CN107937531B - 胶质瘤诊断标志物circ7:73686636|73687095及应用 - Google Patents
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Abstract
本发明属于生物技术领域,公开了胶质瘤诊断标志物circ7:73686636|73687095及应用。在本发明中,首次发现胶质瘤患者血清外泌体中circ7:73686636|73687095的表达水平相比于对照组明显升高(p=0.0012),ROC分析则显示其对胶质瘤具有较高诊断价值(AUC=0.872,P=0.001,灵敏度和特异性分别为76.5%和90.9%)。因此通过检测胶质瘤患者血清外泌体中circ7:73686636|73687095的表达水平,可对胶质瘤患者做出早期、快速的无创性诊断。
Description
技术领域
本发明属于生物技术领域,涉及一种用于胶质瘤诊断的血清circRNA标志物circ7:73686636|73687095、以及检测该标志物的试剂用于制备胶质瘤诊断制剂的应用、还有试剂盒。
背景技术
脑胶质瘤是中枢神经系统最常见的恶性肿瘤,是中枢神经系统的主要疾病之一,居颅内原发性肿瘤发病率的首位。由于其高侵袭性、高复发率的特点使得胶质瘤治愈率低,患者生存期短。神经影像学技术和显微外科技术的不断进展对神经外科的发展起了巨大的促进作用,而分子生物学研究的不断深入为肿瘤的基因治疗提供了广阔前景然而对脑胶质瘤的患者生存率并没有明显提高。因此,寻找胶质瘤诊断标志物对高危人群进行筛查,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。近年来逐渐发现外泌体中也含有大量的circRNA,可能发挥重要作用。目前,由于circRNA具有丰富性、稳定性、高保守性和时空特异性等特点,在肿瘤诊断标志物方面正发挥越来越大的作用。近年研究显示,外泌体是细胞与细胞间通讯的重要的分子,参与诸多生理与病理过程。外泌体所携带的这些RNA统称为外泌体来源RNA,具有完整的序列结构和生物活性,有望作为液体活检分子标志物,在精准医学发展上有着光明的前景。
发明内容
本发明的第一个目的是:提供一种用于胶质瘤诊断的血清外泌体circRNA标志物。
主要内容包括:一种用于胶质瘤诊断的血清外泌体circRNA标志物circ7:73686636|73687095,其序列如SEQ NO:1所示。该circRNA位于人类的第7号染色体上,全长460bp。
本发明的第二个目的是,提供检测所述的circRNA标志物在血清外泌体中表达量的试剂在制备胶质瘤诊断制剂中的应用。
本发明的第三个目的是,提供一种胶质瘤诊断试剂盒,其能够测定血清外泌体中的circ7:73686636|73687095的含量。
所述的胶质瘤诊断试剂盒,含有检测circ7:73686636|73687095含量的PCR引物。优选引物的序列如SEQ NO:2和3所示。
所述的胶质瘤诊断试剂盒,除circ7:73686636|73687095的引物外,还含有从血清中提取外泌体、由外泌体中提取RNA并进行逆转录及荧光定量PCR的所有试剂。
包括:
(1)提取血清外泌体所需试剂:Total Exosome Isolation Reagent(fromserum),可由Invitrogen公司购得,货号4478360;
(2)提取外泌体RNA所需试剂:Trizol试剂、三氯甲烷、异丙醇、75%乙醇、无酶水;
(3)逆转录所需试剂:随机引物(Random Primer)、无酶水、5×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;
(4)荧光定量PCR所需试剂:circ7:73686636|73687095上下游引物、GAPDH内参上下游引物、SYBR染料、无酶水。
本发明的有益效果在于:
首次发现胶质瘤患者的血清外泌体中circ7:73686636|73687095相比正常血清外泌体对照组显著上调(p=0.0012)。ROC曲线分析显示circ7:73686636|73687095作为生物标记物对胶质瘤具有较高诊断价值(AUC=0.872,灵敏性和特异性分别为76.5%和90.9%)。通过该环状RNA在胶质瘤诊断分析中的应用,可以使得胶质瘤的诊断更加方便准确,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circ7:73686636|73687095在胶质瘤血清与正常血清外泌体中的表达差异;
图2为ROC分析血清外泌体来源的circ7:73686636|73687095对胶质瘤早期诊断的特异性,灵敏性。
具体实施方式
以下结合实施方式旨在进一步说明本发明,而非限制本发明。
一、研究对象
40例胶质瘤患者的血清样本由湘雅医院提供,19例正常血清样本为同期进行社区疾病筛查的健康个体。用于研究的样本为同期收取,采样、分装、保存条件均一致。
二、研究方法
1.胶质瘤/正常血清外泌体中RNA的抽提
