MicroRNA and histopathological characterization of pure mucinous breast carcinoma

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MicroRNA_关节炎治疗的新靶点_吴国栋

关节炎是一种常见的累及运动系统的慢性疾病，轻者关节疼痛不适，严重者可丧失运动能力，甚至是丧失生活自理能力．根据其不同的致病机制，可分为骨性关节炎（ osteoarthritis，OA ）和风湿性关节炎（ rheumatoid arthritis，RA）等．关节炎的发病部位常见于全身各处大小关节，其中又以膝关节最为常见．骨关节炎是一类由于关节软骨基质的代谢平衡被打破，继而引发关节产生退行性病变的慢性疾病［1］，其突出特点表现为患者关节的红、肿、热、疼，严重的会引起关节变形，乃至运动功能障碍．骨关节炎的发病机制复杂，导致骨关节炎发生的因素也有所不同，除年龄、外伤等因素外，性别、肥胖、天气等因素都有可能成为骨关节炎的诱因［2］．在我国的高
MicroRNA———New Targets for Arthritis Treatment
WU Guo-Dong，MA Ning，GAO Xu*
（ School of Basic Medical Sciences，Harbin Medical University，Harbin 150086，China）
第 10 期
吴国栋等： MicorRNA———关节炎治疗的新靶点
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方地区患有膝关节疼痛等关节炎症状的农村人口比例明显高于南方的农村人口．除开展必要的防控宣传外，对骨关节炎治疗方法的探索也是分子生物学重要的课题之一．
1 小干扰 RNA：分子治疗骨关节炎的探索

microRNA_一种新型肿瘤分子标志物

microRNA ：一种新型肿瘤分子标志物MicroRNA:A Novel Biomarker of CancerLIANG Dong -yu ，HOU Yan -qiang梁冬雨综述，侯彦强审校（上海交通大学附属第一人民医院松江分院中心实验室，上海201600）摘要：早期诊断、早期治疗是降低肿瘤死亡率的有效途径。

microRNA 是一类内源性的长约18~22个核苷酸的非编码小RNA ，其在肿瘤组织以及循环中的特异表达，为肿瘤的早期诊断带来新的希望。

肿瘤中microRNA 的表达模式不但与肿瘤诊断有关，与肿瘤的分期、进展以及预后也密切相关。

全文就microRNA 在肿瘤早期诊断以及预后判断中的作用作一综述。

主题词：肿瘤；microRNA ；分子标志物中图分类号：R730.4文献标识码：A 文章编号：1671-170X （2011）07-0485-04基金项目：上海市卫生局局级项目（2010104）通讯作者：侯彦强，副主任技师，博士；上海交通大学附属第一人民医院松江分院中心实验室，上海市松江区中山中路746号（201600）；E -mail:houyanqiang@ 。

收稿日期：2011-04-14肿瘤标志物是反映肿瘤存在和生长的化学物质，临床上通过对这些化学物质的检测，可以对相应肿瘤作早期诊断、疗效评估和预后判定。

目前，有多种肿瘤标志物应用于临床，但大多数标志物仍然缺乏足够的组织特异性和肿瘤特异性。

microRNA 是一组长约22个核苷酸的非编码小分子RNA ，其通过转录后水平调控参与细胞的增殖、分化、凋亡等生命活动。

近几年的研究发现mi -croRNA 表达具有明显的组织细胞特异性，且与肿瘤的发生和发展有着密切联系。

最近，Lawrie 等［1］在外周血中检测到microRNA 的存在，且发现循环mi -croRNA 的表达与肿瘤也有一定的相关性，这提示microRNA 可作为一种新型的肿瘤标志物。

微小RNA在卵巢癌中的研究进展

微小RNA在卵巢癌中的研究进展史蔚;万小平【摘要】微小RNA(microRNA,miRNA)是一种内源性非编码小RNA,其在转录后水平负调节靶基因的表达.一个肿瘤相关的微小RNA通常可以同时调节几个癌基因和抑癌基因的表达水平,因此miRNA与肿瘤的发生、发展和预后有着密切的联系.研究发现,一些miRNA在正常卵巢组织和上皮性卵巢癌组织中表达水平明显不同,其表达谱可作为潜在的肿瘤标志物对卵巢癌进行早期诊断和预后判断.此外,对某些在卵巢癌中调节异常的miRNA靶基因的探索,不但可有助于了解卵巢癌的发病机制,同时也可为卵巢癌治疗提供新靶点.【期刊名称】《国际妇产科学杂志》【年(卷),期】2010(037)001【总页数】4页(P60-63)【关键词】微小RNA;卵巢癌;生物学标记;肿瘤相关的微小RNA【作者】史蔚;万小平【作者单位】200080,上海交通大学附属第一人民医院妇产科;上海交通大学附属国际和平妇幼保健院【正文语种】中文上皮性卵巢癌是严重威胁女性健康的常见恶性肿瘤之一，其发病分子机制目前尚不清楚。

