中国生物工程杂志  2016, Vol. 36 Issue (9): 59-74

文章信息

堵晶晶, 谭镇东, 刘辰东, 巫小倩, 张培文, 张顺华, 朱砺.
DU Jing-jing, TAN Zhen-dong, LIU Chen-dong, WU Xiao-qiao, ZHANG Pei-wen, ZHANG Shun-hua, ZHU Li.
长链非编码RNA的研究现状
Research Progress of Long Non-coding RNAs
中国生物工程杂志, 2016, 36(9): 59-74
China Biotechnology, 2016, 36(9): 59-74
http://dx.doi.org/DOI:10.13523/j.cb.20160908

文章历史

收稿日期: 2016-02-01
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引用本文 0
堵晶晶,谭镇东,刘辰东,巫小倩,张培文,张顺华,朱砺. 长链非编码RNA的研究现状[J]. 中国生物工程杂志, 2016, 36(9): 59-74.
DU Jing-jing,TAN Zhen-dong,LIU Chen-dong,WU Xiao-qiao,ZHANG Pei-wen,ZHANG Shun-hua,ZHU Li. Research Progress of Long Non-coding RNAs[J]. China Biotechnology, 2016, 36(9): 59-74.
长链非编码RNA的研究现状
堵晶晶 , 谭镇东 , 刘辰东 , 巫小倩 , 张培文 , 张顺华 , 朱砺     
四川农业大学动物科技学院 成都 611130
收稿日期: 2016-02-01
基金项目: 四川省科技支撑计划项目（2013NZ0041，2013NZ0056），四川省科技富民强县专项行动计划资助项目
通信作者: 张顺华, 363445986@qq.com 朱砺,zhuli7508@163.com
摘要: 长链非编码RNA（lncRNA）是一类长度大于200bp的非编码RNA，无蛋白质编码功能，物种间保守性差，具有较强的组织特异性和时空特异性。研究表明ncRNA具有广泛的生物学功能，如参与RNA的生成与加工、转录调控、染色质重塑等，且作用机制复杂，如能通过绑定特点蛋白质参与转录调节或作为ceRNA参与转录后调控。但lncRNA的结构复杂，功能研究进展缓慢，目前仍难以对其细致分类。从基本特征、分类、功能、数据库、研究工具及其与癌症之间的关系等方面对lncRNA的研究进展进行综述，以期为lncRNA后续研究提供参考。
关键词: 非编码RNA     lncRNA     分类     功能     癌症    
Research Progress of Long Non-coding RNAs
DU Jing-jing , TAN Zhen-dong , LIU Chen-dong , WU Xiao-qiao , ZHANG Pei-wen , ZHANG Shun-hua , ZHU Li     
College of Animal Science and Technology, Chengdu 611130, China
Abstract: Long non-coding RNAs (LncRNAs) are RNAs that larger than 200bp, and cannot encode proteins. Additionally, lncRNAs are badly conserved among different species, but have strong tissue specificity and temporal specificity. Recently, more and more evidences showed that lncRNAs are involved in a wide range of biological functions, including RNA biogenesis and processing, transcription regulation, chromatin modification, etc. by binding special budget proteins or as a ceRNA. However, the structure of lncRNA is very complex, and the research process of lncRNA's functionis very slowly, until now a detailed classification of lncRNA has not been done. Current knowledge of the general characteristics, categories, mechanisms, websites, and methods of lncRNA, and the proved relationship between lncRNA and cancer were reviewed, in order to provide reference for further studying the role of lncRNA.
Key words: Non-coding RNA     lncRNA     Categories     Functions     Cancer    

