CN113755567A - lncRNA在桥本甲状腺炎诊断中的应用 - Google Patents
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Abstract
本发明是lncRNA在桥本甲状腺炎诊断中的应用，具体是ENST00000536112的检测试剂在制备诊断桥本甲状腺炎的产品中的应用。本发明的优点：为桥本甲状腺炎的发病机制提供了新的理论基础，也为桥本甲状腺炎的临床治疗提供了新的思路。
Description
技术领域
本发明涉及的是lncRNA在桥本甲状腺炎诊断中的应用，具体涉及的lncRNA是ENST00000536112，属于生物医药技术领域。
背景技术
桥本甲状腺炎(Hashimoto thyroiditis，HT)是一种自身免疫性甲状腺炎，是最常见的一种器官特异性自身免疫性疾病，以甲状腺内单核细胞浸润为特征。目前认为HT的产生主要是和基因以及环境因素相关，它的发病率逐年上升，主要在45-65岁人群中常见。临床对HT的诊断依赖于病理学诊断和超声波诊断，在治疗上是通过全身给予甲状腺激素的方式为主，以弥补机体的甲状腺功能低下，但是长期给予甲状腺激素，可能导致甲状腺功能亢进(甲亢)的风险增加；若HT伴有甲亢，则需应用抗甲状腺药物；当甲状腺结节生长到足够大，对周围颈椎结构造成压迫时，通过手术切除的方式为主，但是切除甲状腺后也需要长期服用甲状腺激素。因此，由于它复杂的发病过程，其发病机制尚不清楚，所以在临床上仍亟待新的治疗靶点。
近些年，多项针对long noncoding RNAs(lncRNAs)的研究，均发现它们与自身免疫疾病的发生密切相关，多种免疫细胞(如T细胞等)的分化和激活，均需要lncRNA的参与。在体外细胞实验中，通过病毒过表达Smad3基因，可以抑制lnc-Smad3的转录，从而上调诱导型Treg细胞的分化，增加的Treg细胞可以抑制由效应T细胞引发的感染、炎症和自身免疫过程，对机体的免疫稳态起到保护作用；在肝脏肿瘤细胞中，lnc-EGFR的表达水平与肿瘤细胞的体积大小呈现正相关，这一过程也是通过调节Treg细胞的分化水平，从而影响肿瘤细胞的免疫抑制过程来介导的。作为各种基因表达与信号分子调节的重要中间成员miRNA来说，它在免疫疾病过程中也发挥着巨大作用。LncRNAs可以通过ceRNA(competing endogenousRNA)机制，调节下游miRNA的表达，在对重症肌无力(Myasthenia gravis,MG)患者的研究中发现，转录子MALAT-1(Metastasis-associated lung adenocarcinoma transcript 1)的表达下调，在正常细胞中，MALAT-1可以通过ceRNA机制，竞争结合miR-338-3p，从而诱导MSL2(Male-specific lethal 2)的表达，以保证细胞的正常工作；在肺腺癌细胞中，lncRNACCAT2的表达明显上调，促进了细胞的增殖和迁移能力，通过ceRNA机制竞争性结合miR-23b-5p，正反馈调节FOXC1的表达，促进了肿瘤的发展过程。综上所述，lncRNAs在机体的免疫过程中发挥着重要的作用，对于HT而言，lncRNA也很有可能通过ceRNA机制调节下游的miRNA而参与其中。
发明内容
本发明提出的是lncRNA在桥本甲状腺炎诊断中的应用，其目的旨在弥补现有技术存在的上述不足，提供一种桥本甲状腺炎诊断用标志物。
本发明的技术解决方案：ENST00000536112的检测试剂在制备诊断桥本甲状腺炎的产品中的应用。
优选的，所述的产品通过RT-PCR检测ENST00000536112的表达水平以诊断桥本甲状腺炎。
优选的，所述的产品通过RT-PCR检测ENST00000536112在外周血中的表达水平以诊断桥本甲状腺炎。
本发明的优点：为桥本甲状腺炎的发病机制提供了新的理论基础，也为桥本甲状腺炎的临床治疗提供了新的思路。
附图说明
图1是实施例1的流程示意图。
图2是实施例2的流程示意图。
具体实施方式
