CN107586849A - 脑组织来源的circ9:4117768|4118881的应用 - Google Patents
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Abstract
本发明公开了一种脑组织来源的环状RNA(circular RNA,circRNA)circ9:4117768|4118881的应用方法,即检测脑组织中circ9:4117768|4118881表达量的试剂在制备胶质瘤诊断制剂中的应用。该circRNA此前并未报道研究过,通过研究证实采集胶质瘤患者胶质瘤组织后提取RNA,逆转录并进行实时荧光定量分析发现circRNAcirc9:4117768|4118881表达水平下降。通过检测胶质瘤患者胶质瘤组织中circRNAcirc9:4117768|4118881的表达水平,从而对胶质瘤患者做出诊断判断。
Description
技术领域
本发明属于生物技术领域,涉及一种脑组织来源的环状RNA(circular RNA,circRNA)circ9:4117768|4118881的应用,即检测脑组织中circ9:4117768|4118881表达量的试剂在制备胶质瘤诊断制剂中的应用。
背景技术
脑胶质瘤是成年人最为频发的脑肿瘤疾病,占颅内肿瘤的40.49%。从确诊开始,脑胶质瘤患者平均生存寿命不超过五年。为了诊治胶质瘤这种与遗传物质相关性极高的恶性疾病,必须在分子生物学水平,从遗传信息表达的方面来探索其发病机理。目前而言胶质瘤的诊断和治疗方法虽处于不断改进阶段,但是胶质瘤患者生存率并没有明显提高。胶质瘤诊断仍然处于以临床、病理学和影像学信息为基础的经验性阶段,而且一经诊断,绝大多数均为中晚期,手术后的生存率不容乐观。因此,寻找胶质瘤诊断标志物对患者进行诊断分析,尽早确诊病情,并相应地选择合理的后续治疗方案,提高生存率,是神经科学领域亟待解决的研究任务。
circRNA是一类广泛且多样地存在于哺乳动物细胞中、具有调控基因表达作用的内源性非编码RNA分子,具有共价闭合的环形结构,广泛存在于各种细胞中,也是继microRNA(miRNA)后RNA家族的最新研究热点。近年来,随着深度测序技术的广泛应用和生物物理和信息学技术的快速发展,人们发现人类许多外显子的转录本可被非线性地反向剪接或通过基因重排而形成circRNA,且它们在所有剪接转录本中占了相当大的比例,并具有丰富性、稳定性、高保守性和时空特异性等特征,有作为诸多疾病分子标志物的潜力。
如今的胶质瘤分子分型已经越来越细化,根据2016年WHO胶质瘤分子分型,今后的分级方向将更倾向于精准医疗,而circRNA也许今后能作为针对胶质瘤分子分型的新型标志物。
发明内容
本发明的目的是提供检测脑组织中circ9:4117768|4118881表达量的试剂在制备胶质瘤诊断制剂中的应用,该circRNA circ9:4117768|4118881的序列如SEQ NO:1所示。
所述的检测脑组织中circ9:4117768|4118881表达量的试剂为实时荧光定量PCR检测试剂。
所述的实时荧光定量PCR检测试剂包括进行实时荧光定量PCR的特异性引物,序列如SEQ NO:2和3所示。
所述的实时荧光定量PCR检测试剂为试剂盒,
该试剂盒包括:(1)从胶质瘤组织中抽提总RNA所用试剂,包括RNA稳定溶液、Trizol试剂、三氯甲烷、异丙醇、无酶水;(2)以总RNA为模板将circRNA circ9:4117768|4118881逆转录为cDNA所用试剂,包括逆转录缓冲液、三磷酸碱基脱氧核苷酸、RNA酶抑制剂、MMLV逆转录酶以及circRNA circ9:4117768|4118881所用随机引物;(3)将cDNA实时定量PCR所用试剂,包括circRNA circ9:4117768|4118881实时荧光定量PCR特异性引物、GAPDH内参特异性PCR引物、实时荧光定量SYBR染料、无酶水;
circRNA circ9:4117768|4118881实时荧光定量PCR特异性引物:
正向引物:5'-ATACAAGCCCTTCAACGC-3,
反向引物:5'-GAGTTAGAGACACTATTGCTGGAC-3'。
GAPDH内参特异性PCR引物:
正向引物为5′-ATCATCAGCAATGCCTCCT-3′,
反向引物为5′-CATCACGCCACAGTTTCC-3′。
本发明的有益效果在于:首次发现circ9:4117768|4118881这种脑组织中的环状RNA,并发现其对胶质瘤具有较高的诊断价值;通过荧光定量PCR对32例胶质瘤组织与12例正常脑组织发现进行分析发现,circ9:4117768|4118881在两者中的表达差异明显(P=0.0003),此法为胶质瘤的诊断分析提供了强有力的技术支持,可以使得胶质瘤的诊断更加方便易行,为临床医生快速准确掌握患者病情,为提高临床治疗效果奠定基础,并为发现具有潜在治疗价值的新型小分子药物靶标提供帮助。
附图说明
图1为实时荧光定量PCR分析circ9:4117768|4118881在正常脑组织与胶质瘤组织中的表达差异;