蛋白质是基因功能的执行者，RNA在蛋白质合成过程中扮演着重要作用。RNA可分为两类，一类为具有蛋白质编码功能的编码RNA(coding RNA)，另一类为不具有蛋白质编码功能的非编码RNA(non-coding RNA，ncRNA)。与蛋白质编码RNA相比，ncRNA在很长一段时间里都被当做转录的副产物。直到1990年，RNA干扰(RNAi)的首次发现才引起研究者对ncRNA功能的关注[1]。随着深度测序技术的迅猛发展，人们惊奇地发现，在哺乳动物中编码蛋白质的基因仅约占全基因组的2% ，全基因组的70% 最终转录为无编码蛋白质功能的非编码RNA，如转运RNA(tRNA)、核糖体RNA(rRNA)、small interfering RNA(siRNA)、microRNA(miRNA)、小核RNA(snRNA)和长链非编码RNA(long non-coding RNA,lncRNA)等[2-6]。截至目前，如miRNA、siRNA等ncRNA的生物学特性、功能及其分子作用机制已被基本阐释清楚[7-16]。

lncRNA与蛋白质编码mRNA在结构上存在许多相似之处[17]。尽管许多研究表明lncRNA广泛参与了大量生物学调控过程，如X染色体失活、染色质修饰、转录激活、基因组印迹、核内运输及转录干扰等，但由于技术手段和工具的限制，lncRNA的功能研究一直进展缓慢，人们对其基本特征、分类、功能等方面的认识也较为滞后。为此，本文主要从lncRNA的基本特征、分类、功能、相关的数据库、研究方法及其与癌症之间的关系等进行综述，全面展现lncRNA的研究进展。

1 lncRNA的特征

长度大于200bp(200bp~100kbp)、无蛋白质编码功能是lncRNA最基本的特征[18-20]。与编码RNA相比，广泛存在于哺乳动物中的lncRNA拥有更少外显子，缺少开放阅读框(open reading frame,ORF)及典型的起始密码子和终止子。研究者推论这可能是lncRNA不能编码蛋白质的原因[21-26]。lncRNA也有许多类似于mRNA的特征，如绝大多数lncRNA拥有5′帽子结构和polyA尾巴，由RNA转录酶Ⅱ转录，并经多聚腺苷酸化、pre-RNA拼接在内的共转录修饰[27-28]。

lncRNA在细胞质、细胞核、细胞器均有分布，但主要存在细胞核内[20]。哺乳动物全基因组的4% ~9% 最终转录成lncRNA[23, 29]。lncRNA是一类物种内序列进化保守、表达量易受外界环境影响的RNA分子，物种间的序列保守性较差，丰度也低于mRNA[30-31]。lncRNA的组织特异性远强于蛋白质编码RNA，不仅不同组织间的表达量不同，甚至同一组织不同部位的lncRNA都存在不同的表达模式[30, 32-33]。此外，lncRNA具有很强的时空特异性，同一lncRNA的表达量在同一组织或器官的不同发育阶段均有较大差异[34-37]。

2 lncRNA的分类

lncRNA二级、三级结构复杂，功能多样，但截至目前，仍缺乏有效的分类方法。目前，根据在基因组中与邻近蛋白质编码基因的位置关系，研究者将lncRNA分为(图 1)：①反义lncRNA(antisense lncRNA)，由邻近的编码基因反方向转录，与其他蛋白质编码基因存在重叠区域(如共享外显子)；②基因内lncRNA(intronic lncRNA)，起始于蛋白质编码基因的内含子，但与其无重叠区域，由相对邻近的蛋白质编码基因从任意方向转录；③异质性lncRNA(divergent lncRNA)，由邻近的蛋白质编码基因的启动子反方向转录，转录启动时常伴随相邻蛋白质编码基因转录起始位点数百bp的转录；④基因间lncRNA(intergenic lncRNA)，由蛋白质编码基因及那些不共享启动子、外显子或内含子的蛋白质编码基因共转录而来；⑤增强子式lncRNA(enhancer lncRNA)，由增强子转录，可长距离或短距离介导调控转录lncRNA自身的增强子与基因组内其它转录因子间的相互作用[9]。