下面结合实施例和具体实施方式对本发明作进一步详细的说明。
预实验：检测HT患者的外周血，通过实时定量RT-PCR发现IncRNAENST00000536112在HT患者外周血中表达水平差异最大；通过生物信息学筛选分析IncRNAENST00000536112的下游miRNA后，找到miR-20b这个分子，其表达在HT患者中也发生了明显改变，提示IncRNA ENST00000536112与HT的发生密切相关，同时miR-20b可能是一个潜在的下游靶点。
在一些自身免疫疾病中，miR-20b可以通过调节RORγt(RAR-相关孤儿受体γt)的表达，对Th17介导的炎症过程产生作用。Th17细胞与Treg细胞都是辅助T细胞的一种类型，介导脊椎动物的获得性免疫过程。在正常人的血液中，Th17细胞的含量非常低，当受到长期炎症感染时，其含量会显著升高。Th17可以分泌促炎因子IL-17和其他一系列促炎因子IL-21、IL-22等，放大炎症过程：在二型胶原蛋白免疫小鼠的膝关节处过表达IL-17，会造成小鼠膝关节严重受损，当再给予抗-IL-17的抗体时，可以降低小鼠的关节炎症水平起到保护作用13。
在对HT病人的血样检查发现，Th17细胞及其分泌的IL-17的水平和对照组相比，均有显著增加，Th17可以通过抑制Treg细胞的分化过程，促进HT的进展。
除此之外，在比如多发性硬化(Multiple sclerosis，MS)和实验性获得性脑炎(Experimental autoimmune encephalomyelitis,EAE)中，miR-20b可以通过调节STAT3(转录激活因子-3)的表达，抑制Th17的分化，降低IL-17的表达，从而调控与自身免疫相关的转录因子和炎症因子的表达水平。STAT3在炎症过程和免疫系统中均有参与，与免疫相关疾病的产生有紧密联系。在一项针对中国HT患者的研究实验中发现，STAT3基因与HT的发生密切相关，缺失STAT3基因时，可以抑制Th17的分化，抑制其分泌的炎症因子，从而降低炎症来发挥保护作用。
在另一项体外细胞培养实验中，过表达miR-20b，可以抑制T细胞的增殖和激活，当给予miR-20b的抗体时，可以促进这两个过程，这项结果提示miR-20b是调节T细胞在疾病进程中状态的一个关键分子，并且miR-20b对于T细胞增殖和激活的调节是通过抑制NFAT5的表达来实现其保护作用的；通过检测胸腺癌相关重症肌无力患者的胸腺瘤组织和血清样本，观察到了类似结果：患者miR-20b的表达水平降低，而NFAT5的表达增加。
根据预实验结果及以上研究，可推测IncRNA ENST00000536112参与了HT疾病的发展过程中，通过ceRNA机制下调了miR-20b的表达水平，以及抑制NFAT5信号通路，从而促进了T细胞的增殖与激活过程；通过RORγt和STAT3信号通路抑制Treg的分化，促进Th17的分化与IL-17的表达加重炎症反应过程，最终促进了HT病情的发展。
实施例1
如图1所示，临床病人血样lncRNA与下游miRNA分析
1.1临床病人分组情况
选取2016年1月～2018年12月在某医院门诊就诊的桥本甲状腺炎患者170例(包括80例HT患者，50例甲状腺结节性肿大患者，以及40例甲状腺癌症患者)，作为桥本组。所有患者的诊断均符合《中国甲状腺疾病诊治指南》中桥本甲状腺炎诊断标准：凡是弥漫性甲状腺肿大，质地较韧，特别是伴峡部锥体叶肿大，不论甲状腺功能是否有改变，均应怀疑HT。若血清TPOAb和TgAb阳性，即可明确诊断。同时从医院健康体检中心选取性别、年龄相匹配的健康人群60例作为对照组。研究方案经医学伦理委员会批准，实验征得患者及家属同意，并签署知情同意书。
1.2外周血单核细胞(peripheral blood mononuclear cells,PBMC)分离