微小RNA（microRNA，miRNA）是一种新近发现的具有调控基因作用的非编码短序列RNA，其在肿瘤发生过程中扮演重要角色。

研究发现，miRNA在人类卵巢癌组织中异常表达，其表达谱可清楚区分正常卵巢组织和相对应的癌组织。

miRNA在人外周血中稳定表达，提示miRNA可能作为一种潜在的肿瘤标志物对卵巢癌进行早期诊断。

研究者推测出一些miRNA作用的与卵巢癌发生有关的靶基因，提示miRNA可能在人类上皮性卵巢癌的发病机制中起重要作用。

另外，识别miRNA基因甲基化水平的改变可能作为一种表观遗传学机制导致miRNA的异常表达，这也从某种程度上验证了miRNA在卵巢癌中潜在的治疗作用。

本文综述miRNA在卵巢癌中的研究进展。

miRNA及其作用机制miRNA是一类单链小分子RNA，广泛存在于真核生物中，是一组非编码的短序列RNA。

microRNA在动脉粥样硬化发病机制中的作用

microRNA在动脉粥样硬化发病机制中的作用于瑞杰【摘要】微小核糖核酸(microRNA,miRNA) 是一类非编码的小分子RNA,主要在转录后水平调控基因表达.近来,miRNA与动脉粥样硬化(atherosclerosis,As)发病机制的关系成为研究热点.目前已证实miRNA在调节As病变进程相关的血管壁炎性反应、免疫细胞分化和胆固醇代谢等方面均发挥重要作用.miR-155和miR-146a参与调控血管壁的炎性反应以及辅助性T细胞(helper T cell,Th)的分化;miR-29参与调控血管平滑肌细胞(vascular smooth muscle cell,VSMC)迁移以及相关炎性反应;miR-33参与对胆固醇代谢的调控.此外,miR-365、miR-222等分别通过调控内皮细胞的凋亡和新生血管的形成参与As的发生、发展.文中就上述miRNA在As发生、发展过程中的作用机制进行综述,旨在为进一步揭示As的发病机制提供思路.【期刊名称】《医学研究生学报》【年(卷),期】2013(026)009【总页数】4页(P970-973)【关键词】microRNA;动脉粥样硬化;作用机制【作者】于瑞杰【作者单位】210002,南京,南京大学医学院临床学院(南京军区南京总医院)解放军临床检验医学研究所【正文语种】中文【中图分类】R543.120 引言miRNA是长约22个核苷酸的单链、内源性的非编码小RNA，通过与靶mRNA 结合而对基因表达进行转录后水平的调控。

目前，在已发现的miRNA中，大约有721种人源性miRNA和579种鼠源性miRNA［1］。

人类约30%的编码蛋白基因受其调控，1个miRNA可调控多个靶基因，而同一基因可由多个miRNA共同调节［2］。

越来越多的证据表明，miRNA在多种疾病的病理生理过程中起重要作用，尤其与心血管疾病的发生、发展密切相关［3－5］。

As作为心血管疾病的主要病理生理基础，是一种动脉血管壁的慢性炎症性病变［6－7］。

MicroRNA及其在肾肿瘤中的研究现状及前景

MicroRNA及其在肾肿瘤中的研究现状及前景何昊玮;董杰;葛京平【摘要】MicroRNA(miRNA)是大小为19 ～25个核苷酸的单链非编码小分子RNA,在基因的转录和翻译水平进行调控.近期的研究发现,miRNA在细胞分化、增殖、凋亡等生物进程中均起到重要的作用.在多种人类肿瘤中均发现miRNA的表达异常,特定miRNA的异常表达与缺氧、上皮间质变等肾肿瘤关键发病机制密切相关.miRNA将会是肾肿瘤可能的重要标志物,对肾肿瘤的治疗具有重要意义.%MicroRNAs( miRNA )are non-protein-coding short single stranded RNAs with the size range of 19-25 nucleotides associated with gene regulation at the transcriptional and translational level. Kecent studies have proved that miRNAs play important roles in a large number of biological processes, including cellular differentiation,proliferation , apoptosis, etc. . Changes in their expression were found in a variety of human cancers. Specific miRNAs alterations were associated with key pathogenetic mechanisms of renal cell carcinoma like hypoxia or epithelial-mesenchymal transition. miRNAs potential to serve as a powerful biomarker of renal cell carcinoma,is of great significance for the treatment.【期刊名称】《医学综述》【年(卷),期】2013(019)004【总页数】4页(P640-643)【关键词】MicroRNA;肾肿瘤;癌基因;调控;基因表达谱【作者】何昊玮;董杰;葛京平【作者单位】第二军医大学南京临床医学院,南京军区南京总医院泌尿外科,南京,210002;第二军医大学南京临床医学院,南京军区南京总医院泌尿外科,南京,210002;第二军医大学南京临床医学院,南京军区南京总医院泌尿外科,南京,210002【正文语种】中文【中图分类】R737.11MicroRNA(miRNA)是长度为19～22个核苷酸的非编码RNA，最初于1993年由Lee等［1］在研究秀丽隐杆线虫时所发现。

MicroRNA与脂质代谢

MicroRNA与脂质代谢摘要】 MicroRNAs已经成为一种重要的调节脂质代谢的因子。

最近发现的microRNA-33a and b (miR-33a/b)在体内胆固醇和脂肪酸代谢动态平衡中起着很重要的调节作用。

这些microRNA嵌入在固醇响应元件结合蛋白基因（SREBF2 和SREBF1）中，通过抑制参与到胆固醇输出和脂肪酸氧化的基因，比如ABCA1，CROT，CPT1，HADHB和PRKAA1，转录后调节胆固醇和脂肪酸代谢。

miR-33a/b促进细胞内脂质沉积。

在新近的动物实验研究中表明抑制这些小干扰RNA对脂蛋白代谢的调节有很显著的影响，包括增加血浆中高密度脂蛋白（HDL）和减少极低密度脂蛋白（VLDL）中甘油三酯的代谢。

这些新的发现支持了microRNA拮抗剂在治疗血脂异常、动脉粥样硬化和相关代谢疾病中的潜在作用。

【关键词】小RNA 脂肪代谢高密度脂蛋白甘油三酯【中图分类号】R589.2 【文献标识码】A 【文章编号】2095-1752（2014）08-0138-02脂质代谢异常可引起动脉粥样硬化、冠心病、肥胖症等多种与代谢相关的疾病，严重威胁人类健康。

近期研究发现，microRNA参与上述多种病理过程的调控。

本文综述了近些年来microRNA对脂质代谢调控方面的研究进展，并对其在治疗中的潜在作用进行了展望。

1. microRNA的结构与作用机制microRNA是一类大小约18-22个碱基的单链小分子RNA，是由具有发夹结构的约70-90个碱基的单链RNA前体经过Dicer酶加工后生成。

microRNA在真核基因表达调控中有着广泛的作用。

尽管有一部分在所有细胞的各个阶段中均有表达，但是大多数microRNA的表达水平在不同组织、不同发育阶段具有其特异性。

microRNA作用于目的基因的方式与两者的配对程度有关：成熟的microRNA通过Watson-Crick碱基配对识别并结合靶标 mRNA的3’UTR、5’UTR 或编码蛋白外显子区域。