图 1 lncRN分类(基于基因组上的位置) Figure 1 Classification of lncRNA (genomic location) (Marko Koll,et al. Nature Review. 2015,Doi:10.1038/nrendo.2014.229)
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lncRNA具有不同的亚细胞定位[38]，部分研究者根据其亚细胞定位差异，将存在于细胞核内的定义为核lncRNA，存在于细胞质内的定义为质lncRNA(图 2)。Derrien等评估了细胞核、细胞质内lncRNA的相对丰度，其中17% 富集在细胞核内，4% 富集在细胞质内[31]。lncRNA的功能与其所处位置息息相关。前者主要通过染色质修饰、转录激活、转录干扰等方式来行使生物学功能[28-43]；后者主要充当“诱饵分子”与蛋白质、DNA和RNA相互作用，如H19序列中包含数个let-7的结合位点，可吸附let-7形成复合体，抑制let-7所调控的生物学功能[44-47]。近年来在培养细胞中还观察到核lncRNA被短发夹RNA(shRNA)损耗的现象，故在细胞核与细胞质的间隙可能同样存在lncRNA [31, 38]。

图 2 lncRNA分类(基于亚细胞定位) Figure 2 Classification of lncRNA (subcellular localization) (Marko Koll,et al. Nature Review. 2015,Doi:10.1038/nrendo.2014.229)
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3 lncRNA的功能

lncRNA的二级、三级结构复杂，亚细胞定位多样，在RNA加工[48-49]、基因转录调控[50-52]、染色质修饰[53-54]、细胞凋亡[55-56]、端粒维护[57]、蛋白质与蛋白质或DNA与蛋白质交互作用的调控[58-60]等生物学过程中扮演重要角色。但与miRNA相对单一的作用机制不同，lncRNA的功能较复杂，目前主要分为5类。

3.1 转录调节其它基因的表达

lncRNA可作为转录因子在转录水平直接或间接地与靶基因相互作用，调控靶基因的转录与表达。例如，位于SER3上游的lncRNA-SRG1，其3′序列能与SER3的对应序列互补形成RNA-DNA复杂结构，lncRNA-SRG1的积极转录或过表达均会抑制SER3的转录[61]。lncRNA-DEANR1可通过激活FOXA2促进人类内胚层分化[62]。部分lncRNA与其他基因存在重叠区域，当重叠区域位于启动子区时，对应基因的转录会因lncRNA竞争性地占据转录起始因子结合位点而受到抑制。此外，lncRNA本身或其产物可直接与转录因子结合，改变转录因子的结构，降低转录因子活性，甚至无法与目标基因结合，从而抑制目标基因的表达。近年来还有研究发现lncRNA能与核糖核蛋白形成复合体来调控基因的表达。例如，由Dlx5和Dlx6之间的序列转录而来的lncRNA-Efv2可与转录因子Dlx2形成复合体，激活Dlx5、Dlx6的增强子，最终促使Dlx5和Dlx6的转录上调。

3.2 调节组蛋白修饰与染色质重塑

表观遗传是指DNA序列不变，但基因的表达却发生可遗传的变化，主要涉及DNA甲基化、组蛋白修饰和染色体构象的改变。lncRNA可通过招募染色质或组蛋白修饰相关蛋白形成作用复合体，之后到达目标位点，并促使该位点上的基因发生表观遗传修饰，调控下游基因表达(图 3)。PRC2复合体、CoREST/REST及SCMX蛋白是重要的染色质重塑相关蛋白，全基因组分析表明，大约1/3基因间lncRNA都涉及PRC2复合体、CoREST/REST或SCMX蛋白。最典型的例子是lncRNA-RepA可招募PRC2到Xist基因启动子，引发Xist启动子的组蛋白H3第27位赖氨酸发生甲基化(H3K27me3)，最终导致X染色体失活。或lncRNA-Air通过招募组蛋白甲基化转移酶G9a到Igf2启动子区域，使组蛋白H3K9发生甲基化，最终沉默父源染色体提供的相关印迹基因的表达。而lncRNA-HOTAIR则是作为一种反式调控，通过招募PRC2形成复合体，远距离介导HOXD发生H3K27的三甲基化(H3K27me3)，抑制相关基因的表达。lncRNA-Firre 可通过绑定CTCF对细胞核周围不活跃的X染色体定位，维持H3K27me3处的甲基化水平[63]。lncRNA-ADINR由C/EBPα基因上游450bp位置转录而来，在脂肪生成过程中可特异性地结合PA1，招募MLL3/4组蛋白甲基转移酶，增加C/EBPα位点的H3K4me3，最终减少H3K27me3组蛋白修饰。它的损耗可导致严重的脂肪形成缺陷[64]。

