microRNAs (miRNAs)是一类新发现的调节基因，通过抑制靶基因的表达来发挥其转录后调控作用[1-2]。miRNA的生成大多有以下两步：首先，在细胞核内，初始转录本(pri-miRNA)经Ⅲ型RNA核酸酶和双链RNA结合蛋白(Drosha/DGCR8)复合物作用产生miRNA前体(pre-miRNA)；其次，在细胞质内，miRNA前体(pre-miRNA)经Ⅲ型RNA核酸酶和反式激活应答RNA结合蛋白(Dicer/TRBP)复合物作用产生miRNA的成熟体[3]。人、小鼠、猪和鸡miR-155基因分别定位于第21号、16号、13号和1号染色体，其中人、小鼠和猪miR-155前体均为65nt，鸡miR-155前体为63nt；人和鸡miR-155成熟序列完全一致，小鼠和猪miR-155成熟序列完全一致，前两者与后两者只有第12位C→U的一个碱基差异。由以上可知，miR-155在不同物种中的序列保守性较强。miR-155的宿主基因为一长链非编码RNA：B-cell Integration Cluster (BIC)，BIC基因包含3个外显子，但它并没有一个明显且长的开放阅读框，采用Northern blot方法检测发现其在鸡的胸腺和脾脏中高表达[4-5]，笔者曾用荧光定量的方法检测猪miR-155在大白猪脾脏中高表达[6]，用Northern blot方法检测发现其在小鼠的胸腺和脾脏中高表达[7]。miR-155是一个明星基因，本文就miR-155在造血、炎症、免疫、肿瘤、肌肉发育以及脂肪分化等功能研究进展作一综述，旨在讨论miR-155在参与机体多项生命活动中发挥的重要作用及意义。
1 miR-155与造血miR-155参与机体造血分化这一重要的生命过程(图 1)。Georgantas等[8]发现miR-155在未分化的CD34+造血干细胞呈现高表达，它靶向PU.1、C/EBPβ、AGTR1、AGTR2及FOS等造血分化相关分子；miR-155转染有多向分化潜能的K562细胞系，结果显示K562细胞增殖能力不受影响，但红系和巨核细胞分化细胞数目显著减少；而且在CD34+造血干细胞中进行的造血集落试验，miR-155转染组髓系和红系集落的生成少且小；这些数据证明，人类造血干细胞髓系和红系细胞的分化受到miR-155的严密调控。用CSF、IL3、EPO等造血生长因子体外刺激纯化的正常的人红细胞祖细胞分化，结果表明miR-155在未分化的细胞中表达显著上调，而在分化为成熟红细胞的细胞中下调大约200倍，也即占据红系祖细胞的1/200；而高表达的miR-155可限制多能干细胞分化成淋巴干细胞，表明miR-155在人红血球生成过程中发挥重要调节作用，它严密调控红系细胞的分化，是正常红细胞分化的重要调节分子[9]。急性髓细胞性白血病(Acute myeloid leukaemia，AML)中，miR-155在FLT3基因发生内部串联重复(FLT3-ITD)的患者中表达呈现上调[10]，揭示miR-155的失调表达可能是此类AML患者的发病机制。以上研究结果表明miR-155是维持机体正常造血功能的有力调节器。
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| 图 1 miR-155与造血分化 |
miR-155在机体先天性免疫中发挥重要调控作用，主要体现在其与炎症的密切关系(图 2)。大量研究表明miR-155的表达水平与炎症因子密切相关，它是个亲炎症(Pro-inflammtory)分子。研究者用聚肌胞(Poly I:C)和IFN-β刺激鼠源性巨噬细胞RAW264.7，而后采用基因芯片的方法检测相关miRNA的表达变化，结果发现受这两种因子刺激后持续上调表达的miRNA只有miR-155，进一步用药物抑制激酶JNK能阻断Poly I:C或IFN-β诱导生成miR-155，这表明JNK信号通路调控诱导产生miR-155[11]。