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目录 contents

    摘要

    环状RNA(circRNA)是一种共价闭合的非编码RNA,可以调节真核生物中的基因表达. 最近应用高通量RNA测序和生物信息学方法揭示人类细胞中存在大量circRNA. 许多circRNA具有一定的组织和时序特异性,且与生理发育和各种肿瘤等疾病密切相关. circRNA被证明在细胞质中富集和稳定,表明其具有作为肿瘤生物标志物的潜力. 胃癌(gastric carcinoma,GC)是一种常见的恶性肿瘤,在全球癌症相关死亡原因中排第3位. 尽管该疾病在诊断和治疗方面取得了许多进展,但GC患者的预后仍然很差,大多数国家的5年总生存率低于30%. 因此,寻找能调节GC发生发展和评估预后的新分子机制和治疗靶标至关重要. 近年来circRNA在胃癌中的研究不断增多,其在胃癌的发生发展、诊断、治疗及预后过程中扮演重要角色. 本文就circRNA产生机制及一般特征、生物学功能、在胃癌中的研究进展及研究中存在的问题作一综述.

    Abstract

    Circular RNA (circRNA) is a type of covalently closed non-coding RNA that may regulate gene expression in eukaryotes. The recent application of high-throughput RNA sequencing and bioinformatics approaches has revealed a large number of circRNAs in human cells. Emerging evidence indicates that many circRNAs have tissue and timing specificity and are linked to physiological development and various diseases. circRNAs have also been shown to be enriched and stable in extracellular fluid, indicating the potential of circRNAs as cancer biomarkers. Gastric cancer is one of the most common human cancers,and its the third most common cancer-related cause of death worldwide. Despite many advances in the diagnosis and treatment of this disease, the prognosis of patients with GC remains poor, with a 5-year overall survival of less than 30% in most countries. Therefore, the discovery of new molecular mechanisms and therapeutic targets that may control the severity of GC and present a predictive value for prognosis is of great importance. CircRNA has been increasingly studied in gastric cancer in recent years and plays an important role in the development, diagnosis, treatment and prognosis of gastric cancer. Here, we summarize the current knowledge about circRNAs, including their production mechanisms and general characteristics, biological functions, and their research progress in gastric cancer and problems in the research.

    关键词 circRNA,胃癌,肿瘤生物标志物,肿瘤诊断

    20世纪70年代,研究者首次发现RNA病毒中存在单链共价闭合的RNA,并将其命名为环状RNA(circRNA[1,2]. circRNA起初被认为是由于拼接错误产生的,没有引起大家的关[3,4],但近年来circRNA已成为研究热点. circRNA从被发现到备受学者们的关注时隔30多年,其被隐藏多年而未被发现的3个主要原因如[5]:首先,当使用线性基因组作为引物设计的模板时,传统的逆转录酶定量PCR(RT-qPCR)不能区分circRNA和线性RNA;其次,circRNA未映射到线性参考基因组,并且在测序数据中,通常会丢弃通过测序读取的相关序列;最后,circRNA缺乏polyA尾,并且制备RNA测序文库的大多数方案都去除了rRNA的polyA.

    随着RNA高通量测序技术的发展,circRNA在不同的生物中被发现,包括古细菌、植物、斑马鱼、小鼠和人[6,7]. 研究者通过生物信息学分析发现circRNA的种类和物种进化程度成正比, 并且已经在人体内发现了大量的circRNA,是人体内含量最多的 RNA之一.

  • 1 circRNA的产生机制及特征

    多项研究表明,circRNA可以来自基因组上多种基因结构,同一基因来源的circRNA可能存在多种种类. 根据来源不同,circRNA可分为内含子来源的ciRNA(图1a)、单外显子来源的circRNA、外显子-内含子来源的EIciRNA(图1b)以及多外显子来源的ecircRNA(图1c). 此外,最新研究发现,染色体结构的畸变可以导致融合环状RNA(图1d)的形[8,9]. 前体tRNA(图1e)也可形成特殊的环状RNA(tricRNA)[10]. 另外,胞核环型DNA病毒也可形成circRNA[11](图1f). 目前发现的circRNA 80%来源于基因外显子. circRNA由特殊的可变剪切产[12],主要分布于细胞质中,但也有少数内含子来源的circRNA存在于核酸和外泌体[13],具有一定的组织和时序特异性,并且与生理发育和各种肿瘤等疾病密切相[14](图2). circRNA既没有游离的5’和3’末端,又无polyA尾结构,而以共价键形成环状结构,它的环化并不是可变剪切产生的被动效果,而是环化外显子侧翼序列或RNA结合蛋白结合位点主动介导的. 因此,与线性RNA相比,circRNA不易被核酸外切酶所降解,能在体内稳定存在,具有高度的保守性,表明circRNA具有成为新的诊断标记物的明显优势.