图 3 lncRNAs介导染色质重塑 Figure 3 IncRNAs mediate chromatin remodeling [Melanie Weiss,et al. Biol Chem. 2014,395(11):1275-1290]There are lots of lncRNA,which are associated with epigenetic silencing,such as ANRIL (a),ANRASSF1 (b),PCAT-1 (c),SChLAP1 (d)
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3.3 影响其他RNA生成

mRNA由miRNA的前前体(pre-miRNA)及前体(pri-miRNA)剪接而来，许多蛋白质已被证明可直接与Drosha和Dicer互作或绑定miRNA前体去调控miRNA的前体(pri-miRNA)或前前体(pre-miRNA)的生成[65-66]。而lncRNA可通过调节RNA聚合酶Ⅱ的活性来调节RNA的生成[67]。RNA聚合酶Ⅱ是通用转录因子，由SINEs转录而来的lncRNA-Alu和lncRNA-B2可直接抑制RNA聚合酶Ⅱ的活性来改变转录起始复合体的构象[68-69]。lncRNA-FGFR2通过招募多硫蛋白和脱甲基酶KDM2a建立特异性剪接的染色质信号，调控可变剪接[39]。而在RNA结合蛋白HEXIM1的参与下，lncRNA-7SK可与P-TEFb形成复合体，降低P-TEFb活性及磷酸化[70]。此外，源于假基因的转录本也可引起部分具有蛋白质编码功能的mRNA形成小RNA分子，如同样源于假基因的反义lncRNA能和与之相应的、被剪接的mRNA杂交，并经Dicer酶裂解形成内源性siRNAs[71-72]。因此，假基因并非仅扮演非功能性角色，当作为lncRNA转录时，也可作为调控基因表达的关键因子。

3.4 作为竞争性内源RNA(ceRNA)

2011年提出的ceRNA假说认为，当circuRNA、mRNA等具有相同的miRNA应答元件(miRNA response element,MRE)时，它们会竞争性地结合MRE而调控相关基因的表达水平[73]。lncRNA也是一种竞争性内源RNA，能与其它RNA转录体竞争相同的miRNA，进而在转录后水平上间接调控miRNA参与的生物学过程[74-75](表 1)。但与其他ceRNA不同的是，lncRNA与miRNA的作用机制主要有两种。最普遍的是lncRNA直接与miRNA种子序列互补配对，吸附miRNA形成复合体，降低细胞内参与下游基因调控的miRNA数量[图 4(a)]。例如，lncRNA-APF与miR-188-3p的种子序列互补，间接调控miR-188-3p的靶标ATG7的表达量，参与细胞自噬和心肌梗死的发生[76]；肌肉特异性lncRNA-MD1可吸附miR-133、miR-135，进而调节肌肉特异基因的转录激活因子MAML1、MEF2C，影响肌肉分化[77]。而当lncRNA序列里包含miRNA的种子序列时(lncRNA序列内含有可与miRNA竞争结合靶mRNA的3′UTR)，lncRNA也可作为ceRNA发挥功能[图 4(b)]，如lncRNA-Sirt1序列包含miR-34a的种子序列(TGGCAGT)，可竞争性地结合miR-34a的靶标[78]。