多发性骨髓瘤相关microRNA的研究进展

多发性骨髓瘤相关microRNA的研究进展钟焱;胡维新【期刊名称】《生命科学研究》【年(卷),期】2011(015)004【摘要】microRNA (miRNA)是一种内源性非编码的单链小分子RNA,长度约19～24个核苷酸,通过靶向结合mRNA的3'非翻译区域(3 ' UTR)区域,抑制翻译或者降解靶标mRNA而调节基因的表达.miRNA参与一些重要的生理、病理学过程,包括细胞增殖、分化、生长和凋亡等.大量研究发现,miRNA与多发性骨髓瘤(multiple myeloma,MM)的发生、发展及诊断治疗等有着密切关系.深入探讨MM 相关miRNA的调节机制和功能等,可为MM发病机制的研究及诊治提供新的思路.%microRNAs (miRNAs) are small single-strand non-coding RNAs of19~24 nucleotides,which can inhibit translation or degrade the mRNA of target gene by binding to its 3' untranslated region (3' UTR).They have been shown to play the fundamental role in diverse physiologic and pathologic process,including cell proliferation,differentiation,growth and apoptosis,etc.A great number of studies had indicated a strong relationship between the miRNAs and theoccurrence,development,diagnosis,treatment of mutiple myeloma (MM).Further studies on the regulation and function of MM associated miRNA may provide us new sights into MM pathogenesis and its diagnosis and treatment.【总页数】4页(P359-362)【作者】钟焱;胡维新【作者单位】中南大学生物科学与技术学院分子生物研究中心,中国湖南长沙410078;中南大学生物科学与技术学院分子生物研究中心,中国湖南长沙410078【正文语种】中文【中图分类】Q752【相关文献】1.microRNA在多发性骨髓瘤中作用的研究进展 [J], 王灿;曹雅明;冯辉2.MicroRNAs和年龄相关性白内障相关性的研究进展 [J], 徐婕;卢奕3.microRNA与多发性骨髓瘤的研究进展 [J], 张霞4.microRNA在多发性骨髓瘤的诊断、预后和靶向治疗中的研究进展 [J], 张晓洁; 陈志未; 李菲5.microRNA在多发性骨髓瘤的诊断、预后和靶向治疗中的研究进展 [J], 张晓洁; 陈志未; 李菲因版权原因，仅展示原文概要，查看原文内容请购买。

MicroRNA对皮肤毛囊发育调控的研究进展

MicroRNA对皮肤毛囊发育调控的研究进展张桂山;徐晶;姜怀志【期刊名称】《家畜生态学报》【年(卷),期】2013(34)6【摘要】MiRNAs are a family of endogenous non-coding single strand small RNAs (19-25 nt),combining target mRNA through basepair complementarity to degrade mRNA or disrupt translation of mRNA,then modulating gene expression.This review summarized the biogenesis and function of miRNAs,profiling miRNAs Expression in the skin and hair follicle and regulation of miRNAs on skin and hair follicle development.%miRNA是一类由19～25个核苷酸组成的内源性非编码单链小分子RNA,通过与靶基因mRNA3,端非编码区配对结合,降解靶mRNA或阻碍其翻译,进而调节靶基因的表达.文章综述了miRNA的生源说及功能、miRNA在皮肤毛囊中的表达检测以及miRNA对皮肤毛囊发育的调控.【总页数】4页(P1-4)【作者】张桂山;徐晶;姜怀志【作者单位】吉林农业大学动物科学技术学院,吉林长春 130118;吉林农业大学发展学院,吉林长春 130600;吉林农业大学动物科学技术学院,吉林长春 130118【正文语种】中文【中图分类】S811.6【相关文献】1.MicroRNAs对羊生长发育调控作用的研究进展 [J], 林月霞;吕玉华;丁宏林;廖荣荣2.植物MicroRNA对花发育调控研究进展 [J], 陈罡3.绒山羊毛囊发育规律及毛囊发育调控因子的研究进展 [J], 张桂山;姜怀志;徐晶4.microRNAs 在动物皮肤及毛囊发育中的调控作用研究进展 [J], 吴月红;李勇;杨易;何玉龙5.LncRNA在哺乳动物毛囊发育调控中的研究进展 [J], 常永芳;包鹏甲;褚敏;吴晓云;梁春年;阎萍因版权原因，仅展示原文概要，查看原文内容请购买。