图2为Roc分析脑组织来源的circ9:4117768|4118881对胶质瘤诊断的特异性,灵敏性。
具体实施方式
以下结合实施例旨在进一步说明本发明,而非限制本发明。
实施例1制备检测脑组织中circRNA circ9:4117768|4118881表达量的试剂用于制备胶质瘤患者诊断的试剂盒(50次反应)
1.RNA稳定溶液50ml
2.异丙醇100ml
3.三氯甲烷100ml
4.Trizol(来自Molecular Research Center公司)50ml
5.无酶水10ml
6.1μM随机逆转录引物(Thermo公司)50μl
7.5×逆转录缓冲液(Thermo公司)200ml
8.10mM三磷酸碱基脱氧核苷酸(Thermo公司)100ul
9.40U/μl RNA酶抑制剂(Thermo公司)500ul
10.200U/μl MMLV逆转录酶(Thermo公司)50μl
11.Premix Ex Taq(Thermo公司)50μl
12.10μM circRNA circ9:4117768|4118881实时荧光定量PCR特异性引物30μl
circ9:4117768|4118881正向引物:5'-ATACAAGCCCTTCAACGC-3',
circ9:4117768|4118881反向引物:5'-GAGTTAGAGACACTATTGCTGGAC-3';
13.10μM GAPDH特异性引物30ul
正向引物为5′-ATCATCAGCAATGCCTCCT-3′,
反向引物为5′-CATCACGCCACAGTTTCC-3′。
实施例2 circRNA circ9:4117768|4118881在胶质瘤组织的表达量与诊断的关系
1、组织中RNA的抽提:取适量标本于经180℃烘烤6-8h后的研钵中加入液氮研磨标本,研磨至粉末状后于研钵中加入1ml Trizol研钵标本,研磨成液体状后用移至tube管,加200μl氯仿于Tube中,用手震荡15-30s,冰上放置5min,4℃12000rpm离心15min;小心取上层水相入新tube中,加入预冷的异丙醇0.5ml混匀,-20℃冰箱静置20min,4℃12000rpm离心10min;弃上清,加入75%DEPC水稀释的乙醇1-2ml混匀,4℃7500rpm离心5min,尽量弃上清,室温干燥5-10min,加入DEPC水10-20μl溶解RNA。
2、circRNA circ9:4117768|4118881逆转录:使用Thermo公司的逆转录试剂盒。20μL逆转录反应的体系如下:
成分 | 剂量/管 |
随机逆转录引物(1μM) | 1μl |
RNA样本 | 2μg |
无酶水 | To12μl |
逆转录第一步条件:65℃5分钟
成分 | 剂量/管 |
5×逆转录缓冲液 | 4μl |
三磷酸碱基脱氧核苷酸(10mM) | 2μl |
RNA酶抑制剂(40U/μl) | 1μl |
MMLV逆转录酶(200U/μl) | 1μl |
第一步PCR的产物 | 12μl |
总体积 | 20μl |
逆转录第二步程序:25℃5分钟,42℃60分钟,70℃5分钟。
3、汉恒生物科技(上海)有限公司合成的circ9:4117768|4118881特异性引物进行实时定量PCR:先将逆转录产物稀释10倍,混匀。20μL反应体系如下:
PCR的特异性引物:
正向引物:5'-ATACAAGCCCTTCAACGC-3',
反向引物:5'-GAGTTAGAGACACTATTGCTGGAC-3'。
GAPDH内参特异性PCR引物:
正向引物为5′-ATCATCAGCAATGCCTCCT-3′,
反向引物为5′-CATCACGCCACAGTTTCC-3′。
实时荧光定量PCR反应程序:95℃3分钟,40个循环,95℃10秒,60℃30秒。
4、2-ΔΔCT指标的测定:本实验数据采用相对定量的分析方法,GAPDH作为内参基因,数据利用软件GraphPad Prism进行分析。结果表明circ RNA胶质瘤组织中
circ9:4117768|4118881表达水平比正常脑组织中表达水平下降(P=0.0003)。
5、胶质瘤组织与正常脑组织circ9:4117768|4118881表达水平对比的ROC曲线分析显示,circ9:4117768|4118881作为生物标记物对胶质瘤具有较高诊断价值(AUC=0.861,p=0.001,敏感度和特异度分别为75.0%和85.7%)。详细结果见图2。
序列表
<110> 中南大学湘雅医院
<120> 脑组织来源的circ9:4117768|4118881的应用
<160> 5
<170> SIPOSequenceListing 1.0
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<213> 智人(Homo sapiens)
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ggccucaagc augaagcagg agugguccca gggcuacagg gcccucccuu cgcucuccaa 120