取血清200μl于2000g常温离心30分钟,用微量移液器抽取上层清液至新的600μl离心管,加入40μl外泌体提取试剂(Total Exosome Isolation Reagent(from serum),货号4478360,Invitrogen公司)轻轻上下颠倒摇匀,4℃孵育45分钟。孵育结束后10000g常温离心10分钟,弃掉上清液,所得沉淀即为血清中的外泌体。于沉淀中加入200μlTrizol(MRC公司)使沉淀重悬,将悬液移至新的1.5mltube管,补Trizol至1ml。冰上裂解15min。裂解结束后移至1.5ml无酶Tube管,4℃,12000rpm离心10min,上清液移至新的tube管。加氯仿200μl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,冰上静置大于20min,4℃,12000rpm离心10min;弃上清,加入75%DEPC水稀释的乙醇1ml混匀,4℃,7500rpm离心5min,尽量弃上清,室温干燥5-10min,加入无酶水10μl溶解RNA。-80℃保存。
2.cDNA制备
按照逆转录试剂盒(Thermo公司)说明书进行逆转录反应。反应总体积为20μl
成分 | 剂量/管 |
随机逆转录引物(1μM) | 1μl |
RNA样本 | 10μl |
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 |
第一步逆转录的产物 | 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.实时荧光定量PCR
采用汉恒生物科技(上海)有限公司合成的特异性引物(引物序列见SEQ NO:2和3)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:
成分 | 剂量/管 |
SYBR Premix Ex Taq | 10μl |
引物(上下游均为10μM) | 0.5μl |
cDNA产物(稀释后) | 5μl |
无酶水 | To20μl |
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.数据分析:采用2-ΔΔCT表示胶质瘤血清外泌体的circ7:73686636|73687095相对于正常血清外泌体的表达倍数,其中△CT=CT样本–CT内参,ΔΔCT=ΔCT胶质瘤–ΔCT正常。本实验数据采用相对定量的分析方法,GAPDH作为内参基因(引物序列见SEQ NO:4和5),数据利用软件GraphPad Prism及SPSS 17.0进行分析。
三、研究结果
胶质瘤患者的血清外泌体中circ7:73686636|73687095相比正常血清外泌体对照组显著上调(p=0.0012)。具体数据如图1所示。ROC曲线分析显示circ7:73686636|73687095作为生物标记物对胶质瘤具有较高诊断价值(AUC=0.872,灵敏性和特异性分别为76.5%和90.9%),详细结果见图2。
序列表
<110> 中南大学湘雅医院
<120> 胶质瘤诊断标志物circ7:73686636|73687095及应用
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<170> SIPOSequenceListing 1.0
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<213> 智人(Homo sapiens)
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Claims (4)
1.检测circ7:73686636|73687095在血清外泌体中表达量的试剂在制备胶质瘤诊断制剂中的应用,circ7:73686636|73687095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circ7:73686636|73687095在血清外泌体中表达量的试剂含有检测circ7:73686636|73687095含量的PCR引物。
3.根据权利要求2所述的应用,其特征在于,引物的序列如SEQ NO:2和3所示。
4.根据权利要求1或2或3所述的应用,其特征在于,所述的检测circ7:73686636|73687095在血清外泌体中表达量的试剂,除circ7:73686636|73687095的引物外,还含有从血清中提取外泌体、由外泌体中提取RNA并进行逆转录及荧光定量PCR的所有试剂。
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Circular RNAs are abundant,conserved and associated with ALU repeats;Jeck WR et al.;《RNA》;20131231;第19卷(第2期);第141-157页 * |
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