Tili等[12]发现用脂多糖(LPS)刺激RAW264.7，miR-155的表达显著上调，miR-125b的表达下调，肿瘤坏死因子(TNF-α)表达显著上升，同时用LPS腹腔注射C57BL/6小鼠进行体内试验，体内试验结果与体外实验相符合。Ruggiero等[13]发现LPS刺激RAW264.7细胞，miR-155的上调表达归结于其自身从前体到成熟体的生成过程——KSRP，Drosha、Dicer复合物组成部分，单链RNA结合蛋白KH型剪接调控蛋白结合在miR-155前体的终环上，促进miR-155前体成熟，从而提高miR-155成熟体的产生；其中KSRP可促使富含AU元件的mRNA降解，而miR-155所调节的炎症因子mRNA的3’UTR都含有AU元件；在KSRP敲低的小鼠中，miR-155的生成被抑制，LPS诱导产生的炎症因子显著增加；以上结果表明LPS、miR-155以及炎症因子组成一个负反馈调节通路：LPS诱导miR-155持续上调表达，miR-155负反馈调节LPS诱导产生炎症因子。另外，作者分别用IFN-γ，TNF-α，poly (I：C)刺激RAW264.7细胞，结果与LPS刺激效果相一致，miR-155的表达全部上调。Quinn等[14]进行miR-155、LPS与IL10的转录调控研究中发现，转录因子Ets结合于miR-155的启动子区域；在Ets2缺陷小鼠中，结合在miR-155的启动子区域的Ets2有增加，但LPS对miR-155的表达没有影响，LPS诱导miR-155高表达必须有Ets2；抗炎介质IL10可抑制Ets2的mRNA和蛋白表达，减弱Ets2在miR-155初始转录本启动子区域功能的发挥，导致miR-155的表达降低。此研究证明转录因子Ets2是miR-155在炎症反应发挥精细调控作用所必不可少的，IL10抑制miR-155的表达。MiR-155在类风湿性关节炎(Rheumatoid arthritis，RA)等炎症性疾病中高表达。Stanczyk等用TNF-α刺激风湿性关节炎患者和骨关节炎患者的滑膜成纤维细胞，发现类风湿性关节炎患者细胞中的miR-155表达量显著上调并高于骨关节炎患者；类风湿性关节炎患者的滑膜组织中的miR-155可以被TNF-α、IL-1β、LPS、poly (I:C)和细菌脂蛋白进一步诱导上调，表达量同样高于骨关节炎患者；上调表达的miR-155抑制Toll样受体配体，抑制RA患者损伤程度标志基因基质金属蛋白酶MMP-3和MMP-1的表达；作者推测MiR-155是一个保护性的miRNA，降低MMP-3和MMP-1的表达，减少组织损伤引发的炎症反应，减缓类风湿关节炎对机体的破坏性[15]。另外，在类风湿性关节炎患者的外周血中，miR-155的表达水平与炎症因子TNF-α，IL1β的释放存在正相关，是通过miR-155靶向调节SOCS1的表达来实现的[16]。以小鼠为模型研究人类关节炎疾病发现，miR-155敲除小鼠，炎症因子IL6、TNFα的产生都受限，miR-155发挥促炎作用[17]。在人类囊性纤维化中，miR-155呈现高表达，高表达的miR-155诱使炎症因子IL8的释放增多，加强了炎症反应[18]。用土拉弗朗西斯菌(Francisella tularensis) (能引发兔热病的一种革兰氏阴性菌)感染人单核细胞，检测到miR-155表达显著增加，并且上调表达的miR-155对促炎因子TNFα、IL1β、IL6的生成发挥正调控作用[19]。笔者用Poly I:C或LPS刺激PK15细胞，发现miR-155表达显著上调，TLR3/4下游的marker基因CD80、CD86、IL6和IL1β表达模式与miR-155相同；miR-155过表达情况下，CD80、CD86、IL6和IL1β表达也有显著增加，Poly I:C、LPS刺激效果更强，miR-155发挥正调控作用[6]。MiR-155与炎症因子的关系十分复杂，它不但发挥促炎作用，也发挥抑制炎症作用，是个分子变阻器。