ccacggcucu cagaauggcc uugaucuagg ggaucuccuu agccuuccuc ccgggacauc 180
cauguccagc aauagugucu cuaacucauu accauccuac cuuuuuggca cggaaaguag 240
ccacucuccu uacccuaguc cucggcacuc auccaccagg ucccacucgg cccgcuccaa 300
gaagagagcg cuguccuugu ccccgcuguc cgauggcauc gggauagauu ucaauaccau 360
cauccgcacg ucgcccacgu ccuugguggc cuacaucaac gggucgaggg cuucgccggc 420
caaccugucc ccgcagccgg aggucuacgg gcauuuccug ggcgugcgcg gcagcugcau 480
uccccagccg cgcccggugc ccggcagcca gaagggcgug cugguggccc cuggaggccu 540
ggcgcugccg gccuacggcg aggacggggc ccuggagcac gagcgcaugc aacagcugga 600
gcacggcggc cugcagccag gccuggucaa ccacauggug gugcagcaug gccugccggg 660
ccccgacagc cagucggccg gccuguucaa gaccgaacgc cuggaggagu ucccgggcag 720
caccguagac cuaccccccg cgccuccgcu cccuccucug ccgccgcccc caggcccccc 780
acccccuuac caugcccaug cgcaccuuca ccacccggag cucgggcccc acgcccagca 840
gcuggccuug ccccaggcca cccuggacga cgacggggag auggacggca ucgggggcaa 900
gcauugcugc cgcuggaucg acugcagcgc ccuguacgac cagcaggagg agcucgugcg 960
gcacaucgag aagguccaca ucgaccagcg caaaggggag gacuucacuu gcuucugggc 1020
cgguugcccu cgaagauaca agcccuucaa cgcccgcuau aaacugcuga uccacaugag 1080
aguccacucu ggggagaagc ccaacaagug uacg 1114
<210> 2
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<212> DNA
<213> 未知(Unknown)
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atacaagccc ttcaacgc 18
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<213> 未知(Unknown)
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gagttagaga cactattgct ggac 24
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atcatcagca atgcctcct 19
<210> 5
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<212> DNA
<213> 未知(Unknown)
<400> 5
catcacgcca cagtttcc 18
Claims (3)
1.检测脑组织中该circRNA circ9:4117768|4118881表达量的试剂在制备胶质瘤诊断制剂中的应用,该circRNA circ9:4117768|4118881的序列如SEQ NO:1所示。
2.根据权利要求1所述的应用,其特征在于,所述的检测脑组织中circ9:4117768|4118881表达量的试剂为实时荧光定量PCR检测试剂。
3.根据权利要求2所述的应用,其特征在于,所述的实时荧光定量PCR检测试剂包括进行实时荧光定量PCR的特异性引物,序列如SEQ NO:2和3所示。
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Cited By (1)
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CN111437391A (zh) * | 2020-05-29 | 2020-07-24 | 南通大学 | 敲降circHECTD1在制备治疗胶质瘤药物中的应用 |
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