    图1
                            circRNA的形成和生物学功能

    图1 circRNA的形成和生物学功能

    Fig. 1 Formation and biological function of circRNA

    注:环状RNA的形成:(a)基因外显子的共价组合构成套索驱动的环化.(b)内含子对驱动的双内含子互补对的环化.(c)RNA结合蛋白和反式作用因子促进环化.(d)染色体易位产生融合环状 RNA. (e)前体tRNA切割形成tricRNA.(f)环形DNA病毒基因产生环状RNA. 环状RNA的生物学功能:(g~h)基因转录的调节;(i)充当miRNA海绵;(j)充当RBP海绵;(k)翻译蛋白质;(l)融合环状RNA促进肿瘤的发展;(m)作为生物标志物.

    图2
                            CircRNA和肿瘤

    图2 CircRNA和肿瘤

    Fig. 2 circRNA and tumor

  • 2 生物学功能

  • 2.1 circRNA作为竞争性内源RNA( ceRNA)[15]

    circRNA主要作为 miRNA“海绵”,其含有数量和种类不等的 miRNA应答元件(MRE),并通过与 miRNA结合位点特异性结合吸附特定的miRNA,竞争性抑制miRNA与相应位点的结合,调控下游靶基因的表达. 来源于CDR1基因的circRNA(ciRs-7)可以结合吸附miR-7,从而降低miR-7的活性,间接上调miR-7相关靶基因的表达,对兴奋性神经元的突触活动和神经电生理产生影[16,17,18]. ciRS-7含有miR-7的MRE超过70个,其在与 miR-7竞争性结合后可影响中脑神经组织的发育,促进胰岛素细胞分泌胰岛素以及肝癌和结肠癌的发展,增加心血管疾病发作的风[19]. 同样,Zhong[20]研究表明circRNA MYLK作为竞争性内源RNA(competing endogenous RNA, ceRNA)在膀胱癌中发挥重要作用. 在膀胱癌细胞系中过表达circRNA MYLK可以显著降低miR-29 a的表达水平,而敲低circRNA MYLK则具有相反的效应,但是miR-29 a不影响circRNA MYLK的表达. Zheng[21]发现,来源于HIPK3基因Exon2的circRNA(circHIPK3)能够结合9种miRNA并且找到18个潜在结合位点,特异性结合miR-124并抑制miR-124活性,促进肿瘤细胞的增殖. 以上这些发现增加了ceRNA网络的复杂性.

  • 2.2 circRNA顺式调控亲本基因的表达

    circRNA通过不同方式调控其亲本基因的表达: 其一,circRNA与RNA结合蛋白(RBPs)相互结合,影响亲本基因的表达; 其二,circRNA在形成过程中,通过内含子间竞争性互补配对与线性RNA达成平衡,从而影响mRNA的表达,进而影响蛋白质翻译. circRNA还可以通过RNA-DNA、RNA-RNA和RNA-蛋白质相互作用,建立重要的生物网络而调控靶基因的表达. circRNA可用于存储、分类或传递 RBPs到特定的亚细胞位置. 研究表明,circRNA可以稳定地与RBPs(如AGO[15,21])结合,后者已被证明参与miRNA依赖性或独立的肿瘤发生. Lai[22]证明hsa_circ_0047905和hsa_circ_0138960与其亲本基因SERPINB5和GDA mRNA的表达成正相关. 敲低胃癌细胞中hsa_circ_0047905和hsa_circ_0138960后,亲本基因表达下调. 在人类细胞中,由套索内含子产生的ciRNA通常在细胞核中积累,并且可以通过与PolⅡ机制相互作用顺式调节其亲本编码基因的转录(图1g);外显子和内含子来源的可变环化EIciRNA首先与U1 SnRNP结合形成复合体,进一步与polⅡ结合促进亲本基因转录(图1h). 外显子来源的circRNA可以充当miRNA、RBP海绵(图1i,j),间接发挥调控mRNA表达的作用.

