CN111004850B - circRNAs分子在制备肝癌诊断试剂盒中的应用及应用该分子的试剂盒 - Google Patents
circRNAs分子在制备肝癌诊断试剂盒中的应用及应用该分子的试剂盒 Download PDFInfo
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Abstract
本发明涉及一种circRNAs分子检测试剂在制备肝癌诊断试剂盒中的应用，具体的说在于提供一种基于hsa_circ_0028185表达检测的肝癌诊断策略和应用。包括用于肝癌诊断的hsa_circ_0028185荧光定量PCR检测试剂盒。本发明检测试剂盒提供一种hsa_circ_0028185测诊断肝细胞肝癌的标准。本发明方法是通过检测血清中hsa_circ_0028185表达变化的情况，预警肝组织的癌变是否发生及肝癌的发生发展情况，为肝癌的确诊及预后、靶向肿瘤代谢的个体化治疗提供必要的依据。
Description
技术领域
本发明涉及一种circRNAs分子在试剂盒中的应用及试剂盒，特别涉及circRNAs分子在肝癌诊断试剂盒中的应用及试剂盒，属于生物医药领域。
背景技术
肝细胞肝癌是全世界范围内最常见的恶性肿瘤之一，发病率位列全世界第四位，且在世界范围内逐年上升；而死亡率位居各大恶性肿瘤的第三位。我国一直是肝细胞肝癌的高发区，每年新增患者数约占全球约55％。由于缺乏有效的筛查手段，导致60％-70％的肝癌患者诊断时已处于晚期，错失根治性切除机会。可见，早期诊断，早期治疗是增加肝癌患者生存率，降低肝癌死亡率最有效的途径。
血清学标志物的检测有助于肝细胞肝癌早期诊断、疗效观察及术后随访、复发或预后评估等。但肝细胞肝癌血清标志物众多，尚没有一个特异性、敏感性俱佳的理想指标。根据《原发性肝癌诊疗规范(2017年版)》，甲胎蛋白(AFP)是当前临床应用最广泛的肝细胞肝癌肿瘤标志物，但长期的临床实践表明，AFP灵敏度(40％～65％)和特异性(76％～96％)却不甚令人满意，仍存在约40％的漏诊率及一定的误诊率。尽管超声、CT、MRI等影像学检查方法可以作为AFP检测的补充，但由于检查费用昂贵，而且这些方法的检出率依赖于肿瘤大小及操作者的经验等因素，因而可能出现误诊、漏诊的情况。因此，发现新的高敏感性、高特异性，且低廉又易于检测的肝癌早期诊断标志物具有重要的临床意义。
环状RNA(circRNAs)是一类呈闭合环状结构，不具有5'末端帽子和3'末端尾巴的特殊内源性非编码RNA分子，主要由外显子转录产物组成，具有结构稳定、丰度高及组织特异性表达等特征。其主要功能除作为miRNA“海绵”，竞争性结合miRNA发挥转录后调控作用；还与细胞核内核糖核蛋白或RNA聚合酶II相互作用调控转录；或直接与转录因子结合，调控经典的RNA剪接；编码蛋白质等，并可通过多种作用方式参与基因表达调控。近年来的研究表明，异常表达的circRNAs分子参与了肿瘤的发生与发展过程。由于circRNAs具有高度保守性、组织特异性与阶段特异性的特点；同时，circRNAs闭合环状的特殊结构，可逃避核酸外切酶降解，使其在血液、体液中可稳定存在。因此，循环circRNA具有作为肿瘤等疾病无创性生物标志物的潜能，适用于高危人群筛查。
发明内容
本发明所要解决的技术问题是提供一种有效诊断肝癌的诊断标志物以及应用该标志物的诊断试剂盒。
为了解决上述问题，本发明提供了一种circRNAs分子检测试剂在制备肝癌诊断试剂盒中的应用，所述circRNAs分子为hsa_circ_0028185。hsa_circ_0028185为人体肝癌分子标志物。
所述肝癌诊断试剂盒以hsa_circ_0028185作为诊断标记物，所述肝癌诊断试剂盒是通过荧光定量PCR技术检测疑似肝癌患者外周静脉血中hsa_circ_0028185的水平，所述hsa_circ_0028185与肝癌呈正相关。
提出了一种用于实时荧光定量PCR检测肝癌细胞标志物的试剂盒，包含检测hsa_circ_0028185表达水平的试剂。
所述检测hsa_circ_0028185表达水平的试剂包含一对通过实时荧光定量PCR特异性扩增hsa_circ_0028185的引物，其引物序列为：
F:5’-GCAGAGTCCAAGAAGCAATAATC-3’
R:5’-CTCGTGCCAGTAGGTAGCCAT-3’。