microRNA的修饰

Leading EdgeReviewModiﬁcations of Small RNAsand Their Associated ProteinsYoung-Kook Kim,1Inha Heo,1and V.Narry Kim1,*1School of Biological Sciences and Center for National Creative Research,Seoul National University,Seoul151-742,Korea*Correspondence:narrykim@snu.ac.krDOI10.1016/j.cell.2010.11.018Small regulatory RNAs and their associated proteins are subject to diverse modiﬁcations that can impinge on their abundance and function.Some of the modiﬁcations are under the inﬂuence of cellular signaling,thus contributing to the dynamic regulation of RNA silencing.IntroductionThe past decade has witnessed an explosion of research on small regulatory RNAs that has yielded a basic understanding of the many types of small RNAs in diverse eukaryotic species, the protein factors involved,and the functions of key factors along the RNA silencing pathways.Much more remains to be learned,however,with recent studies unveiling interesting new layers of regulation and complexity associated with small RNAs.We now know that both small RNAs and their associated protein factors can be modiﬁed at multiple steps in their biogen-esis and effector pathways.Insight into modiﬁcations of small RNAs came initially from sequencing efforts,which made it clear that most microRNA (miRNA)loci generate multiple isoforms(called isomiRs)apart from the reference sequence(Morin et al.,2008).Alternative/ inaccurate processing partly explains the heterogeneity,but a substantial portion of the variation is due to RNA modiﬁcations. Small RNAs are modiﬁed either internally or externally by untem-plated nucleotide addition,exonucleolytic trimming,20-O-methyl transfer,and RNA editing.Protein factors in RNA silencing path-ways are also subject to various posttranslational modiﬁcations, including phosphorylation,hydroxylation,ubiquitination,and methylation.In this Review,we focus on the recent develop-ments in the modiﬁcations of RNAs and proteins in RNA silencing pathways.Small RNA BiogenesisRNA silencing is a widespread mechanism of gene regulation in eukaryotes.At the core of all RNA silencing pathways lie small RNAs(20–30nt in length)associated with the Argonaute family proteins(Kim et al.,2009).Small RNAs provide the speciﬁcity of regulation by base-pairing to the target nucleic acids while the Argonaute proteins execute the silencing effects.The Argo-naute(Ago)proteins are grouped into Ago and Piwi subfamilies, and in animals,three types of small RNAs have been described: microRNAs(miRNAs),small interfering RNAs(siRNAs),and Piwi-interacting RNAs(piRNAs).miRNAs( 22nt)induce mRNA degradation and/or transla-tional repression.Nucleotides2–7,from the50end of the miRNA, are referred to as the‘‘seed’’and are critical for hybridization to the targets(Bartel,2009).As a class,miRNAs are found in all tissues,although each miRNA species displays a unique spatio-temporal pattern of expression.An miRNA originates from a long primary transcript(pri-miRNA)containing a local hairpin struc-ture(Kim et al.,2009).In animals,the nuclear RNase III Drosha liberates the hairpin-shaped precursor miRNA(pre-miRNA) (Figure1).The cytoplasmic RNase III Dicer removes the terminal loop to produce a small RNA duplex,consisting of the functional miRNA strand and the passenger(*)strand(miRNA/miRNA*). The duplex then binds to the Argonaute loading complex (comprised of Dicer,TRBP,and Ago),whose action leads to the incorporation of the functional miRNA strand(mature miRNA) into Ago.The plant miRNA system differs from its animal coun-terparts in several aspects(Figure2).The plant homolog of Dicer, Dicer-like1(DCL1),cleaves both pri-miRNA and pre-miRNA in the nucleus.Plant miRNAs generally show extensive comple-mentary to their target mRNAs and induce endonucleolytic cleavage of the targets.Endogenous siRNAs(endo-siRNAs, 21nt)are similar to miRNAs in their binding to the Ago subfamily proteins,in their dependence on Dicer for biogenesis,and in exerting their regu-latory effects posttranscriptionally(Kim et al.,2009).But unlike miRNAs,endo-siRNAs originate from long double-stranded RNA precursors(dsRNAs),and their biogenesis does not require processing by Drosha.Endo-siRNAs are abundant in lower eukaryotes and in plants,whereas in mammals,they are found in restricted tissues such as the ovary.Piwi-interacting RNAs(piRNAs,21–30nt)associate with the Piwi subfamily of Argonaute proteins.piRNAs mediate the silencing of repetitive elements in gonads via transcriptional and posttranscriptional silencing mechanisms.Production of piRNAs is not dependent on RNase III nucleases,and the steps and factors involved in their biogenesis remain largely unknown. Modiﬁcations of Small RNAs30End Modiﬁcations:Uridylation,Adenylation,and20-O-MethylationThe30ends of mature miRNAs are highly heterogeneous, whereas the50ends are relatively invariable.The patterns and sources of heterogeneity seem to vary depending on the miRNA species and the cell types.The30end often contains extra1–3nucleotides that do not match the genomic DNA sequences.These untemplated nucleotides are added by Cell143,November24,2010ª2010Elsevier Inc.703terminal nucleotidyl transferases that preferentially introduce uridyl or adenyl residues to the 30terminus of RNA.The ﬁrst indication of 30end modiﬁcation of small RNA came from a hen1mutant of Arabidopsis (Li et al.,2005).HEN1is a methyl transferase that adds a methyl group to the 20-OH at the 30end of RNA (Yu et al.,2005).In hen1mutants,miRNAs are reduced in abundance and become heterogeneous in size due to uridylation at the 30end.Because U tailing correlates with the exonucleolytic degradation of mRNAs (Shen and Goodman,2004),it was postulated that uridylation induces degradation of plant miRNAs and that the 20-O-methyl moiety is required to protect small RNAs from uridylation and decay (see below).Consistent with this notion,in green algae Chlamy-domonas ,a nucleotidyl transferase,MUT68,uridylates the 30end of small RNA,and the RRP6exosome subunit facilitates small RNA decay in a manner dependent on MUT68in vitro (Ibra-him et al.,2010).Deletion of MUT68results in elevated miRNA and siRNA levels,indicating that MUT68and RRP6collaborate in the turnover of mature small RNAs in plants.Similar links between 20-O-methylation,uridylation,and decay appear to exist in animals.A recent study on the zebraﬁsh Hen1homolog shows that piRNAs are uridylated and adenylated andthat piRNA levels are reduced in hen1mutant germ cells (Kam-minga et al.,2010).In ﬂies and mice,piRNAs are methylated by HEN1orthologs,but the connection to stability control remains unclear (Horwich et al.,2007;Kirino and Mourelatos,2007;Ohara et al.,2007;Saito et al.,2007).In ﬂies,dAgo2-bound RNAs (mostly siRNAs)are protected by 20-O-methylation from being uridylated/adenylated,which in turn induces 30exonucleolytic trimming (Ameres et al.,2010).In nematode worms,the role of 20-O-methylation has yet to be determined.However,a subset of endo-siRNAs associated with an Ago homolog CSR-1is uridylated at the 30end,and the uridyl trans-ferase CDE-1(also known as CID-1or PUP-1)negatively regu-lates these