  • 2.3 翻译蛋白质的功能

    circRNA虽然属于非编码RNA,但有研究表明,有少数circRNA具有翻译蛋白质的功能. Wang[23,24]发现circRNA中存在m6A修饰,并且在热休克刺激下该修饰能促进circRNA的翻译. Yang[25]对10例病理诊断为胶质母细胞瘤的标本及其相邻的正常脑组织进行circRNA深度测序,并使用RNA印迹、Sanger测序、抗体和液相色谱Tandem质谱仪等方法,证实circ-FBXW7可以编码一种抑制胶质瘤的蛋白质 FBXW7-185aa. 同时,Zhang[26]证明在脑胶质瘤病人中来自SHPRH基因的circRNA circ- SHPRH能够编码多肽,研究首次表明人类转录本中存在重叠密码子编码蛋白质产物,该多肽是在跨过接口位点后终止翻译的产物,这项研究再一次更新了科学界对circRNA的认识,对进一步拓展circRNA研究思路提供有力的保障. 与此同时,Pamudurti[27]基于果蝇大脑中核糖体印迹分析,发现了大量的circRNA翻译蛋白质或多肽的情况. Legnini[28]介绍发现了环状RNACirc-ZNF609可直接翻译蛋白质,该蛋白质参与肌肉发生过程. Zhang[29]发现Linc-PINT的第二外显子通过自身环化可以形成Circ-PINT,并且证实Circ-PINT通过内部核糖体插入位点(IRES)驱动翻译一个由87个氨基酸组成的全新多肽PINT87aa,其可以抑制恶性胶质瘤的发生发展. 此外Sun[30]发现circPVRL3可以通过IRES,开放阅读框(ORF)和m6A修饰等结构编码蛋白质(图1k). 随着研究的深入,circRNA具有翻译蛋白质功能的研究开始进入人们的视野.

  • 2.4 其他功能

    在疾病的发展中,circRNA不仅单独起作用,而且还通过其他生理机制发挥作用. circHIPK2以 miR-124-2HG为靶点在转录后水平联合自噬及内质网应激,调控星形胶质细胞活[31]. Yu[32]报道发现,circBIRC6参与干细胞多能性调控. circRNA的研究还处于初期阶段,作为一种丰富而保守的非编码RNA,其功能远不止于此,需要进一步研究.

  • 3 作为疾病的生物标志物

    最近研究表明,circRNA可以在多种癌症中发挥重要作用,在癌症发生发展过程中扮演癌基因或抑癌基因角色,从而作为肿瘤的生物标志物. circRNA具有较强的组织表达特异[13]. Li[33]检测了101例胃癌组织标本,研究发现 has-circ-002059在胃癌中异常低表达,且与肿瘤远处转移、淋巴结转移、性别及年龄高度相关,且在细胞中稳定性高,提示其是一个潜在的胃癌诊断标志物. Han[34]分析了circRNA在肝细胞癌(hepatocellular carcinoma,HCC)组织中的表达谱,发现circMTO1低表达患者存活时间短,表明它可能是肿瘤抑制因子,证实miR-9为circMTO1相关的miRNA,发现miR-9可以下调p21,导致 HCC细胞增殖和侵袭. 有研究报道指出融合环状RNA在癌症中发挥重要作用(图1l). Tan[8]研究发现,融合基因EML4能产生F-circEA,影响非小细胞肺癌细胞的增殖,并且在EML4-ALK阳性的肺癌患者血清中能检测到F-circEA,表明F-circEA可能作为EML4-ALK阳性非小细胞肺癌的诊断标志物. 体液检查是一种非侵入性的体外诊断方法,相关研究显示circRNA在人血液、唾液、尿液和外泌体中含量丰富且稳定性高,这些特征使circRNA成为癌症诊断、预后和治疗的非侵入性生物标志物的理想候选者(图1m). Li[35]通过对肝癌细胞外泌体中circRNA进行测序,发现与正常细胞相比,其在外泌体中大量富集且差异明显,同时血清中肿瘤相关circRNA的富集程度与肿瘤的大小相关,表明体液中的circRNA可能是未来疾病诊断和治疗的潜在靶标.

  • 4 circRNA在胃癌中的研究进展

    胃癌是一种常见的恶性肿瘤,在全球癌症相关死亡原因中排第3位,其愈后与肿瘤分期有关.早期胃癌患者往往无明显症状,确诊时已是胃癌的晚期,因此寻找新的诊断方法以及评估预后指标,确定其特征的生物靶标成为时下的热点及难点.