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| 图 2 miR-155与炎症反应 |
免疫系统最基本单位是免疫细胞，参与先天性免疫反应的有：巨噬细胞、树突状细胞、单核细胞和中性粒细胞等；参与获得性免疫反应的细胞主要有：B细胞和T细胞。近年来众多研究表明miR-155在机体免疫调节中发挥重要作用(图 3)，miR-155在激活的免疫细胞(巨噬细胞、淋巴细胞等)中是高表达的[11, 20-21]。Rodriguez等[22]发现，miR-155敲除小鼠的T淋巴细胞、B淋巴细胞以及DC (树突状)细胞的功能都遭到破坏，说明miR-155对于维持机体正常的免疫功能是必不可少；敲除miR-155基因，致使其它基因的活性改变，有效的免疫反应活动受到抑制，容易发生自身免疫和感染。Wang等[20]用RNA病毒感染小鼠巨噬细胞，结果发现miR-155上调表达，进而增强Ⅰ型干扰素信号通路，达到减弱病毒复制的目的。进一步研究发现是通过miR-155靶向抑制SOCS1表达的途径，通过去除SOCS1对Ⅰ型干扰素信号通路的反馈抑制，来增强巨噬细胞抵抗微生物的能力。Ceppi等[21]用LPS刺激树突状细胞，在其成熟过程中，miR-155上调表达，靶向抑制重要转录因子TAB 2的表达，通过抑制Toll样受体/IL1信号通路而负反馈调节机体在微生物入侵后产生炎症性细胞因子的能力。
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| 图 3 miR-155与免疫应答 |
MiR-155在系统性红斑狼疮等自身免疫性疾病中高表达。Zhou等[23]研究发现在激活的浆细胞样树突状细胞(pDC)中，MiR-155*在早期被诱导，它通过靶向IRAKM促进Ⅰ型干扰素的产生；miR-155在刺激的后期被诱导，它通过靶向TAB 2抑制Ⅰ型干扰素的产生；同时发现pDC自身分泌的Ⅰ型干扰素以及被激活的KHSRP蛋白可以在转录后水平反向调控miR-155和miR-155*的产生，揭示了来自于同一前体的miR-155*和miR-155却能在不同的时间点被诱导的原因。由于miR-155的上调表达抑制靶基因SHIP1的表达，导致B细胞过度激活而引起自身抗体的过度产生。Thai等[24]用实验室狼疮小鼠作为模型，删除miR-155之后，有害抗体产生受到阻止，从而缓解狼疮小鼠的疾病症状。Leiss等[25]用异十八烷诱导miR-155缺失的小鼠发生狼疮，发现miR-155缺失的小鼠可降低自身抗体水平，并减轻肾炎和肺炎的症状。暗示在未来中和或降低miR-155水平会是治疗系统性红斑狼疮的一种有效途径。
MiR-155在活化的B淋巴细胞和T淋巴细胞中上调表达，调节机体获得性免疫反应。MiR-155调控由活化的B淋巴细胞增殖形成的生发中心，并靶向调控c-Maf、PU.1和AID等基因在B淋巴细胞中的成熟以及作用发挥，促进高亲和力抗体的产生，形成记忆性B淋巴细胞。MiR-155缺失，降低B细胞滤泡外和生发中心的反应，减少高亲和力IgG1抗体的产生，当在B细胞中miR-155下调表达时，PU.1表达上调，IgG1抗体的产生降低，PU.1参与调节miR-155缺失表型[26]。AID (活化诱导胞嘧啶核苷脱氨酶)是B淋巴细胞免疫球蛋白基因多样化所必须的，并促进染色体易位。MiR-155通过靶向降低由AID产生的潜在的致癌染色体易位发挥肿瘤抑制器作用[27-28]。