siRNAs,indicating that uridylation serves as a trigger for decay (van Wolfswinkel et al.,2009).Although mature miRNAs lack methylation in animals,uridyla-tion plays a signiﬁcant role in the control of miRNA biogenesis.In mammalian embryonic stem cells,let-7biogenesis is sup-pressed by the Lin28protein that binds to the terminal loop of the let-7precursors (Heo et al.,2008;Newman et al.,2008;Rybak et al.,2008;Viswanathan et al.,2008).Of interest,Lin28induces 30uridylation of pre-let-7by recruiting the terminal nucleotidyl transferase TUT4(also known as ZCCHC11)(HaganFigure 1.Modiﬁcations in the AnimalMicroRNA Pathway(Left)MicroRNAs (miRNAs)are subject to diverse modiﬁcations.Pri-miRNAs are edited by ADARs,which convert adenosine to inosine (I).RNA editing inhibits processing and/or alters target speciﬁcity.Pre-let-7is regulated through uridylation.Lin28recognizes pre-let-7and,in turn,recruits a nucleo-tidyl transferase TUT4(mammal)or PUP-2(worms),which adds an oligo-uridine tail at the 30end of RNA.The uridylated pre-miRNA is resistant to Dicer processing and subject to decay.TUT4also uridylates mature miRNA (miR-26),which reduces miRNA activity.Another nucleotidyl trans-ferase GLD-2adenylates mature miRNAs,which reduces the activity of miRNA and/or increases the stability of speciﬁc miRNAs (such as miR-122).(Bottom)Mature miRNAs are degraded through several mechanisms.In worms,a 50/30exonu-clease XRN-2degrades miRNAs that are released from Ago.In ﬂies and humans,extensive pairing between miRNA/siRNA and target RNA triggers tailing as well as 30/50trimming of miRNA/siRNA.(Right)Protein factors,which are involved in the miRNA pathway,are also subject to various post-translational modiﬁcations.Human Drosha is phosphorylated at two serine residues,S300/S302,by an unknown kinase.Phosphorylation localizes Drosha to the nucleus,where the pri-miRNA processing occurs.MAP kinases Erk1/2phosphorylate human TRBP at S142,S152,S283,and S286,which increases the protein stability of TRBP and Dicer.Ago2is regulated by multiple modiﬁcations.A prolyl hydroxylase C-P4H(I)hydroxylates P700in human Ago2,which enhances stability of Ago2and increases P body localization.Phosphorylation of human Ago2at S387by MAPKAPK2,which is induced by p38pathway,also promotes P body localization of Ago2.However,the biological signiﬁcance of P body localization of Ago2remains unclear.In mice,a stem cell-speciﬁc E3ligase,mLin41,ubiq-uitinates Ago2and targets it for proteosome-dependent degradation.704Cell 143,November 24,2010ª2010Elsevier Inc.et al.,2009;Heo et al.,2009).The oligo U-tail added by TUT4blocks Dicer processing and facilitates the decay of pre-let-7.The homologs of TUT4may have related functions in other organisms.In nematode worms,PUP-2uridylates pre-let-7in vitro and suppresses the let-7function in vivo (Lehrbach et al.,2009).Let-7is unlikely to be the only miRNA uridylated at the pre-miRNA level.In support of this notion,untemplated 30uridine is frequently found in other mature miRNAs originating from the 30arm of pre-miRNAs (but signiﬁcantly less frequently in those from the 50arm)(Burroughs et al.,2010;Chiang et al.,2010).Because untemplated uridylation is observed in cells lacking Lin28,it will be interesting to determine which pre-miRNAs other than pre-let-7are controlled by uridylation and to identify addi-tional factors required for pre-miRNA uridylation.Although uridylation is generally thought to induce the decay of small RNAs,adenylation may have the opposite conse-quence.In cottonwood P.trichoacarpa ,many miRNA families are adenylated at their 30ends,and adenylation prevents miRNA degradation in in vitro decay assay (Lu et al.,2009).In the case of mammalian miR-122,which is adenylated by cytoplasmic poly (A)polymerase GLD-2(or TUTase2),30end adenylation is also implicated in its stabilization (Katoh et al.,2009).In the liver of Gld-2knockout mice,the steady-state level of mature miR-122is reduced,and the abundance of target mRNAs of miR-122increases.However,a recent study indicates that GLD-2adenylates most miRNAs,and the adenylation may affect their activity rather than stability (Burroughs et al.,2010).Deep sequencing of Ago-associated small RNAs shows that adenylated miRNAs are relatively depleted in the Ago2and Ago3complexes,suggesting that adenylation may interfere with Ago loading.Similarly,it has been reported that uridylation of mature miR-26by TUT4results in the reduction of miR-26’s activity without altering the miRNA levels (Jones et al.,2009).Therefore,it remains an inter-esting but yet unresolved issue whether or not uridylation/adenylation affects the stability of miRNAs in animals.One may speculate that 30modiﬁed miRNAs enter the silencing complex with altered frequencies,which in turn affects the small RNA’s sensitivity to nucleases.Further examination is needed to iden-tify the players involved in these processes,particularly the nucleases that recognize a U/A tail,and to dissect their action mechanisms.miRNA DecaySeveral nucleases degrade small RNAs (Figures 1and 2).An Arabidopsis enzyme SDN1(small RNA degrading nuclease,a 30-to-50exonuclease)degrades single-stranded miRNAs in vitro (Ramachandran and Chen,2008).miRNAs accumulate in a mutant lacking SDN1and its related nucleases SDN2and SDN3,indicating that the SDN proteins may act redundantly to degrade plant miRNAs.The 20-O-methyl group at the 30end of miRNAs,which is a general feature of plant miRNAs,has a protective effect against SDN1in in vitro assays.Of note,uridy-lation causes a small but detectable protective effect in the same in vitro assay,indicating that SDN1is unlikely to be the nuclease responsible for U-tail-promoted degradation.Given that RRP6(a 30-to-50exonuclease)facilitates decay of small RNAs in a MUT68-dependent manner in Chlamydomonas extracts,multi-ple enzymes may be involved in small RNA decay in plants,playing partially overlapping but differential roles (Ibrahim et al.,2010).In C.elegans ,XRN-2(a 50-to-30exonuclease)is involved in the degradation of mature miRNAs (Chatterjee and Grosshans,2009).Because miRNAs are tightly bound to and protected by Ago,it is unclear how XRN-2accesses the 50end of an miRNA for decay.Of interest,larval lysate promotes efﬁcient release of miRNA in vitro,implicating an as yet unknown factor that assists the release of miRNA from the otherwise tightly associated Argo-naute protein (Chatterjee and Grosshans,2009).In Arabidopsis ,two XRN-2homologs,XRN2and XRN3,degrade the loop of miRNA precursor following processing,but they do not affect mature miRNA levels (Gy et al.,2007).In mammals,a general nuclease for miRNAs has yet to be identiﬁed.Knockdown of XRN-1or an exosome subunit in human cells results in only partial upregulation of miR-382,and XRN-2depletion does not have a signiﬁcant effect (Bail et al.,2010).Thus,it awaits further investigation whether or not there is one major conserved pathway for miRNA decay in mammals.There have been intriguing reports of regulated decay of miRNAs.For instance,miR-29b is degraded in dividing cells more rapidly than in mitotically arrested cells (Hwang et al.,2007).In