  • 4.1 circRNA与胃癌的发生发展

    circRNA与肿瘤的发生和发展密切相关,是一种有前景的生物标志物,甚至是治疗靶点,为肿瘤的治疗提供了新的思路. 随着二代测序技术的兴起,检测到超过100万个的circRNA存在于人类组织中,并且大部分在细胞质中,其丰度远超同源线性RNA. 已有报道circRNA与胃癌、肺癌、肝癌、结肠癌、乳腺癌、头颈部肿瘤、宫颈癌、白血病、淋巴瘤等肿瘤疾病的发生发展有关(表1). 近年来circRNA在胃癌中的研究不断增多. Li[36]研究发现,circ-104916在胃癌中低表达,且与肿瘤浸润深度、分期和淋巴结转移呈负相关,其低表达降低了对N-cadherin、Vimentin和Slug的抑制作用,从而促进胃癌转移及侵袭. 胃癌相关差异circRNA与其互作基因联合分析发现,circRNA可以通过竞争结合miRNA对目标基因进行调控. Zhang[37]研究发现circLARP4主要存在于细胞质中,通过竞争性结合miR-424抑制胃癌的侵袭和转移. Lai[22]通过功能测定实验发现抑制hsa_circ_0047905、hsa_circ_0138960和has-circRNA7690-15的表达可以抑制胃癌细胞增殖和侵袭. Zhou[38]发现circRNA-0023642在胃癌组织和细胞系中上调. 其异常表达可以促进胃癌细胞增殖、迁移和侵袭以及诱导细胞凋亡. 此外circRNA-0023642还可以通过促进EMT作为转移激活剂从而促进胃癌的发展. Sun[30]通过胃癌细胞系MKN-45和MGC-803体外测定证明,敲低circPVRL3显著促进胃癌细胞增殖. Sui[39]发现CD44、CXXC5、MYH9、MALAT1差异表达基因可通过circRNA和miRNA之间以及miRNA和mRNA之间的相互作用等多种机制促进胃癌的发生. 此外,Ming等发现,circRNA可以存在于外泌体中,其可能通过外泌体参与胃癌疾病的发生及转移(Yan Y, et al. Scand J Gastroenterol, 2017, 52(5): 499-504).

    表1 circRNA和肿瘤

    Table 1 CircRNA and tumor

    circRNA名称肿瘤类型亲本基因表达变化参考文献
    hsa_circ_0001946胃癌CDR1上调[44]
    hsa_circ_0003789胃癌TSN上调[45]
    hsa_circ_0035431胃癌CGNL1下调[46]
    hsa_circ_0076304胃癌PGC下调[46]
    hsa_circ_0076305胃癌PGC下调[47]
    hsa_circRNA_400071胃癌未说明上调[39]
    circRNA0047905胃癌SERPINB5上调[22]
    hsa_circ_0004214肺癌Amotl1上调[47]
    hsa_circ_0013958肺癌ACP6上调[48]
    hsa_circ_0023404肺癌RNF121上调[49]
    hsa_circ_0043256肺癌ACACA上调[50]
    hsa_circ_0004214乳腺癌Amotl1上调[47]
    hsa_circ_0006528乳腺癌PRELID2上调[51]
    hsa_circ_0002874乳腺癌GLIS3上调[51]
    hsa_circ_0001667乳腺癌HEATR2上调[51]
    hsa_circ_0007915肝癌IPO11上调[52]
    hsa_circ_0000284肝癌HIPK3上调[53]
    hsa_circRNA_100338肝癌SNX27上调[54]
    hsa_circRNA_104075肝癌NUP153上调[54]
    hsa_circ_0001946结直肠癌CDR1上调[55]
    hsa_circ_0007031结直肠癌TUBGCP3上调[56]
    hsa_circ_0024169结直肠癌CUL5下调[57]
    hsa_circRNA_105055结直肠癌未说明上调[58]
    hsa_circ_0018289宫颈癌SYT15上调[59]
    hsa_circ_0004214宫颈癌Amotl1上调[47]
    hsa_circ_0013339头颈部肿瘤SLC30A7上调[60]
    hsa_circRNA_100855头颈部肿瘤未说明上调[61]
    hsa_circRNA_104912头颈部肿瘤未说明下调[61]
    hsa_circ_0058106头颈部肿瘤FN1上调[62]
    hsa_circ_0004277白血病WDR37下调[63]
    hsa_circ_0035381白血病PIGB上调[63]
    hsa_circ_0004136白血病KCNQ5上调[63]
    f-circM9白血病NA上调[9]
  • 4.2 circRNA与胃癌的诊断

