胞，48 h后裂解细胞并检测荧光素酶活性，结果表明miR-222可靶向调控DKK2的表达。MTT检测结果表明，与对照组相比，转染了miR-222模拟物的胶质瘤细胞存活率升高；而转染了miR-222抑制物的胶质瘤细胞存活率显著降低。裸鼠异位植瘤实验发现对miR-222沉默处理可显著抑制肿瘤发生。

Wang等[7]运用qRT-PCR和蛋白印迹等实验技术证实β-catenin/TCF4与miR-30a-5p基因启动区的两个位点结合，从而促进miR-30a-5p的生成。miR-30a-5p可通过靶向作用于神经细胞黏附分子(neural cell adhesion molecule, NCAM)3＇UTR的两个位点，从而抑制NCAM的表达。由此可知，Wnt/β-catenin信号通路通过miR-30a-5p实现了对NCAM表达水平的调控，从而可以调节神经胶质瘤细胞的生长速率和侵袭活性。Wnt/β-catenin-miR-30a-5p-NCAM这一新型调节轴在调控胶质瘤细胞侵袭活性及肿瘤发生等方面扮演了重要角色。

外囊泡以外泌体的形式转运胞内蛋白或核酸(包括各种miRNAs)来传递细胞间的信息。Rui Shi等[8]检测了胶质瘤复发患者脑脊液中肿瘤相关的miRNAs水平，比较并评估了脑脊液、血清及外泌体中miR-21水平变化对患者预后的价值。其样本来源于70位胶质瘤(术后)患者，以脑外伤患者作为非肿瘤对照组。结果表明，实验组(胶质瘤患者)脑脊液外泌体中miR-21水平显著高于对照组，然而两组血清样本中miR-21水平则无显著性差异。脑脊液源外泌体中miR-21的含量水平不仅与肿瘤转移有关，还与肿瘤好发部位的复发几率有关。研究者从另外198个胶质瘤组织样本中证实miR-21含量水平与肿瘤诊断分级有关，且与患者总生存时间的中值呈负相关。用慢病毒抑制剂抑制U251细胞中miR-21的表达后，其靶基因PTEN、RECK和PDCD4所对应的蛋白表达水平均有提升。由此可知，外泌体中miR-21的含量水平可作为胶质瘤诊断和预后的一项可靠指标，特别是用于预测肿瘤复发和转移。神经胶质瘤中表达上调的miRNAs及其作用靶点、miRNA对胶质瘤的影响或其在诊疗中的应用详见表1。

上述miRNAs，如miR-222、miR-30a-5p、miR-21等在神经胶质瘤中的表达水平较正常脑组织是上调的，在肿瘤发生发展过程中起到了一定程度的促进作用。若患者血清或脑脊液中出现上述miRNAs表达水平升高，则可为临床上胶质瘤的确诊提供辅助依据。在治疗过程中，可考虑靶向导入该类miRNAs的抑制剂，使其表达水平趋于正常，从而改善患者预后。

表1　胶质瘤中表达上调的miRNAs及其靶点

4　胶质瘤中表达下调的miRNAs及其作用靶点

在人的U251细胞中，miR-125b是最早被发现表达水平下调的miRNA之一。提高其含量水平时，细胞周期调节蛋白CDK6和CDC25A的表达受到抑制，导致胶质瘤细胞周期停滞在G1/S期，从而抑制胶质瘤细胞的增殖[18, 19]。另有文献报道[20]，在CD133阳性的胶质瘤干细胞(glioma stem cells, GSCs )中，miR-125b的下调会引起E2F2蛋白表达的升高，从而调节肿瘤干细胞的新陈代谢及分化。Shi等[18]发现miR-125b对CD133阳性的GSCs侵袭活性的抑制是通过调节MMP-2、MMP-9及其相应的抑制物RECK、TIMP3的表达水平来实现的。miR-128可靶向调节癌症相关的受体酪氨酸激酶，如EGFR和PDGFR[21, 22]。近来有研究表明[21]，伴随着组蛋白甲基化(H3K27me)和Akt磷酸化，miR-128会出现过表达。此外，Bmil作为一种干细胞生物标志物同时又是癌基因，受miR-128靶向调控[22]。p70S6K1是mTOR下游的一个关键靶点，在胶质瘤血管生成过程中起到了重要重用。若提高miR-128水平，可抑制p70S6K1的活性及其下游信号分子如HIF-1和VEGF的表达，从而减缓细胞增殖、肿瘤生长及血管生成[23]。另有文献报道[24]，转录因子E2F3亦是miR-128的作用靶点。

通用抗癌基因p53在GSCs中，也与MicroRNAs有关联。与野生型p53胶质瘤相比较，突变型p53胶质瘤中，miR-34a的表达是下调的[25]。转染了miR-34a的胶质瘤细胞，其生存、增殖及侵袭活力均会受到抑制。胶质瘤异种移植后的体内实验表明，miR-34a可抑制肿瘤生长并诱导GSCs分化[25, 26]。此外，最近一项研究[27]证实，miR-34a可通过调控Akt和Wnt信号通路来抑制GSCs的增殖及肿瘤生长。在GSCs中，miR-34a还可靶向调控一些癌基因，如c-Met, Notch-1及Notch-2[26]。miR-34家族的其它成员，如miR-34c-3p和miR-34c-5p，也能影响胶质瘤细胞的增殖及侵袭活力[9]。神经胶质瘤中表达上调的miRNAs及其作用靶点、miRNA对胶质瘤的影响或其在诊疗中的应用详见表2：

miR-125b、miR-34a等miRNAs在神经胶质瘤中的表达水平较正常脑组织是下调的，在肿瘤发生发展过程中起到了一定程度的抑制作用。若患者血清或脑脊液中出现上述miRNAs表达水平降低，则可为临床上胶质瘤的确诊提供辅助依据。在治疗过程中，可考虑靶向导入该类miRNAs或其靶蛋白的抑制剂，使其表达水平趋于正常，从而改善患者预后。

表2　胶质瘤中表达下调的miRNAs及其靶点

5　展望

胶质瘤患者在接受传统的手术切除、放疗及化疗后，其预后仍然较差，因而寻找新的早期诊断指标或治疗靶标势在必行。在神经胶质瘤组织中，不同的miRNAs，表达水平及作用靶点亦有不同。将miRNAs作为神经胶质瘤早期诊断的生物标志物，以miRNAs及其抑制物为基础的疗法，引起众多研究者的关注。但如前文所述，miRNAs具有复杂的网络作用机制，将具体的某种miRNA作为早期诊断指标或治疗靶标时，有必要阐明其在肿瘤微环境中的具体生物学功能。且无论是肿瘤干细胞还是其后分化形成的肿瘤细胞，miRNAs都需要借助传递系统以到达其分子靶标。因此，miRNAs在胶质瘤临床应用的另一挑战在于透过血脑屏障和其它胞外基质组分以到达肿瘤组织，从而发挥其相应的生物学功能。

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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

抗肿瘤药物评价公共服务平台的建立(2015A040404026)。

刘太奇(1990-)，女，硕士在读，研究方向： 小分子RNA与神经胶质瘤。E-mail： 1214298640@qq.com。

黄韧(1959-)，男，研究员，研究方向： 实验动物学。E-mail： 1649405216@qq.com。

研究进展

R-33

A

1671-7856(2016)07-0079-06

10.3969.j.issn.1671-7856.2016.07.014

2016-03-22