the central nervous system of Aplysia ,the levels of miR-124and miR-184decrease in 1hr after treatment with the neurotransmitter serotonin (Rajasethupathy et al.,2009).Figure 2.RNA Modiﬁcations in the Plant miRNA PathwayIn plants,both pri-miRNA and pre-miRNA are cleaved by DCL1/HYL1complex.After cleavage,30ends of miRNA duplex are 20-O-methylated by a methyl transferase HEN1.The methylation protects miRNAs from uridylation and exonucleolytic degradation.In the green algae Chlamydomonas ,the nu-cleotidyl transferase MUT68attaches uridine residues at the 30end of mature miRNA lacking a methyl group.Then,the RRP6exosome subunit,a 30-to-50exonuclease,degrades the uridylated miRNAs.In Arabidopsis ,a 30/50exonuclease SDN1is reported to degrade mature miRNAs.Cell 143,November 24,2010ª2010Elsevier Inc.705Because U0126,an inhibitor of mitogen-activated protein kinase (MAPK),blocks the reduction of miR-124,the decay process may be dependent on the MAPK pathway.Of interest,a study on mammalian neuronal cells shows that most miRNAs turn over more rapidly in neurons than in other cell types (Krol et al.,2010).Neuronal activation accelerates decay of the miRNAs,whereas blocking neuronal activity stabilizes the miRNAs.It will be exciting to discover the nuclease(s)and the upstream signals for miRNA degradation in these systems.Recently it has been shown that a polynucleotide phosphory-lase (PNPase,a type I interferon-inducible 30-to-50exonuclease)binds speciﬁcally to several miRNAs (miR-221,miR-222,and miR-106b)and induces rapid turnover in a human melanoma cell line (Das et al.,2010).Because there is no apparent commonality in terms of the sequences,it is unclear how PNPase recognizes the miRNAs speciﬁcally.As mentioned above,there is substantial evidence linking uri-dylation/adenylation and exonucleolytic attack on small RNAs.A recent study provides evidence that extensive complemen-tarity between a small RNA and its target RNA triggers uridyl/adenyl tailing as well as 30/50trimming in ﬂies and humans (Figure 1)(Ameres et al.,2010).Animal small RNAs with high complementarity to the targets,such as piRNAs and ﬂy endo-siRNAs,appear to be generally protected by 20-O-methylation at the 30end like plant small RNAs.It has been postulated that animal miRNAs,which do not carry methylation,maintain only partial complementarity with their targets so as to avoid tailing and trimming of miRNAs.Of note,viruses seem to exploit a related miRNA decay pathway to invade host cells more effec-tively.Herpesvirus saimiri ,a family of primate-infecting herpesvi-ruses,expresses viral noncoding RNAs called HSURs (H.saimiri U-rich RNAs).A recent report reveals that HSURs rapidly down-regulate host miR-27and that base-pairing between HSUR and miR-27is required for the degradation (Cazalla et al.,2010).These discoveries imply an additional layer of stability controlof small RNAs,which is inﬂuenced by the interaction with the target RNA.miRNA EditingAdenosine deaminases acting on RNAs (ADARs)convert adenosine to inosine on the dsRNA region of small RNA precur-sors (Figure 1and Figure 3A).Because inosine (I)pairs with cytosine instead of uridine,such edits could alter the structure of small RNA precursor,thereby interfering with processing.For instance,editing of pri-miR-142by ADAR1and ADAR2suppresses Drosha processing (Yang et al.,2006),whereas that of pre-miR-151by ADAR1interferes with Dicer processing (Kawahara et al.,2007a ).Because hyperedited dsRNAs can be targeted by the nuclease Tudor-SN,RNA editing may also desta-bilize small RNA precursors (Scadden,2005).In rare cases,RNA editing occurs in the seed sequence of miRNA,changing the targeting speciﬁcity.In the brain,where ADAR is abundant,miR-376cluster miRNAs are frequently edited in the seed region and are redirected to repress a different set of mRNAs (Kawahara et al.,2007b ).High-throughput sequencing of the ﬂy endo-siRNA pool also reveals evidence for RNA editing (Kawamura et al.,2008).The precursors of endo-siRNAs (long hairpins and sense-antisense pairs)may be targeted by ADARs,although the functional signiﬁcance of this siRNA modiﬁcation is unknown.Posttranslational Protein Modiﬁcations Phosphorylation of RNase III EnzymesHuman Dicer interacts with two related dsRNA-binding proteins,TRBP and PACT.Although they do not inﬂuence Dicer process-ing itself,TRBP and PACT stabilize Dicer and may also function in RISC assembly (Chendrimada et al.,2005;Haase et al.,2005;Lee et al.,2006).A recent study indicates that four serine residues of human TRBP (S142,S152,S283,and S286)are phosphorylated by the MAP kinase Erk,which controls cell proliferation,survival,and differentiation (Figure 1)(Paroo etal.,Figure 3.Modiﬁcations in the Endo-siRNA and piRNA Pathways(A)Endogenous small interfering RNAs (endo-siRNAs)are processed from long dsRNAs in a Dicer-dependent manner and are loaded onto Ago proteins.High-throughput sequencing data show that the adenosine-to-inosine (I)editing occurs in ﬂy endo-siRNAs,likely by ADAR,although the role of RNA editing is unknown.Fly endo-siRNAs bound to dAgo2are 20-O-methyl-ated by HEN1homolog,which protects RNAs from uridyl/adenyl tailing and degradation.In worms,a subset of endo-siRNAs,which are asso-ciated with an Ago homolog CSR-1,is uridylated at the 30end by the nucleotidyl transferase CDE-1.(B)piRNAs are generated from single-stranded RNA precursors that are processed by primary processing and/or secondary processing (ping-pong ampliﬁcation cycle).piRNAs are associated with Piwi subfamily proteins (PIWI).Animal piRNAs are 20-O-methylated by HEN1orthologs.In zebra-ﬁsh,depletion of hen1induces uridylation of piRNAs and facilitates decay,suggesting that methylation stabilizes piRNAs.However,the phys-iological signiﬁcance of piRNA methylation in ﬂiesand mammals remains unclear.PIWI proteins are methylated at arginine residues (sDMA,symmetrical dimethyl arginine)at their N termini by orthologs of the methyl transferase PRMT5.In ﬂies and mice,TDRD proteins interact with PIWI proteins through sDMA and may play important roles in piRNA metabolism.706Cell 143,November 24,2010ª2010Elsevier Inc.2009).Phosphorylation enhances protein stability of TRBP, consequently elevating Dicer protein levels.Intriguingly,TRBP phosphorylation preferentially increases growth-promoting miRNAs such as miR-17,whereas tumor-suppressive let-7is reduced.The mechanism of selective downregulation of let-7 is unclear,but it may be an indirect effect.An interesting implica-tion of theseﬁndings is that the MAPK/Erk pathway exerts its effects,in part,by regulating miRNA biogenesis.Drosha,a nuclear enzyme for pri-miRNA processing(Lee et al.,2003),has recently been shown to be a direct target of posttranslational modiﬁcation(Tang et al.,2010).Mass spec-trometry and mutagenesis studies reveal that human Drosha is phosphorylated at serine300(S300)and serine302(S302) (Figure1).Phosphorylation of these residues is essential for the nuclear localization of Drosha and is required for pri-miRNA processing.Because both endogenous and overexpressed Drosha localize to the nucleus constitutively,it