    circRNA在胃癌的诊断中也发挥重要的作用. Xie[40]采用RT-PCR检测127例胃癌组织及癌旁相对正常组织,83例胃炎组织及6例胃癌细胞株中hsa_circ_074362的表达水平. 结果显示,胃癌组织、胃炎组织和胃癌细胞株中hsa_circ_0074362表达水平显著下调,并且其表达水平与淋巴结转移有关. 表明hsa_circ_0074362可能在胃癌的发生中起作用并且可能是胃癌的潜在生物标志物. Chen[41]采用qRT-PCR检测104例配对胃癌组织及癌旁组织和104例配对胃癌患者血浆标本及健康标本中hsa_circ_000190的表达水平. 发现hsa_circ_0000190在胃癌组织和胃癌患者血浆样品中下调,其表达水平与肿瘤直径、淋巴结转移、TNM分期和CA19-9水平有关. 这些结果表明hsa_circ_0000190可能是胃癌诊断的新型非侵入性生物标志物.此外,Tang[42]通过高通量测序和微阵列分析不同TNM分期的10个胃癌患者和5个作为对照的健康个体血浆样品中circRNA的表达差异谱. 结果显示,与正常对照相比,胃癌患者血浆中circ-KIAA1244的表达降低且与TNM分期和淋巴转移呈负相关. 并且作者发现circ-KIAA1244还可以在胃癌血浆外泌体中检测到,揭示circ-KIAA1244可能是用于诊断胃癌的新型循环生物标志物. Shao[43]发现hsa_circ_0001895在胃癌细胞中的表达水平均显著低于正常胃上皮GES-1细胞,且在胃癌癌前病变中也出现下调. 进一步研究发现hsa_circ_0001895的表达水平与细胞分化、Borrmann分型和CEA表达显著相关. 此外,Shao等还通过circRNA芯片分析胃癌中的circRNA表达谱,共发现308个circRNA,其中107个表达上调,201个表达下调,其中hsa_circ_0014717在大部分胃癌组织中显著下调,并且在胃癌组织中的表达与肿瘤分期、远端转移、组织CEA和CA199表达有关. 另外,hsa_circ_0014717还可以稳定存在于体液中,在胃癌筛查中具有潜在的应用价值,有可能成为筛选高危胃癌患者的新型生物标志物.

  • 4.3 circRNA与胃癌的治疗和预后

    尽管胃癌在诊断和治疗方面取得了许多进展,但是胃癌患者的预后仍然很差,因此发现新的分子机制和治疗靶点,并对预后提出预测价值十分重要. Zhang[64]研究显示,circRNA-100269及其线性异构体的表达水平在胃癌组织中下调,并通过靶向miR-630抑制肿瘤细胞生长,其下游目标miR-630表达与circRNA-100269表达呈负相关,表明circRNA可以通过类似circRNA-100269-miR-630信号传导途径在胃癌诊断和治疗中发挥作用. Huang[65]研究显示,circRNA-0026在胃癌中低表达,并且可调控胃癌的RNA转录、RNA代谢、基因表达、基因沉默等生物学功能,表明circRNA-0026是胃癌诊断和靶向治疗的有希望的生物标志物. 随着技术的不断成熟,已有研究发现人造circRNA海[66]可以吸附miR-21抑制胃癌细胞的增殖,为胃癌的分子治疗提供新的方法. miR-125作为经典的抑癌分子,Chen[67]研究发现circPVT1具有结合miR-125家族分子的功能,竞争性结合内源miR-125,从而增强细胞的增殖能力. 此外,circPVT1可独立于肿瘤大小、TNM分期等指标作为胃癌预后指标,并且报告显示,与circPVT1低表达和PVT1高表达的患者相比,具有高表达circPVT1和低表达 PVT1的患者生存率明显升高,通过联合检测circPVT1与PVT1的表达水平作为胃癌的预后指标更有价值. Zhang[37]研究发现circLARP4在胃癌组织中表达下调,是胃癌患者总生存时间的独立预后因子. Tang[42]研究显示,胃癌患者血浆中circ-KIAA1244的表达降低,并且与胃癌患者的总生存呈正相关. 临床数据表明,胃癌复发常出现在三期患者接受根治性切除术后一年内,Zhang[68]利用芯片筛选得到的46个差异circRNA,通过分析发现circRNA可作为三期胃癌根治术后的预后因子. 虽然circRNA在胃癌的发生发展、诊断、治疗及预后过程中扮演重要角色,但由于circRNA的研究才刚刚起步,技术和功能研究还不够成熟, circRNA逆转录时存在滚环扩增现象且有些circRNA表达丰度较低,检测难度较大,所以circRNA与胃癌的关系还需更进一步的研究.