表 1 lncRNA作为ceRNA参与生物学调控 Table 1 lncRNA as ceRNA and regulates biological processes
LncRNAmiRNA细胞类型功能年份参考文献
CCAT1Let-7HCC cell促进肝癌的恶化2015[79]
MEG3miR-29HCC cell促进肝癌的恶化2011[80]
MDRLmiR-484心肌细胞抑制线粒体分裂2014[46]
CARLmiR-539心肌细胞促进线粒体分裂，心肌梗死2014[81]
UCA1miR-16UMUC2 and 5637 cells促进GLS2代谢，抑制肺癌细胞内的ROS2015[45]
UCA1miR-216HCC cell促进肝癌恶化2015[47]
HOTAIRmiR-331MGC-803,SGC-7901,BGC-823,and AGS cells促进胃癌恶化2014[34]
MALAT1miR-22HUVECs cell抑制内皮细胞功能紊乱2015[82]
MALAT1miR-217HBE cell对抗上皮细胞功能紊乱2015[83]
MALAT1miR-205HK-2和A-498 cells促进肾癌2015[84]
MALAT1miR-101,217ESCC cell促进食管癌恶化2015[85]
MIATmiR-150HUVECs和HMVECs cells对抗心血管疾病2015[86]
HOTTIPmiR-125bHCC cell促进肝癌恶化2015[87]
NEAT1miR-1403T3-L1 cell促进脂质形成2015[88]
CASC2miR-21Human U251,U87 glioma cells,HEK-293 cell对抗神经胶质瘤2015[89]
TUG1miR-144GEC cell调节血脑屏障2015[90]
CHRFmiR-489心肌细胞调节心脏肥大2014[91]
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图 4 lncRNA与miRNA的作用机制 Figure 4 Mechanism of lncRNA mediating miRNA (a) lncRNA as miRNAs sponges (b) The seed sequence of miRNAs exist in the lncRNA sequence
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3.5 作为小RNA分子的前体

通常情况下，miRNA由长转录本经Drosha酶和Dicer酶连续不断剪接而来[92-94]，Piwi-interacting RNAs(piRNAs)由长的单转录本生成[95]，但仍有许多小RNA的功能与作用机制并不特别明晰。随着高通量测序技术的发展，发现部分lncRNA内包含某些小RNA，如Wilusz等从lnc-MALAT1中鉴定出一段长度约为61bp、序列高度保守的小RNA分子[96-97]。部分功能验证性实验已证明lncRNA可以作为某些长度小于200bp的小RNA(如miRNA、piRNAs)的前体分子，参与转录后调控[98-99]，如lncRNA-Xist和lncRNA-Tsix可能是通过这种机制调控哺乳动物X染色体失活的[100]。

4 lncRNA的相关数据库

随着大量lncRNA的发现，收集、整理、分类lncRNA并构建lncRNA相关信息的数据库成为lncRNA研究的重要任务。近年来，研究人员结合生物信息学技术建立了多个与lncRNA 相关的基础数据库(表 2)，同时推出了以lncRNA功能为侧重点的生物信息数据库，如lncRNASNP、StarBase(表 2)。这些数据库的建立不仅提供各物种的lncRNA 的综合信息，还为挖掘lncRNA功能、研究lncRNA与其它分子之间的调控关系提供了一个非常重要的信息参考平台。

表 2 lncRNA相关数据库 Table 2 Websites of lncRNA
数据库名称网址相关功能
LNCcipediahttp://www.Lnccipedia.org人类lncRNA序列和结构全面注释
Noncodehttp://www.Noncode.org/ NONCODEv3ncRNA全面注释，可预测lncRNA 功能
ChIPBasehttp://deepbase.sysu.edu.cn/chipbase/提供lncRNA的表达图谱及专利调控的全面鉴定、注释。同时整合提供RNA-seq鉴定的lncRNA与CHIP-seq鉴定的转录因子的结合位点
Noncoding RNA databasehttp://biobases.ibch.poznan.pl/ncRNA/具有生物学功能的ncRNA注释
NREDhttp://jsm-research.imb.uq.edu.au/NRED提供人和小鼠的lncRNA在芯片数据上的表达信息
ncFANshttp://www.ebiomed.org/ncFANs/lncRNA功能注释
DIANA-LncBasehttp://www.microrna,gr/lncBase整理提供lncRNA上靶miRNA及功能注释等综合信息
lncRNAdbhttp://www.lncrnadb.org/提供有生物学功能的lncRNA的全面注释
fRNAdbhttp://www.ncrna.org/收集H-inv、Noncode和RNAdb三个数据库已注释或未注释的ncRNA
Gencodehttp://www.gencodegenes.org/提供人和小鼠已注释lncRNA的比较
NPInterhttp://www.bioinfo.org/NPInter/提供已被实验验证的ncRNA与DNA、蛋白质、RNA互作的信息
lncRNA Dieasehttp://210.73.221 .6 /lncrnadisease提供文献已报道的与疾病相关的lncRNA的注释
RNA22https://cm.jefferson.edu/rna22/lncRNA Sponge miRNA的预测
RNAhybridhttp://bibiserv.techfak.uni-bielefeld.de/lncRNA靶标的鉴定
LncRNASNPhttp://bioinfo.life.hust.edu.cn/lncRNASNP/提供lncRNA SNP位点及功能预测
StarBasehttp://starbase.sysu.edu.cn/mirCircRNA.phplncRNA调控网络的预测
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5 lncRNA的研究方法