is unclear whether or not the phosphorylation at S300/S302is a regulated process. Understanding the physiological signiﬁcance of this regulation will require the identiﬁcation of the kinase that phosphorylates Drosha.Argonaute2Is a Target of Multiple ModiﬁcationsAgo2is subject to multiple posttranslational modiﬁcations (Figure1).Human Ago2binds to the type I collagen prolyl-4-hydroxylase(C-P4H(I))that hydroxylates Ago2at proline700 (Qi et al.,2008).Depletion of C-P4H(I)reduces the stability of the Ago2protein and,accordingly,downregulates siRNA-medi-ated silencing.Furthermore,hydroxylation is required for Ago2 localization to the processing body(P body),a cytoplasmic granule that is thought to be a site for RNA storage and degrada-tion.P body localization of Ago2is also enhanced by phosphor-ylation at serine387,which is mediated by the p38MAPK pathway(Zeng et al.,2008).However,given the controversy over the direct role of P body in small RNA-mediated silencing, the biological signiﬁcance of P body localization of Ago2remains unclear.Ubiquitination also plays a part in the control of Ago2.Mouse Lin41(mLin41or Trim71),a stem cell-speciﬁc Trim-NHL protein, inhibits the miRNA pathway(Rybak et al.,2009).As an E3ubiq-uitin ligase,mLin41ubiquitinates Ago2and targets it for protea-some-dependent degradation.Of interest,mLin41is a target of let-7miRNA,suggesting that mLin41and let-7may be engaged in a reciprocal negative feedback loop.Recently,other Trim-NHL proteins have been reported to associate with the Argonaute proteins and affect miRNA pathway.Mei-P26(ﬂy)inhibits miRNA biogenesis,whereas TRIM32(mouse)and NHL-2(worm)acti-vate the miRNA pathway(Hammell et al.,2009;Neumu¨ller et al.,2008;Schwamborn et al.,2009).Their mechanism of action appears to be different than that of mLin41because the E3ligase activity of Mei-P26and TRIM32is dispensable for their effects and because NHL-2enhances miRNA activity without a change in miRNA levels.Tudor Regulates PIWI ProteinsThe PIWI(P element-induced wimpy testis)clade proteins bind to Piwi-interacting RNAs(piRNAs)and silence transposable elements in gonads.Mouse has three PIWI homologs(MILI, MIWI,and MIWI2),and there are three PIWI proteins inﬂies (Aubergine[Aub],AGO3,and Piwi)(Kim et al.,2009).Recent studies have revealed that PIWI proteins carry symmetrical dimethyl arginine(sDMA)at their N termini.Arginine methylation of PIWI is mediated by a methyl transferase PRMT5(dPRMT5/ capsuleen[csul]/dart5in Drosophila)(Figure3B)(Heo and Kim, 2009;Siomi et al.,2010).sDMA is recognized by Tudor domain-containing proteins(TDRDs),which are critical for germ-line development.In bothﬂies and mice,deletion of TDRDs alters piRNA abundance and/or composition,indicating that TDRDs play important roles in the piRNA metabolism through speciﬁc binding to the sDMAs of PIWI proteins.How TDRDs act in the piRNA pathway at a molecular level awaits further investigation. PerspectivesAs we delve deeper and wider into the small RNA world,the emerging landscape becomes ever more complex on both the RNA and protein sides.High-throughput analyses have uncov-ered a considerable heterogeneity in small RNA populations. Some isomiRs are expressed differentially in certain tissues, suggesting that these variations may be associated with speciﬁc regulatory functions(Chiang et al.,2010).Biochemical and genetic studies also provide substantial evidence for the regula-tory roles of the modiﬁcations discussed in this Review.Thus,it is likely that at least some of the observed heterogeneity reﬂects multiple layers of regulation.We should be cautious,however,in extrapolating the current evidence because it is unclear how much fraction of the small RNA and protein modiﬁcations trans-late into functional consequences and whether certain modiﬁca-tions simply reﬂect the noise of RNA metabolism.In addition to the functionality issue,a number of key questions remain to be answered.Are there conserved pathways and enzymes for RNA and protein modiﬁcations?If so,what are the similarities and differences?20-O-methylation is applied to many small RNA pathways,but the details differ signiﬁcantly in different systems.For instance,plant HEN1acts on dsRNA duplexes,whereas animal HEN1homologs methylate ssRNA loaded on Argonaute proteins.Uridylation/adenylation is carried out by a family of ribonucleotidyl transferases.How each member selectively recognizes its substrates is largely unknown. RNA stability is likely to play important roles in RNA silencing pathways.Decay pathways of small RNA are beginning to be unraveled,but there is no consensus between different species as yet.One possibility is that multiple enzymes act in parallel as in the mRNA decay pathway,which involves several30exonucle-ases,50exonucleases,and endonucleases.Some of the decay enzymes may function redundantly,and it remains one of the major challenges in theﬁeld to identify them.Protein modiﬁca-tion is also emerging as one of the key regulatory layers. Outstanding questions include which enzymes are involved, what the in vivo signiﬁcance of such modiﬁcations is,and whether the protein modiﬁcations are developmentally regu-lated.Future studies will reveal new types of modiﬁcations,addi-tional regulatory factors,and their biological relevance.The RNA silencing machinery should respond accurately to developmental and environmental cues.Most signaling path-ways are thought to be connected to RNA silencing,but we are just beginning to understand the molecular links between RNA silencing and cell signaling.What the upstream signals are,how certain RNAs and proteins get speciﬁcally recognized, Cell143,November24,2010ª2010Elsevier Inc.707and what the downstream effects of the modiﬁcations are await elucidation.We also need to understand the interplay between different modiﬁcations.There appears to be a crosstalk between certain modiﬁcations of RNA(such as methylation,uridylation, and decay),which may inﬂuence their fate and function.It is likely that there is a crosstalk between the different posttranslational modiﬁcations in the proteins involved in the biogenesis and effector functions of small RNA silencing pathways.Under-standing these networks will undoubtedly provide ample oppor-tunities to manipulate RNA silencing and will reveal new lessons about gene regulation.ACKNOWLEDGMENTSWe thank members of V.N.K.’s laboratory for helpful discussions and comments.This work was supported by the Creative Research Initiatives Program(20100000021)and the National Honor Scientist Program (20100020415)through the National Research Foundation of Korea(NRF) and the BK21Research Fellowships(I.H.)from the Ministry of Education, Science and Technology of Korea.We apologize to authors whose work has not been covered because of space limitations.REFERENCESAmeres,S.L.,Horwich,M.D.,Hung,J.H.,Xu,J.,Ghildiyal,M.,Weng,Z.,and Zamore,P.D.(2010).Target RNA-directed trimming and tailing of small silencing RNAs.Science328,1534–1539.Bail,S.,Swerdel,M.,Liu,H.,Jiao,X.,Goff,L.A.,Hart,R.P.,and Kiledjian,M. 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循环microRNA:潜在的疾病诊断生物标志物