  • 5 circRNA在胃癌中的研究策略

    随着circRNA研究的不断深入,技术不断成熟以及数据库和分析工具的开发,circRNA在胃癌中的研究日益完善. 我们可以采用全转录组测序和微阵列分析筛选出胃癌组织、血液、唾液、尿液以及对照组中的差异circRNA分子. 通过PCR、原位杂交、RNA印迹等分子实验方法进行验证,分析circRNA的表达情况和亚细胞定位. 以及通过过表达或敲除实验进行circRNA的功能研究. 或者通过生物信息学方法进行预测分析,结合RNA质谱、RNA免疫沉淀、荧光素酶报告基因实验、RNA下拉实验探索circRNA与miRNA或者circRNA与蛋白质之间关系. 此外,我们还可以通过生物信息学方法分析circRNA是否具有m6A修饰、ORF和IRES等蛋白质翻译相关元件,进一步研究circRNA翻译蛋白质的功能. 目前已经开发了很多的数据库和分析工具供研究者使用(表2,表3). circBase是一个通过收集和整合已经发布的circRNA数据构建的数据库. 目前该数据库收集6个物种的circRNA信息,通过在搜索界面中的list search提交circBase支持的circRNA ID号或基因组区域位置信息,可以快速查询相关circRNA信息,也可以进行条件设置,筛选自己所需要的circRNA数据. CSCD是一个肿瘤特异性circRNA数据库. 该数据库收集了87种细胞系(包括胃癌细胞)的circRNA数据. 总共汇总得到了272 152种肿瘤特异性的circRNAs,并且给出了基因界面和circRNA界面的信息,为胃癌中circRNA的研究创造了条件. 随着对circRNA研究的不断深入,针对circRNA研究的数据库和工具在不断的更新. 其实用性以及对科研课题数据的挖掘可以起到事半功倍的作用,为circRNA在胃癌中的研究方法、技术路线、可视化等提供思路和指导.

    表2 环状RNA在线数据库

    Table 2 Online circRNA databases

    名称功能链接PMID
    CircbankcircRNA综合数据库http://www.circbank.cn/25234927
    CircbasecircRNA综合数据库http://www.circbase.org/25234927
    Circpedia v2注释反向剪接和可变剪接http://www.picb.ac.cn/rnomics/circpedia/27365365
    CircRNADisease整合已有实验支持的疾病特异circRNAhttp://cgga.org.cn:9091/circRNADisease/29700306
    TSCD人和鼠组织特异circRNAhttp://gb.whu.edu.cn/TSCD/27543790
    CSCD癌症特异circRNAhttp://gb.whu.edu.cn/CSCD/29036403
    CircnetcircRNA-miRNA-gene调控网络http://circnet.mbc.nctu.edu.tw/26450965
    Circinteractom引物设计、结合位点预测https://circinteractome.irp.nia.nih.gov/26669964
    ORF Finder翻译蛋白功能预测https://www.ncbi.nlm.nih.gov/orffinder/11814675
    IRESite翻译蛋白功能预测http://iresite.org/IRESite_web.php19917642
    Primerbank特异引物设计和现有引物查询https://pga.mgh.harvard.edu/primerbank/index.html22086960
    Circ2Traits人类疾病相关circRNA数据库http://gyanxet-beta.com/circdb/24339831
    Starbase v3.0miRNA-circRNA 相互作用http://starbase.sysu.edu.cn/index.php24297251
    Deepbase v2.0深度测序获得的miRNA、lncRNA和circRNA的数据库http://deepbase.sysu.edu.cn/26590255
    ExoRBase人类血液特异circRNA、lncRNA and mRNAhttp://www.exoRBase.org30053265

    表3 环状RNA分析工具

    Table 3 Circular RNA analysis tool

    名称作用运行系统PMID
    CircPro鉴定具有蛋白质编码潜力的circRNAMac OS X or Linux29028266
    ISEScan内部核糖体进入位点分析工具Linux29077810
    Pfam 31.0预测蛋白质编码潜力Java26673716
    CircViewcircRNA可视化探索工具Java29106456
    CIRI-AScircRNA的鉴定Perl25583365
    Sailfish-cir定量circRNA表达Python28334396
    CircPrimer注释circRNA并确定circRNA引物的特异性Java30075703
  • 6 circRNA研究中存在的问题

    circRNA研究中的技术还不是很成熟,而且circRNA的鉴定、定量和验证,以及过表达和沉默都依赖于特定的背拼接连接,对生物和实验条件特别敏感,造成实验的失败和假阳性的出现. 在研究circRNA过程中,研究人员通过采用第二代测序的RNA-Seq技术,极大地提高了研究转录组的能力,并且开发了用于多种线性 RNA分子RNA拼接的信息学分析算法. 但如何提高RNA拼接检测的准确性依旧十分困难,从一些实验结果来看,仍然存在着信息学分析结果与实验结果不能对应的情[69]. 其次,circRNA的量化并不容易,必须通过RT-qPCR进行特定连接的定量. 一方面,如果仅对线性RNA进行分析,不考虑环状 RNA的情况,仍有可能出现假阴性结果;另一方面,如果充分考虑环状 RNA,则RNA拼接分析的准确性会更低. 在样品制备中,样品的纯度、RNA和cDNA水平分子大小过滤,以及样品碎片和添加程序中都可能存在假阳性. 在随后的逆转录和数据库构建也可能导致人为干扰,从而出现假阳性结[70]. 在RNA-Seq分析中,相同RNA序列的不同位点之间的定位效率通常存在很大差异,其原因仍不清[71]. 如何在实验过程中降低假阳性,使实验的可靠性和成功率获得提高,需要未来进一步的研究和探索.