测量研究对象的收缩压(SBP)和舒张压(DBP)，所有研究对象隔夜空腹10h以上，采集10ml肝素化的静脉血，将全血转移至50ml离心管中，加入10mlPBS溶液稀释，轻轻混匀；配制细胞培养基：RPMI1640+10％FBS+1％P/S；配制细胞冻存液：FBS中加入10％DMSO。取两支15ml离心管，分别加入5ml Ficoll溶液。将稀释混匀后的血液轻轻加入到两支离心管的Ficoll溶液上层，避免两种溶液直接混合，每支离心管均加入10ml稀释混匀的血液；用离心机2000rpm离心20分钟，降速步骤设置为no break；PBMC所在细胞层为白色，用吸管将该层细胞吸取后加入至另一干净的15ml离心管中；加入PBS至10～15ml，1500rpm，10min离心后去掉上清，再加入培养基进行相同操作的清洗；加入5～10ml培养基重悬细胞，进行后续计数培养或者铺板；细胞冻存：将细胞离心收集之后，用细胞冻存液重悬。取1～1.5ml细胞至冻存管中，放入冻存盒(冻存盒可事先在4℃冰箱预冷)。再将冻存盒放置于-80℃冰箱过夜。第二天将细胞转入液氮中长期保存。
1.3差异性表达lncRNA与miRNA筛选
取1.2中收集的PBMC细胞，使用TRizol试剂(Invitrogen,Carlsbad,CA,USA)分离PBMCs的总RNA，用Invitrogen SuperScript ds-cDNA synthesis kit合成双链cDNA，进行荧光标记并杂交漂洗，用Agilent芯片扫描仪(G2565CA)进行扫描，使用Agilent FeatureExtraction(v10.7)软件对杂交图片进行分析并提取数据。使用Agilent Gene Spring软件对数据进行归一化和差异化分析。差异筛选标准：fold>1.5&P<0.05。根据芯片的表达数据结果，将桥本组与对照组的lncRNA与miRNA表达谱进行比较，筛选表达值差异最大且具有统计学意义的lncRNA与miRNA。
1.4ceRNA网络的建立
通过检索miRcode数据库，查阅单个lncRNA-miRNA的配对组合情况，根据上一步中筛选出的具有统计学意义的lncRNA与miRNA进行ceRNA网络整合，交互作用分析软件(cytoscape software)可用于此处网络整合分析。
1.5酶联免疫吸附剂测定(ELISA)
取1.2中收集的桥本组与对照组血清，用ELISA试剂盒(R&D Systems)检测血清中IL-17(900-K84,Peprotech)水平：将所用抗原用包被稀释液稀释，每孔所用抗原包被量为100μL，置于37℃孵育4小时；加入5％胎牛血清，每个反应孔中均加满，并去除所有孔中气泡，将板置于37℃封闭40分钟，封闭结束后吸干孔内的液体，然后将洗涤液注满孔中，放置2分钟略作摇动，吸干孔内液体后，将板置于吸水纸上拍干，重复洗涤3次，每次3分钟；用稀释液将每孔样品稀释，将稀释后的样品加入酶标反应孔中，每个样品加双孔，每孔100μl，置于37℃孵育1小时；用洗涤液洗涤3次，每次3分钟；加入酶标抗体，在37℃孵育40～60分钟；洗涤同前；每孔加入100μl TMB-过氧化氢尿素溶液，置于37℃避光放置3～5分钟，加入终止液50μl终止反应，在450nm波长下检测；用测定标本孔的吸收值与一组阴性标本测定孔平均值的比值(P/N)表示，当P/N>2时，作为抗体的效价。
1.6数据分析
采用SPSS v.22.0进行数据分析。数据以％或mean±standard error(SEM)形式呈现。分类变量采用数字或者率来表示，连续变量采用平均数+标准差表示；连续变量采用组间t检验的方法分析两组间，桥本组与对照组的lncRNA表达含量分析用Fisher’s exactprobability test检验，对于所有测试，p<0.05认为具有统计学意义。
实施例2
在体外细胞模型中检测miR-20b对HT的保护作用及其机制
2.1自身免疫性甲腺炎动物模型构建
从实验动物中心处购买6周大、体重10～12g的C57BL/6雄鼠20只，随机均分为两组：实验组和对照组。所有动物实验均符合实验动物管理和使用条例。将动物饲养于12h光暗循环的正常动物房内，正常饮食，并在实验组小鼠饮用水中添加0.05％NaI，饲养8周后，给予小鼠甲状腺球蛋白(Tg)，加强小鼠的免疫反应；对照组小鼠给予蒸馏水。