T淋巴细胞据其表面标志和功能特征分为辅助性T细胞(Th)，调节性T细胞(Treg)等几个亚群。Th又可根据分泌细胞因子的不同再次分类：Th1分泌IFNγ，Th2分泌IL4，Th17分泌IL17、IL23；Treg是一类发挥抑制作用的CD4+T淋巴细胞亚群。Rodriguez等[22]发现，抗原刺激miR-155敲除小鼠，Th0细胞偏向Th2分化，表现出Th1/Th2分化不平衡，究其原因发现miR-155的缺失，导致其靶基因c-maf表达上升，致使IL4的产生增加。该结果在后来的研究中也进一步得到证实：Th细胞活化过程中，miR-155上调表达，促进Th0分化为Th1细胞；相反，miR-155缺失条件下，促进Th0分化为Th2细胞；缺失miR-155的CD4+T细胞偏爱向Th2细胞分化，而在活化的CD4+T细胞中过表达miR-155，则向Th1细胞分化，表明单个miRNA的缺失可影响CD4+T细胞的分化。在活化8 d的T细胞中，可检测到影响IL4产生的miR-155的靶基因c-Maf的表达，miR-155的靶基因SOCS1也通过负调控细胞因子信号通路影响Th1和Th2的分化，揭示了miR-155调控Th1/Th2分化平衡机制[29]。Lu等[30]发现转录因子Foxp3影响miR-155的表达，miR-155通过靶向调控SOCS1的表达影响Treg细胞的功能。O’Connell等[31]发现miR-155促进Th17和Th1细胞亚群等促炎性T细胞发育，而在敲除miR-155的小鼠中T细胞呈现缺陷发育，Th17和Th1细胞亚群表达量减少，使敲除小鼠呈现对实验性自身免疫性脑脊髓炎(Experimental autoimmune encephalomyelitis，EAE)高度耐药。在人类多发性硬化症中，也发现miR-155调控Th17和Th1细胞亚群的分化[32]。另外，CD8+T细胞反应也受miR-155的调控，超表达miR-155可增强CD8+T细胞免疫应答，与之相反，缺失miR-155则抑制CD8+T细胞[33]。以上研究表明miR-155对T细胞发育发挥重要调控作用。
4 miR-155与肿瘤众所周知，miR-155是一个原癌基因。它在多种肿瘤中高表达，如乳腺癌、淋巴癌、胰腺癌、白血病和肺癌等[4, 34-37]。miR-155与肿瘤的发生密切相关(图 4)。研究发现丙型肝炎病毒(HCV)患者的miR-155呈现高水平表达，miR-155的转录受到核因子-kappa B (NF-κB)的调控，且p300可以提高NF-κB依赖的miR-155的表达。miR-155过表达显著抑制肝细胞凋亡，促进细胞增殖。当miR-155受到抑制时，诱导G0/G1细胞周期发生阻滞。miR-155的上调表达导致β-catenin核积聚以及cyclin D1、c-myc和survivin的伴随增高。体内外获得及丧失功能(Gain/loss-of-function)研究证实miR-155通过增强Wnt信号促进了肝细胞增殖和肿瘤形成。当Wnt信号抑制子DKK1过表达时肝细胞中miR-155生物作用受到抑制。此外，负调控Wnt信号的结肠腺瘤性息肉病基因(Adenomatous polyposis coli，APC)是miR-155的直接和功能性靶点。即HCV诱导miR-155上调通过激活Wnt信号促进肝癌形成[38]。Zhang等[39]研究发现miR-155是恶性肿瘤甲状腺乳头状瘤(PCT)的致癌因子。体内或者体外过表达miR-155能显著促进PTC细胞的细胞活性和增殖，miR-155能促进肿瘤生长。miR-155通过靶向抑制APC基因的表达，激活Wnt/β-catenin信号，调节下游基因c-Myc、cyclinD1、TCF-1和LEF-1的表达，据此作者推测miR-155有望作为PCT的潜在治疗靶点。乳腺癌中，miR-155表达上调，导致靶基因TRF1 (Telomeric repeat binding factor 1)蛋白表达受到抑制，进一步导致端粒脆性增加，影响细胞中期的结构；降低miR-155的表达水平，则可增强端粒功能和基因组的稳定性[40]。另外，有观点认为由机体细胞的突变累积引发肿瘤。Tili等[41]研究发现miR-155靶向调控WEE1基因，WEE1基因可停止细胞分裂过程，让受损的DNA得以修复；而当乳腺癌细胞暴露在TNFα或LPS炎症因子下，miR-155表达增加，高水平的miR-155导致WEE1表达下调，低水平的WEE1让存在DNA损伤的细胞继续分裂，使得更多突变产生。