目前，lncRNA的研究主要集中在lncRNA数据挖掘和lncRNA功能验证两方面。lncRNA芯片和lncRNA-seq是当前lncRNA数据挖掘的重要手段。lncRNA芯片基于已发现的lncRNA数据定制，研究者可通过与数万个芯片位点的结合分析来获知目标样本中的lncRNA表达谱，鉴定与研究目标相关的lncRNA，准确度较高[101-103]。而与传统的lncRNA芯片检测技术相比，基于去除核糖体RNA(rRNA)的建库方法及高通量测序技术的lncRNA-seq不仅可以检测识别基因家族中相似基因或由可变剪切造成的不同转录本的单碱基差异，还可检测到低丰度的稀有转录本，发掘新的lncRNA[30, 104-105]。因此，lncRNA-seq 更适用于大规模测序、发掘新的lncRNA。

lncRNA功能验证应该包括细胞水平验证与动物活体水平验证。但截至目前，尚未有在动物活体水平上对lncRNA进行功能验证的研究报道。在细胞水平上，可运用的研究工具较多，但主要分为以下几类。第一，通过qRT-PCR对目标lncRNA在样本中的变化进行定量分析或对lncRNA-seq测序数据进行验证[30, 40, 106-107]，但lncRNA的结构复杂、存在诸多重叠区域，在对lncRNA引物设计时需要综合考虑众多因素。第二，lncRNA的作用机制与其位置密切相关，因此lncRNA核质定位信息可为lncRNA功能预测提供有力参考。

目前，研究者既可通过原位杂交技术、lncRNA-FISH对lncRNA定位分析，也可基于核质RNA分离抽提技术，通过qRT-PCR对细胞核与细胞质内目标lncRNA定量来对lncRNA进行定位分析[35, 101]。第三，一直以来，细胞内目的片段的缺失或获得是研究目的片段功能最为直接的手段，lncRNA也不例外。目前，研究者可通过siRNA、反义寡核苷酸链(ASO)等工具抑制细胞内目标lncRNA的表达，或构建lncRNA载体，对lncRNA进行功能缺失或获得性研究[76, 101, 108-109]。但lncRNA较长，作用机制复杂，其载体的构建存在一定难度，目前仅有少数研究者运用了这种研究方法[81]。一般情况下，功能验证性lncRNA的过表达载体应为全长，而在验证lncRNA与miRNA的靶标关系时，构建与miRNA种子序列互补区域的上下游200~500bp即可。第四，可以通过RNA pull down、CHIRP-seq、RNA-IP等方法来确定能与目的lncRNA互作的蛋白质、DNA、RNA[26, 104, 110-113]。第五，身处大数据时代，生物信息技术已成为分析目标数据的必备手段，lncRNA也不例外。通过生物信息技术与lncRNA-seq(或芯片)的结合分析，研究者可筛选出差异表达的lncRNA、构建共表达网络，并对lncRNA的功能进行预测，为后续的功能性细胞实验提供强有力的科学依据(图 5)[28, 40]。