循环microRNA：潜在的疾病诊断生物标志物焦志军【摘要】microRNAs (miRNAs)是一类非编码的内源性小RNA,在细胞生长发育、分化、凋亡过程中发挥重要的作用.研究发现miRNAs可从细胞内释放,广泛而稳定地存在于细胞外液,统称为循环miRNAs(circulating miRNAs).在疾病状态下如肿瘤、自身免疫性疾病、心血管疾病等,其表达谱发生异常改变.miRNAs作为分子标志物,克服了蛋白质分子标志物在抗体制备和定量分析上所遇到的瓶颈.而且循环miRNAs具有样本易于采集、保存期长及检测手段简便等特点,临床应用价值也更明显,已成为生物标志物及转化医学研究的热点领域.【期刊名称】《临床检验杂志》【年(卷),期】2012(030)010【总页数】7页(P850-856)【关键词】循环微小RNA;生物标志物;转化医学【作者】焦志军【作者单位】江苏大学附属医院检验科、中心实验室,镇江市医学免疫学重点实验室,江苏镇江210200【正文语种】中文【中图分类】Q74;R73microRNAs(miRNAs)是一类广泛存在于动植物体内的内源性非编码单链RNA，由19～23个核苷酸组成(3＇端可有 1～2个碱基长度的变化)。

miRNAs通过与靶信使核糖核酸(mRNA)特异结合抑制转录后基因表达，在调控基因表达、细胞周期、生物体发育时序等方面发挥重要作用，具有极其重要的病理和生理意义［1］。

miRNAs也因此于2002年入选《Science》年度十大科学发现之首。

过去一直认为miRNAs可能被细胞外大量存在的RNA酶所降解，初期研究主要针对细胞内miRNAs。

2008年，牛津大学Lawrie等［2］首次报道B细胞淋巴瘤血清中miR-155，miR-210及miR-21增高。

随后大量实验证明miRNAs可以广泛而稳定地存在于细胞外液，包括血清、血浆、组织间液及各类体液中，统称为循环miRNAs (circulating miRNAs)［3］。

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