  • 7 展望

    circRNAs作为一种新型RNA分子,具有重要的分子生物学功能和作为分子生物标志物的潜力. 近年来,对circRNA研究不断深入,进一步对其功能和机制研究尤为重要. 例如:circRNA与所在基因在转录水平、转录后水平等不同层次的相互关系的研究;除了m6A修饰,其他修饰类型是否也可存在于circRNA中,以及对这些修饰相关的病理生理机制的研究;circRNA进入外泌体可能存在选择性,对其机制和病理生理意义的研究;circRNA亚细胞定位的机制以及circRNA组织/疾病特异性表达形成原因的研究. 在肿瘤研究中, circRNA在肿瘤的发生发展中发挥重要作用. 特别是circRNA在肿瘤诊断、预后和治疗中显示出巨大的潜力.由于circRNA含量丰富且高度稳定等特征,作为肿瘤的生物标志物,circRNA可以对某些类型的肿瘤进行早期筛查,显著增加患者生存率. circRNA有望开启肿瘤诊断和治疗的新篇章.

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王攀

机 构:南华大学衡阳医学院肿瘤研究所,肿瘤细胞与分子病理学湖南省重点实验室,衡阳 421001

Affiliation:Cancer Research Institute of Hengyang Medical College, University of South China; Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang 421001, China

徐高生

机 构:岳阳市妇幼保健院,岳阳 414000

Affiliation:Yueyang Maternal and Child Health Hospital, Yueyang 421001, China

马蔚

机 构:岳阳市妇幼保健院,岳阳 414000

Affiliation:Yueyang Maternal and Child Health Hospital, Yueyang 421001, China

叶东梅

机 构:南华大学衡阳医学院肿瘤研究所,肿瘤细胞与分子病理学湖南省重点实验室,衡阳 421001

Affiliation:Cancer Research Institute of Hengyang Medical College, University of South China; Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang 421001, China

李昱萱

机 构:南华大学衡阳医学院肿瘤研究所,肿瘤细胞与分子病理学湖南省重点实验室,衡阳 421001

Affiliation:Cancer Research Institute of Hengyang Medical College, University of South China; Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang 421001, China

罗苇如

机 构:南华大学衡阳医学院临床医学卓越医师班,衡阳 421001

Affiliation:Clinical Medicine Excellent Undergraduate of Medical College, University of South China, Hengyang 421001, China

肖懿洋

机 构:南华大学衡阳医学院临床医学卓越医师班,衡阳 421001

Affiliation:Clinical Medicine Excellent Undergraduate of Medical College, University of South China, Hengyang 421001, China

张志伟

机 构:南华大学衡阳医学院肿瘤研究所,肿瘤细胞与分子病理学湖南省重点实验室,衡阳 421001

Affiliation:Cancer Research Institute of Hengyang Medical College, University of South China; Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Hengyang 421001, China