图 5 lncRNA的数据分析及研究思路 Figure 5 Data analysis and research ideas of lncRNA
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6 lncRNA参与调控癌症发生

癌症的发生受多种因素调控，如遗传。癌症的发生常伴随着大量异常基因的出现，但目前的证据倾向于癌症并非由蛋白质编码序列的改变而引发。最近，越来越多的lncRNA被发现可作为致癌或抑癌因子(表 3)，许多致癌的基因组位点也主要是由那些在癌症诱发过程中扮演着重要角色的lncRNA转录而来。随着高通量技术的迅猛发展，大量与肿瘤发生相关的lncRNA被鉴定出。例如，Nicole等鉴定了111种与肺癌相关的基因间lncRNA[114]，Matthew等利用高通量测序确定了58 000个涉及正常组织和常见类型癌症的lncRNA[115]。

表 3 lncRNA在癌症里扮演的角色 Table 3 lncRNA plays roles of cancer
类型lncRNA相关功能年份参考文献
前列腺癌SChLAP1与前列腺癌发生呈正相关2015，2014[123-125]
PCAT29抑制前列腺癌细胞的增殖、迁移2014[126]
NEAT1促前列腺恶化2014[127]
PCAT-1促前列腺癌细胞增殖，破坏DNA修复2015，2014[128-129]
H19抑制前列腺癌细胞转移2014[130]
PCA32015[131]
HOTAIR调节雄激素，促进癌细胞增殖、迁移2015[132-133]
PCG调控一个涉及前列腺癌发生的网络2015[134]
P21有助于区分前列腺癌和良性疾病2015[135]
Linc00963抑制前列腺癌细胞迁移2014[136]
乳腺癌HIT抑制TGF-β诱导的癌细胞迁移、侵袭2015[137]
M41提高癌细胞的侵袭能力及其三苯氧胺耐药性2015[138]
BC200抑制乳腺癌细胞凋亡2015[56]
Smad7抑制乳腺癌细胞凋亡2014[120]
BCAR4调节乳腺癌细胞内信号转导2015[139]
SPRY-1T1促进乳腺癌细胞增殖2015[140]
AK023948促进乳腺癌的发生2015[141]
HOTAIR增强ER信号，促进乳腺癌细胞增殖2015[142]
Hh促进乳腺癌的发生2015[143]
ATB促进乳腺癌的发生2015[144]
膀胱癌ZEB2NAT促进膀胱癌细胞侵袭2015[145]
UCA1增强膀胱癌细胞耐药性2014[146]
HOTAIR调节介导膀胱癌恶化的exosome2015[147]
H19促进膀胱癌细胞的增殖、迁移2015[148]
TUG1促进膀胱癌中上皮细胞向间充质细胞转化2015[149]
直肠癌ATB涉及直肠癌的预后2015[150]
MALAT1促进直肠癌的恶化2014[151]
CCAL促进直肠癌的恶化2015[152]
RP11-462C24调节直肠癌细胞的转移2014[153]
GAS5抑制直肠癌细胞增殖2014[154]
肺癌AK126698增强肺癌细胞对顺氯氨铂的耐药性2013[155]
SCAL1调节肺癌细胞的恶化2013[156]
GAS5调节肺癌细胞的增殖、凋亡2013[157]
CCAT2促进肺癌细胞的侵袭2014[158]
甲状腺癌PTCSC3抑制甲状腺癌恶化2013[159]
胃癌H19促进胃癌细胞的增殖2012，2014[160-161]
AC096655调节胃癌细胞的转移2013[162]
MEG3促进胃癌细胞增殖、胃癌恶化2014[163]
HULC促进胃癌细胞的增殖、迁移，抑制胃癌细胞的凋亡2014[164]
胰腺癌HOTAIR促进胰腺癌细胞的增殖2013[165]
H19促进胰腺癌细胞的迁移2014[166]
肝癌MEG3促进肝癌细胞增殖2011[80]
TCF7促进肝癌细胞自我更新2015[167]
HOTTIP促进肝癌恶化2015[168]
UCA1促进肝癌恶化2015[47]
表选项