本发明通过试验及结果分析发现，肝细胞肝癌患者血清中hsa_circ_0028185表达上调，提示hsa_circ_0028185是肝细胞肝癌中的高表达circRNAs。本发明中提供的试剂盒具有灵敏度高、特异性强、操作简单的特点，适合各类医院推广使用。
附图说明
图1血清circRNA芯片聚类分析肝细胞肝癌患者vs.健康体检者血清中差异表达的circRNAs，发现hsa_circ_0028185在肝细胞肝癌患者血清中呈高表达(n＝4)。
图2实时荧光定量PCR法检测hsa_circ_0028185及内参18s的熔解曲线。
图3与及健康对照者相比，肝细胞肝癌患者血血清hsa_circ_0028185表达水平升高(p＝0.005)。
具体实施方式
以下结合实施例对本发明进行进一步详细说明。
实施例1：血清circRNAs芯片表达分析。
一、材料和方法
1、在患者知情的情况下，采用含促凝剂和分离胶的真空采集管采集4例肝细胞肝癌患者和4例健康对照者各5ml外周静脉血，血样在室温(15-25℃)放置1小时处理后3,000r/min离心15min，吸取1ml血清，置于无菌EP管内，-80℃冻存备用。
2、采用Arraystar Human circRNA Microarray芯片检测血清circRNAs的表达。芯片检测交给上海康成生物有限公司完成，包括RNA提取和质量控制，样品使用荧光标记探针标记，探针与芯片杂交反应，芯片洗涤与结果扫描数据采集等步骤。使用Aglient FeatureExtraction v11.0软件获得芯片图谱及原始数据。最后使用Aglient GeneSpring GXv12.1对原始数据进行标准化，再筛选出高质量的探针，即保留在8个样本中均被标记的探针进行下一步分析，初步筛选出两组样本中差异表达circRNAs谱。
二、结果
关于血清circRNA芯片聚类分析见图1。芯片筛查发现在肝细胞肝癌患者vs.健康对照者血清中差异表达的circRNAs中，hsa_circ_0028185在肝细胞肝癌患者血清中呈显著高表达，鉴于其可能在肝细胞肝癌患者血清中存在特异性表达，本发明通过以下实施例采用大规模样本进行该指标的重复验证。
实施例2：qRT-PCR验证hsa_circ_0028185在肝细胞肝癌患者和健康对照者血清中的差异表达。
一、材料和方法
1、在患者知情的情况下，采用含促凝剂和分离胶的真空采集管采集50例肝细胞肝癌患者、30例良性肝病对照者和35例健康对照者各5ml外周静脉血，血样在室温(15-25℃)放置1小时处理后3,000r/min离心15min，吸取1ml血清，置于无菌EP管内，-80℃冻存备用。
2、引物设计：从Ensemble数据库提取hsa_circ_0028185相关的转录本序列，并用根据转录本的序列通过NCBI的引物设计工具(Primer BLAST)设计引物；
F:5’-GCAGAGTCCAAGAAGCAATAATC-3’
R:5’-CTCGTGCCAGTAGGTAGCCAT-3’。
3、血清总RNA的提取：按北京BioTake有限公司的血清总RNA提取试剂盒说明书提取样本中血清总RNA。使用德国Nanodrop 1000紫外可见分光光度计测定所提取的RNA浓度和纯度。
4、逆转录合成cDNA：使用High-Capacity cDNA逆转录试剂盒(Invitrogen)进行RNA逆转，20μl反应体系由2μl 10×RT Buffer，0.8μl 25×dNTP Mix(100mM)，2μl 10×RTRandom Primers，1μl MultiScribe Reverse Transcriptase，2000ng RNA和DEPC水(补足到20μl)组成。反应体系的配置均在冰上进行，反应体系混合均匀后进行反转录程序，包括退火、延伸、逆转录酶失活三步(退火25℃10min，延伸40℃80min，失活72℃10min，4℃保存。所得cDNA产物于-20℃冻存备用。
5、实时荧光定量PCR：采用SYBR GREEN(Applied Biological Materials Inc)法进行实时荧光定量PCR。内参为18s，内参上游引物：GTAACCCGTTGAACCCCATT，内参下游引物：CCATCCAATCGGTAGTAGCG。引物由上海英骏生物有限公司合成。10μl实时荧光定量PCR反应体系由5μl SYBR GREEN Mix，2.4μl Nuclease-Free水，上游引物(10μM)0.3μl，下游引物(10μM)0.3μl和2μl cDNA模板组成。使用ABI 7500Real-Time PCR System进行PCR扩增。扩增程序为：95℃30sec；95℃5sec，60℃30sec(第二三步循环40次)，最后添加溶解曲线：95℃15sec；60℃1min；95℃15sec(观察扩增产物特异性)。每个样品均采用三平行检测，取平均值。荧光定量PCR结果用2-△△CT法进行分析各实验组表达差异。
