CN107937532A - 胶质瘤诊断标志物hsa_circ_0021827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hsa_circ_0021827及应用。在本发明中，首次发现：胶质瘤患者血清外泌体中hsa_circ_0021827的表达水平相比于对照组明显升高(p＝0.025)，ROC分析则显示其对胶质瘤具有较高诊断价值(AUC＝0.823，p＝0.003，敏感度和特异度分别为70％和90.9％)。因此通过检测胶质瘤患者血清外泌体中hsa_circ_0021827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hsa_circ_0021827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。
环状RNA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环状RNA，且它们在所有剪接转录本中占了相当大的比例。近年来也逐渐发现外泌体中也含有大量的环状RNA，可能发挥重要作用。外泌体是指包含了复杂RNA和蛋白质的小膜泡(30-150nm)，现今，其特指直径在40-100nm的盘状囊泡。1983年，外泌体首次于绵羊网织红细胞中被发现，1987年Johnstone将其命名为“exosome”。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。外泌体中不仅包含蛋白质成分，还包括一些RNA成分，如微小RNA(microRNA,miRNA)、长链非编码RNA和mRNA、环状RNA(circular RNA,circRNA)。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hsa_circ_0021827，其序列如SEQ NO:1所示。
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hsa_circ_0021827的含量。
所述的胶质瘤诊断试剂盒，含有检测hsa_circ_0021827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hsa_circ_0021827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：hsa_circ_0021827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hsa_circ_0021827相比正常血清外泌体对照组显著上调(p＝0.025)。ROC曲线分析显示hsa_circ_0021827作为生物标记物对胶质瘤具有较高诊断价值(AUC＝0.823，p＝0.003，敏感度和特异度分别为70％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hsa_circ_0021827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hsa_circ_0021827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，15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200μl Trizol(MRC公司)使沉淀重悬，将悬液移至新的1.5ml tube管，补Trizol至1ml。冰上裂解15min，裂解结束后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20μl溶解RNA。-80℃保存。由实验员每天定时记录冰箱温度。
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(总RNA10μl，Random primer 1μl,无酶水1μl，5×Reaction Buffer 4μl，RI 1μl，RT 1μl和10mMdNTP 2μl)。
| 成分 | 剂量/管 |
| 随机逆转录引物(1μM) | 1μl |
| RNA样本 | 10μl |
| 无酶水 | To 12μl |
逆转录第一步条件：65℃5分钟
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
采用广州吉赛生物工程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 |
| 特异性引物(上下游均10μM) | 0.5μl |
| cDNA产物(稀释后) | 5μl |
| 无酶水 | To 20μl |
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hsa_circ_0021827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GraphPadPrism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hsa_circ_0021827相比正常血清外泌体对照组显著上调(p＝0.025)。具体数据如图1所示。ROC曲线分析显示hsa_circ_0021827作为生物标记物对胶质瘤具有较高诊断价值(AUC＝0.823，p＝0.003，敏感度和特异度分别为70％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 hsa_circ_0021827及应用
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Claims (6)
1.一种胶质瘤诊断标志物hsa_circ_0021827，其序列如SEQ NO:1所示。
2.检测权利要求1所述的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。
3.一种胶质瘤诊断试剂盒，其特征在于，能够测定血清外泌体中的hsa_circ_0021827的含量。
4.根据权利要求3所述的胶质瘤诊断试剂盒，其特征在于，含有检测hsa_circ_0021827含量的PCR引物。
5.根据权利要求4所述的胶质瘤诊断试剂盒，其特征在于，引物的序列如SEQ NO:2和3所示。
6.根据权利要求3或4或5所述的胶质瘤诊断试剂盒，其特征在于，除hsa_circ_0021827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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| CN114214411A (zh) * | 2021-12-27 | 2022-03-22 | 上海解颐生物科技有限公司 | 用于胶质瘤诊断circRNA标志物及胶质瘤诊断试剂盒 |
| CN114277031A (zh) * | 2022-01-25 | 2022-04-05 | 上海纽仁生物医药科技有限公司 | hsa_circ_0006420环状RNA及其在胶质瘤诊断、预后评估中的应用 |
| CN114921553A (zh) * | 2022-06-14 | 2022-08-19 | 中国医科大学附属第一医院 | 人脑胶质瘤标志物hsa_circ_0009362及其应用 |
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| CN114214411A (zh) * | 2021-12-27 | 2022-03-22 | 上海解颐生物科技有限公司 | 用于胶质瘤诊断circRNA标志物及胶质瘤诊断试剂盒 |
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| CN114921553A (zh) * | 2022-06-14 | 2022-08-19 | 中国医科大学附属第一医院 | 人脑胶质瘤标志物hsa_circ_0009362及其应用 |
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