在常见肿瘤里，lncRNA的功能并不单一，它们促进或抑制肿瘤的发生。例如，参与了转录调控和转录后调控的lncRNA-MALAT1在许多肿瘤组织或细胞内都高表达，与癌细胞的转移、复发相关[116-117]；又如，Lai等[118]通过对9种肝癌细胞系、112个肝癌病例分析发现，MALAT1可以作为一个独立的肝癌复发的预测因子，它的抑制可显著降低HepG2的生存率、迁移能力。Liu等[119]发现，MALAT1于胰腺癌组织高表达，且其表达水平随着肿瘤的不断增大、恶化而逐渐升高。Arase等[120]通过对小鼠乳腺上皮细胞测序鉴定出lncRNA-Smad7，并发现其可以靶向调控TGF-β,增强乳腺癌细胞抗凋亡作用。lncRNA-H19位于染色体11p15.5，可与EZH2结合，抑制E-cad的表达，提高膀胱癌细胞的新陈代谢能力与迁移能力，其被认为是膀胱癌早期复发的一个标志物[121]。

lncRNA在癌症抑制过程也扮演着重要角色。COX-2介导的炎症会在癌症的早期阶段促进肿瘤的生长和扩散，但在肿瘤晚期COX-2却会将扩散中的肿瘤细胞暴露给免疫系统。因此，COX-2的活性在癌症晚期往往会被抑制。2014年Krawcczyk等[122]在Elife上发文表示，一种被命名为PACER的lncRNA能抑制COX-2基因的启动抑制因子p50，从而增强COX-2在晚期癌症细胞内的活性以便协助免疫系统对抗癌症。p53被认为与癌症之间存在不容质疑的相关性，有研究者通过全基因组测序和CHIP-seq分析鉴定出18种可受p53直接调控的、在癌细胞里低表达的lncRNA，p53可通过调节这些lncRNA建立一个监管循环反馈系统，促进p53肿瘤抑制因子的活化[28, 40]。如图 6所示，有研究者将lncRNA涉及癌症发生的普遍机制进行了归纳。

图 6 lncRNA涉及癌症发生的普遍机制及其相关实例 Figure 6 Universal mechanisms and examples that lncRNAs mediate cancer There are various mechanisms of lncRNAs,such as charomatin remodeling(a),transcriptional co-activator and -repression(b),protein inhibition(c),post-transcriptional modifications(d),decoy(e) (Cheetham S W,et al. British Journal of Cancer,2013,108:2419-2425)
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7 小结与展望

无蛋白质编码功能的lncRNA已成为时下核酸研究的热点领域。从目前的研究证据来看，lncRNA结构复杂，作用机制多样，参与了表观遗传调控、转录调控、转录后调控，牵涉细胞的增殖、分化、凋亡等生命环节，在遗传信息逐级流动过程中扮演着不可或缺的监管角色。越来越多的证据表明lncRNA与疾病的发生息息相关，如参与癌症的诱发或抑制，未来可被作为癌症的潜在生物学靶标或开发作为分子类药物运用于疾病的诊断与治疗。此外，基础研究是推动科学文明发展的基石，lncRNA的基础研究亟须更多的研究团队加入，更多、更快地研究、阐释lncRNA在生命体发育过程扮演的角色及其作用机制。

尽管如此，由于研究手段或技术的欠缺，成本高昂等原因，lncRNA的研究还处于起步阶段，特别是在利用高通量测序数据挖掘涉及生物学调控的lncRNA和lncRNA的功能性研究方面。想全面了解lncRNA介导生物学调控的分子作用机制仍有很长一段路要走。而身处大数据时代，我们急需构建高质量的lncRNA数据库，对lncRNA进行细致、精确的数据收集、整理、分类，而且需要对已知信息进行更精准的关联分析、预测，推进lncRNA的功能性研究；亟须开发并完善lncRNA的研究工具和手段。只有切实可行、成本低廉的实验方法、工具及高质量可靠的数据库之间的协同作用才能最终铺平对lncRNA的研究道路。

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