2.2检测甲状腺自身抗体水平
用放射性免疫试剂盒：TgAb test kit和TPOAb test kit(Jiu Ding Company,Tianjin,China)检测对照组和实验组小鼠血清中TgAb和TPOAb的水平。
2.3体外Th17细胞和Treg细胞诱导(In vitro induction of Th17cell and Tregcell)
取实验组自身免疫性甲腺炎模型成功小鼠的脾脏细胞，制备单细胞悬液。通过CD4MicroBeads(Miltenyi Biotec)分离CD4+T细胞。用96孔圆底培养皿(Costar)纯化细胞，每个孔中种5x104个细胞，并以cell:beads的比例为1:1，添加
Mouse T-activator CD3/CD28。
Th17细胞诱导：配制TGF-β(3ng/ml)(DB-100B，R&D Systems)，IL-6(30ng/ml)(900-M16,Peprotech),IL-21(25ng/ml)，IL-1β(12.5ng/ml)的混合液，加入96孔板中。
Treg细胞诱导：配制TGF-β(20ng/ml)和0.1mM的NaCl(对照组)或NaI(实验组)的混合液，与CD4+T细胞混合培养，5～7天后可收集Treg细胞。
2.4BrdU细胞增殖检测(BrdU proliferation assay)
BrdU检测试剂盒购买于BD Biosciences(San Jose,CA)。将BrdU与细胞混合培养1小时，BrdU的终浓度为10μM。用PE偶联的抗小鼠CD4抗体与细胞在冰上混合15分钟。用Cytofix/Cytoperm Buffer和Cytoperm Permeabilization Buffer Plus分别固定和透化细胞。用BrdU抗体进行染色，样本留存待进行检测。
2.5免疫印迹实验(Western blot)
蛋白提取：在1ml的冷裂解液(Beyotime,Shanghai,China)中各加入10ul的磷酸酶抑制剂、蛋白酶抑制剂和PMSF；混匀，放置在冰上备用；107个细胞需要裂解液1ml；贴壁细胞：弃去培养基，用冷的PBS洗两次，弃去PBS，然后加入计算好的细胞裂解液；在冰上用细胞刮刀进行刮离细胞，将刮离的细胞裂解液移入EP管中，颠倒裂解20-30min，悬浮细胞：4℃400g离心收集细胞，用冷的PBS洗两次细胞，同样按细胞数加入裂解液，涡旋10s，放置冰上裂解10min，重复3-4次；裂解完毕之后，将细胞裂解液4℃12000g离心10min；将上清移入新的EP管中；进行蛋白定量或者变性进行蛋白实验。(提取好的蛋白建议保存于-80℃，即用即取，避免反复冻融，避免长时间储存。)
2.6流式细胞仪检测分析(Flow cytometry assay)
取对数生长期细胞，倒去细胞培养液，用胰酶适度消化细胞，用培养液吹打，800rpm，离心15分钟后去除伤情；PBS洗2次，加入0.5ml PBS彻底吹匀；用5ml注射器将细胞吸起，用力打入预冷过的5ml 70％乙醇中，用封口膜封口，4℃过夜；800rpm离心15分钟，收集固定处理后的细胞，用PBS洗2次；用0.4ml的PBS重悬细胞并转移至Tube中轻轻吹打(防止细胞破碎)；加入RNase-A约3μl至终浓度约为50μg/ml，在37℃水浴锅中消化30分钟；加入PI约50μl至终浓度为65μg/ml，在冰浴中避光染色30分钟；用300目(孔径40～50微米)尼龙网过滤后，上机检测。
2.7质粒构建、慢病毒包装和转染(Construction of plasmids,lentiviruspackaging,and transduction)