6、用SPSS19.0、Graphpad Prism 6进行数据统计分析及绘图。结果见图3。相比健康对照，肝细胞肝癌患者血清中hsa_circ_0028185呈高表达(p＝0.005)；相比良性肝病，肝细胞肝癌患者血清中hsa_circ_0028185也呈高表达(p＝0.016)；而良性肝病对照者组和健康对照者组之间无统计学差异(p＝0.220)。
由于circRNAs闭合环状的特殊结构，可逃避核酸外切酶降解，使其在血液、体液中可稳定存在。肝细胞肝癌患者血清中hsa_circ_0028185呈显著高表达。因此，本发明为辅助诊断肝癌提供了一种准确性高、非侵入性的方法，具有重要的科学意义、临床意义和应用价值。
Claims (3)
1.circRNAs分子检测试剂在制备肝癌诊断试剂盒中的应用，其特征在于：所述circRNAs分子为hsa_circ_0028185。
2.如权利要求1所述的circRNAs分子检测试剂在制备肝癌诊断试剂盒中的应用，其特征在于：所述肝癌诊断试剂盒以hsa_circ_0028185作为诊断标记物，所述肝癌诊断试剂盒是通过荧光定量PCR技术检测疑似肝癌患者外周静脉血中hsa_circ_0028185的水平，所述hsa_circ_0028185与肝癌呈正相关。
3.如权利要求1所述的circRNAs分子检测试剂在制备肝癌诊断试剂盒中的应用，其特征在于：所述检测hsa_circ_0028185表达水平的试剂包含一对通过实时荧光定量PCR特异性扩增hsa_circ_0028185的引物，其引物序列为：
F:5’-GCAGAGTCCAAGAAGCAATAATC-3’
R:5’-CTCGTGCCAGTAGGTAGCCAT-3’。
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| AU2020100457A AU2020100457A4 (en) | 2019-12-31 | 2020-03-25 | USE OF circRNA IN PREPARATION OF DIAGNOSTIC KIT FOR HEPATOCELLULAR CARCINOMA AND KIT USING circRNA |
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| CN111549138A (zh) * | 2020-05-22 | 2020-08-18 | 中山大学孙逸仙纪念医院 | 一种基于CD90posi细胞检测肿瘤的试剂盒 |
| CN111778334A (zh) * | 2020-07-13 | 2020-10-16 | 中山大学孙逸仙纪念医院 | 一种CircRNA作为肝癌肿瘤标志物的评价方法 |
| CN113943798B (zh) * | 2020-07-16 | 2023-10-27 | 中国农业大学 | 一种circ RNA作为肝细胞癌诊断标志物及治疗靶点的应用 |
| CN112063715B (zh) * | 2020-09-07 | 2021-09-14 | 清华大学 | 一种用于肝细胞癌早期筛查的系统 |
| CN112501292B (zh) * | 2020-11-09 | 2022-12-02 | 中国人民解放军海军军医大学 | cFAM210A在制备肝癌诊断或术后预测试剂盒以及药物中的应用 |
| CN112695074A (zh) * | 2020-12-25 | 2021-04-23 | 东莞市寮步医院 | 血清中环状circZKSCAN1基因的非诊断性荧光定量检测方法 |
| CN115725736B (zh) * | 2022-08-12 | 2025-10-17 | 上海卡序生物医药科技有限公司 | 一种诊断和治疗肝癌的circRNA标志物及其应用 |
| CN116064780B (zh) * | 2023-01-19 | 2023-09-26 | 中山大学附属第三医院 | 相关生物标记物在肝硬化心肌病中的应用 |
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