MiR-155提高了突变率，可能在炎症引发的肿瘤中扮演了关键角色。以上研究表明miR-155在许多肿瘤组织上调表达，这提示我们它可能在肿瘤诊断和治疗中具有重要意义[42]，有研究者预测：监测机体组织或者体液中miR-155的表达水平，或许可作为肿瘤诊断和预后的分子标记[43]。研究表明血浆中miR-155被确认为早期胰腺癌诊断的标志物[44]；胰腺癌患者血清中miR-155同样呈现高表达，血清miR-155也是对胰腺癌诊断和预后有价值的标志物[45]。脓毒症患者血清中miR-155-5p表达上调，可作为影响脓毒症诊断和预后判断的标志物[46]。肺结核患者中miR-155-5p呈现高表达，miR-155-5p可能是肺结核感染者的生物诊断标志物[47]。在肺癌患者中，过表达的miR-155可能是良好预后的标志物[37]。在甲状腺机能亢进(Graves’ disease，GD)的患者中，miR-155在GD的发病机理中发挥重要作用，而且miR-155的表达水平是GD疾病诊断的标志物[48]。在以上研究表明miR-155确实是一些疾病诊断或预后评估有价值的分子标志物。
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| 图 4 miR-155与肿瘤 |
在大部分人们关注miR-155与机体造血、免疫炎症及肿瘤密切关系的同时，部分研究者将目光转向miR-155与肌肉发育、脂肪分化的关系(图 5)。2011年，一个课题组通过免疫组化染色，免疫印迹以及qRT-PCR等技术发现miR-155通过靶向抑制MEF2A (Myocyte enhancer factor 2A，肌细胞增强因子2A)的表达来抑制C2C12细胞成肌分化[49]；时隔3年，另一课题组构建miR-155过表达腺病毒载体，并感染C2C12细胞，通过形态学观察，成肌marker基因的mRNA和蛋白水平的检测，发现miR-155靶向抑制TCF4 (T cell factor 4，T细胞因子4)表达，而且过表达miR-155抑制C2C12细胞成肌分化[50]。miR-155通过靶向调控OLFML3基因的表达，来调控猪骨骼肌发育[51]。另外，在3T3-L1前脂细胞系中，TNFα可上调miR-155的表达，miR-155通过靶向转录因子C/EBPβ来抑制脂肪生成[52]。Chen等[53]通过体外和体内实验验证，miR-155通过一个双稳态系统图调控棕色脂肪的生成，在TGFβ信号通路的刺激下，miR-155表达上调，miR-155的表达上调导致其靶基因C/EBPβ表达受到抑制，从而影响棕色脂肪的生成；C/EBPβ在成脂激素的影响下表达上调，C/EBPβ的上调表达负反馈抑制miR-155的表达，从而影响前脂细胞的增殖。
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| 图 5 miR-155与肌肉发育和脂肪分化 |
近年来，随着对miR-155的深入研究，miR-155的靶基因被越来越多地发现(表 1)，miR-155参与机体生命过程中的调控作用和机制不断被阐明。miR-155调节造血细胞分化；miR-155调控各种免疫反应及在相关信号通路发挥重要调节作用；miR-155在多种肿瘤中高表达，与相关靶基因互作，还被作为一些疾病诊断或预后评估有价值的分子标志物；miR-155调控机体肌肉发育和脂肪分化，影响机体对肌肉发育和脂肪分化的精细调控。不断阐明miR-155在机体生命过程中发挥的多种多样生物学功能，将为miR-155被人们运用于多种疾病的治疗中提供新思路、新方法。例如，对各种癌症新药的靶点开发，对心血管疾病、自身免疫性疾病、炎症、肿瘤、免疫缺陷疾病和器官移植免疫等具有重要的临床应用价值。
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