慢病毒介导miR-20b过表达质粒构建：将分离纯化后的CD4+T细胞分为未转染对照组、阴性对照及miR-20b模拟物组，阴性对照组及miR-20b模拟物组采用Lipofectam ine2000reagent分别转染miR-20b scramble和miR-20b mimics，未转染对照组用PBS处理，作为空白对照，miR-20b模拟物组转染序列：miR-20b mimics正向引物：5'-CAAAGUGCUCAUAGUGCAGGUAG-3'，miR-20b mimics反向引物：5'-ACCUGCACUAUGAGCACUUUGUU-3’；阴性对照组转染序列：miR-20b NC正向引物：5'-UUCUCCGAACGUGUCACGUTT-3'，miR-20bNC反向引物：5'-ACGUGACACGUUCGGAGAATT-3'。
2.8RNA提取及实时定量聚合酶链反应(Quantitative RT-PCR)
用All-in-One microRNA抽提试剂盒和All-in-One miRNA实时荧光定量聚合酶链反应(quantitative real-time polymerase chain reaction，q RT-PCR)检测试剂盒提取和分离miRNAs，ABI Prism 7700系统的SYBR Green Reagents qRT-PCR，在ABI 7500实时定量PCR仪中，以U6小核RNA作为内参，使用2-ΔΔCt方法定量，量化miR-20b相对表达水平。
2.9细胞凋亡检测(Cell apoptosis assay)
分离后的CD4+T细胞，在Th17细胞诱导条件下，转染miR-20b NC或者mimics后72小时，收集细胞，用annexin V–allophycocyanin细胞凋亡检测试剂盒(天津Sungene)，通过流式细胞仪检测细胞凋亡水平。
2.10数据分析
采用SPSS v.22.0进行数据分析，数据以mean±standard error(SEM)形式呈现，组间差异用two-tailed t检验；对于所有测试，P<0.05被认为具有显著差异。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
序列表
<110> 无锡准因生物科技有限公司
<120> lncRNA在桥本甲状腺炎诊断中的应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 417
<212> DNA
<213> 人源(2 Ambystoma laterale x Ambystoma jeffersonianum)
<400> 1
cctgcctttc caatacctat tcaggagcaa aaaccatgat aaactccctt tgcatctttt 60
gtaagagagc tagacaaacg ccggagagtt tctctgcagt tgtgtgacct tgggtagttt 120
cttcaactac agaaagagag ttgagcagat gctccggctg ccactccatc atatattgga 180
aacagcatta ctttatagta aatcatgacc acggtgtatg gcaatgaagt tgcatctgaa 240
gcagccggca ccctatgtgc tagctggctt ttagaccagg agactgtgaa tctgtggtca 300
ggatctcttt agggctgcta aatatatact acccactatc actcgctgga gctgcagacc 360
ctagttttag agtttcactt cttaaagacc ttcatcctta ttaaaatggt aatatcc 417
Claims (3)
1.ENST00000536112的检测试剂在制备诊断桥本甲状腺炎的产品中的应用。
2.如权利要求1所述的应用，其特征在于，所述的产品通过RT-PCR检测ENST00000536112的表达水平以诊断桥本甲状腺炎。
3.如权利要求1所述的应用，其特征在于，所述的产品通过RT-PCR检测ENST00000536112在外周血中的表达水平以诊断桥本甲状腺炎。
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