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circRNA名称肿瘤类型亲本基因表达变化参考文献
hsa_circ_0001946胃癌CDR1上调[44]
hsa_circ_0003789胃癌TSN上调[45]
hsa_circ_0035431胃癌CGNL1下调[46]
hsa_circ_0076304胃癌PGC下调[46]
hsa_circ_0076305胃癌PGC下调[47]
hsa_circRNA_400071胃癌未说明上调[39]
circRNA0047905胃癌SERPINB5上调[22]
hsa_circ_0004214肺癌Amotl1上调[47]
hsa_circ_0013958肺癌ACP6上调[48]
hsa_circ_0023404肺癌RNF121上调[49]
hsa_circ_0043256肺癌ACACA上调[50]
hsa_circ_0004214乳腺癌Amotl1上调[47]
hsa_circ_0006528乳腺癌PRELID2上调[51]
hsa_circ_0002874乳腺癌GLIS3上调[51]
hsa_circ_0001667乳腺癌HEATR2上调[51]
hsa_circ_0007915肝癌IPO11上调[52]
hsa_circ_0000284肝癌HIPK3上调[53]
hsa_circRNA_100338肝癌SNX27上调[54]
hsa_circRNA_104075肝癌NUP153上调[54]
hsa_circ_0001946结直肠癌CDR1上调[55]
hsa_circ_0007031结直肠癌TUBGCP3上调[56]
hsa_circ_0024169结直肠癌CUL5下调[57]
hsa_circRNA_105055结直肠癌未说明上调[58]
hsa_circ_0018289宫颈癌SYT15上调[59]
hsa_circ_0004214宫颈癌Amotl1上调[47]
hsa_circ_0013339头颈部肿瘤SLC30A7上调[60]
hsa_circRNA_100855头颈部肿瘤未说明上调[61]
hsa_circRNA_104912头颈部肿瘤未说明下调[61]
hsa_circ_0058106头颈部肿瘤FN1上调[62]
hsa_circ_0004277白血病WDR37下调[63]
hsa_circ_0035381白血病PIGB上调[63]
hsa_circ_0004136白血病KCNQ5上调[63]
f-circM9白血病NA上调[9]
名称功能链接PMID
CircbankcircRNA综合数据库http://www.circbank.cn/25234927
CircbasecircRNA综合数据库http://www.circbase.org/25234927
Circpedia v2注释反向剪接和可变剪接http://www.picb.ac.cn/rnomics/circpedia/27365365
CircRNADisease整合已有实验支持的疾病特异circRNAhttp://cgga.org.cn:9091/circRNADisease/29700306
TSCD人和鼠组织特异circRNAhttp://gb.whu.edu.cn/TSCD/27543790
CSCD癌症特异circRNAhttp://gb.whu.edu.cn/CSCD/29036403
CircnetcircRNA-miRNA-gene调控网络http://circnet.mbc.nctu.edu.tw/26450965
Circinteractom引物设计、结合位点预测https://circinteractome.irp.nia.nih.gov/26669964
ORF Finder翻译蛋白功能预测https://www.ncbi.nlm.nih.gov/orffinder/11814675
IRESite翻译蛋白功能预测http://iresite.org/IRESite_web.php19917642
Primerbank特异引物设计和现有引物查询https://pga.mgh.harvard.edu/primerbank/index.html22086960
Circ2Traits人类疾病相关circRNA数据库http://gyanxet-beta.com/circdb/24339831
Starbase v3.0miRNA-circRNA 相互作用http://starbase.sysu.edu.cn/index.php24297251
Deepbase v2.0深度测序获得的miRNA、lncRNA和circRNA的数据库http://deepbase.sysu.edu.cn/26590255
ExoRBase人类血液特异circRNA、lncRNA and mRNAhttp://www.exoRBase.org30053265
名称作用运行系统PMID
CircPro鉴定具有蛋白质编码潜力的circRNAMac OS X or Linux29028266
ISEScan内部核糖体进入位点分析工具Linux29077810
Pfam 31.0预测蛋白质编码潜力Java26673716
CircViewcircRNA可视化探索工具Java29106456
CIRI-AScircRNA的鉴定Perl25583365
Sailfish-cir定量circRNA表达Python28334396
CircPrimer注释circRNA并确定circRNA引物的特异性Java30075703

图1 circRNA的形成和生物学功能

Fig. 1 Formation and biological function of circRNA

图2 CircRNA和肿瘤

Fig. 2 circRNA and tumor

表1 circRNA和肿瘤

Table 1 CircRNA and tumor

表2 环状RNA在线数据库

Table 2 Online circRNA databases

表3 环状RNA分析工具

Table 3 Circular RNA analysis tool

image /

环状RNA的形成:(a)基因外显子的共价组合构成套索驱动的环化.(b)内含子对驱动的双内含子互补对的环化.(c)RNA结合蛋白和反式作用因子促进环化.(d)染色体易位产生融合环状 RNA. (e)前体tRNA切割形成tricRNA.(f)环形DNA病毒基因产生环状RNA. 环状RNA的生物学功能:(g~h)基因转录的调节;(i)充当miRNA海绵;(j)充当RBP海绵;(k)翻译蛋白质;(l)融合环状RNA促进肿瘤的发展;(m)作为生物标志物.

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  • 参 考 文 献

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      Chen L L, Yang L. Regulation of circRNA biogenesis. RNA Biol, 2015, 12(4): 381-388

    • 2

      Diener T O. Potato spindle tuber "virus". IV. A replicating, low molecular weight RNA. Virology, 1971, 45(2): 411-428

    • 3

      Grabowski P J, Zaug A J, Cech T R. The intervening sequence of the ribosomal RNA precursor is converted to a circular RNA in isolated nuclei of Tetrahymena. Cell, 1981, 23(2): 467-476

    • 4

      Pasman Z, Been M D, Garcia-Blanco M A. Exon circularization in mammalian nuclear extracts. RNA, 1996, 2(6): 603-610

    • 5

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