CN107937539A - 胶质瘤预后标志物hsa_circ_0135404及应用 - Google Patents
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Abstract
本发明公开了一种胶质瘤预后标志物hsa_circ_0135404及应用，即检测胶质瘤来源的circRNA hsa_circ_0135404的试剂用于制备胶质瘤患者的预后制剂。通过研究证实胶质瘤中circRNA hsa_circ_0135404表达量较高的患者，拥有更高的术后生存率。通过检测胶质瘤患者胶质瘤组织中circRNA hsa_circ_0135404的表达水平，从而对胶质瘤患者做出预后判断。
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预后的circRNA标志物、以及检测该标志物的试剂用于制备胶质瘤预后制剂的应用、还有试剂盒。
背景技术
胶质瘤是最常见的中枢神经系统的恶性肿瘤,具有较强的侵袭性和进展性。目前临床治疗上采用的主要方法有手术切除、放疗及化疗的综合疗法,但由于胶质瘤的生长特性,与周围脑组织界限不清,手术难以切除完全,而放疗、化疗由于胶质瘤对其耐受性等治疗的局限性,疗效有限,患者中位生存期较短,尤其对于高级别胶质瘤,治疗后复发率较高,预后差,中位生存期不足一年,病死率高,严重威胁患者生命影响人类健康。因此，寻找胶质瘤预后标志物对患者进行预后分析，以提高胶质瘤患者的术后生活质量，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，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。
发明内容
本发明的第一个目的是：提供一种用于胶质瘤患者预后的胶质瘤组织来源的circRNA标志物hsa_circ_0135404，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标志物在胶质瘤组织中表达量的试剂在制备胶质瘤预后制剂中的应用。
本发明的第三个目的是，提供一种胶质瘤预后试剂盒，能够测定胶质瘤组织中的hsa_circ_0135404的含量。
所述的胶质瘤预后试剂盒，含有检测hsa_circ_0135404含量的PCR引物。优选引物的序列如SEQ NO:2和3所示。
所述的胶质瘤预后试剂盒，除hsa_circ_0135404的引物外，还含有从胶质瘤组织中提取RNA并进行逆转录及荧光定量PCR的所有试剂。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hsa_circ_0135404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hsa_circ_0135404所用随机引物；
(3)将cDNA实时定量PCR所用试剂，包括circRNA hsa_circ_0135404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。
申请人通过荧光定量PCR与生存曲线分析发现在22例胶质瘤患者中，胶质瘤组织来源的circRNA hsa_circ_0135404与患者的生存率相关，含量越高，生存率越高。此法为胶质瘤的预后分析提供了强有力的技术支持，有助于提高胶质瘤患者的术后生活质量，制订术后治疗方案，提高生存率，具有深远的临床意义和推广性。
附图说明
图1为实时荧光定量PCR分析hsa_circ_0135404在正常脑组织与胶质瘤中的表达差异；
图2为生存曲线分析胶质瘤组织来源的hsa_circ_0135404表达高低对胶质瘤患者的预后影响。
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circRNA hsa_circ_0135404表达量的试剂用于制备胶质瘤患者预后的试剂盒(50次反应)
1.RNA稳定溶液 50ml
2.异丙醇 100ml
3.三氯甲烷 100ml
4.Trizol 50ml
5.无酶水 10ml
6.1μM随机逆转录引物 50μl
7.5×逆转录缓冲液 200ml
8.10mM三磷酸碱基脱氧核苷酸 100μl
9.40U/μl RNA酶抑制剂 500μl
10.200U/μl MMLV逆转录酶 50μl
11.Premix Ex Taq 50μl
12.10μM circRNA hsa_circ_0135404实时荧光定量PCR特异性引物 30μl
circRNA hsa_circ_0135404正向引物：5'-TTGTGGAGGTCGAGTGTCAT-3'，
circRNA hsa_circ_0135404反向引物：5'-ATGGCCACATCCATCAGCAA-3'；
13.10μM GAPDH特异性引物30μl
正向引物为5’-ATCATCAGCAATGCCTCCT-3’，
反向引物为5’-CATCACGCCACAGTTTCC-3’。
实施例2：组织样本circRNA hsa_circ_0135404的检测
1、收集待测胶质瘤组织放入盛有RNA稳定溶液的冻存管中，放至-80℃冰箱备用。
2、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，研磨成液体状后移至tube管，于冰上静止裂解15分钟。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。-80℃保存。由实验员每天记录冰箱温度。
3、circRNA hsa_circ_0135404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 | 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。
4、广州吉赛生物工程有限公司的hsa_circ_0135404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：
qRT-PCR的特异性引物：
正向引物：5'-TTGTGGAGGTCGAGTGTCAT-3'，
反向引物：5'-ATGGCCACATCCATCAGCAA-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。
5、2-ΔΔCT指标的测定：本实验数据采用30例胶质瘤患者和12例正常人脑组织，以及采用相对定量的分析方法，GAPDH作为内参基因，将qRT-PCR测得的circRNA hsa_circ_0135404CT值与同组织来源的GAPDH的CT值作差得到ΔCT，再将ΔCT与ΔCT对照作差得到ΔΔCT(取正常样本ΔCT的平均值为ΔCT对照)，数据利用软件GraphPad Prism进行Welch检验分析。分析发现，胶质瘤组织中circRNA hsa_circ_0135404与正常脑组织的circRNA hsa_circ_0135404表达量具有差异(见图1)，差异有显著性(P＝0.0011)。
6、通过对实验所采用的30例胶质瘤患者随访统计资料发现，8例患者在随访时由于手机停机或者换号或者其他原因联系不上，最后能联系上的胶质瘤患者或家属为22例，这22例患者或家属接受后续的随访分析。我们详细询问了这些患者或家属首次发病的时间，治疗情况，复发状况及死亡时间等，随访时间为1-42个月。在所选取的胶质瘤患者中，选取荧光定量PCR分析的表达值为参考标准，所得结果降序排列后高于中位数的为hsa_circ_0135404高表达，共15例，接受随访为11例，其他为hsa_circ_0135404低表达，共15例，接受随访为11例。经Kaplan-Meier生存分析，hsa_circ_0135404高表达患者的生存期较hsa_circ_0135404低表达的患者长，预后好。差异有统计学意义(P＝0.018)，见图2。
7、以上研究表明，CircRNA hsa_circ_0135404可作为胶质瘤患者预后的特异性分子标志物。
序列表
<110> 中南大学湘雅医院
<120> 胶质瘤预后标志物 hsa_circ_0135404及应用
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Claims (6)
1.一种胶质瘤预后标志物hsa_circ_0135404，其序列如SEQ NO:1所示。
2.检测权利要求1所述的标志物在胶质瘤组织中表达量的试剂在制备胶质瘤预后制剂中的应用。
3.一种胶质瘤预后试剂盒，其特征在于，能够测定胶质瘤组织中的hsa_circ_0135404的含量。
4.根据权利要求3所述的胶质瘤预后试剂盒，其特征在于，含有检测hsa_circ_0135404含量的PCR引物。
5.根据权利要求4所述的胶质瘤预后试剂盒，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所述的胶质瘤预后试剂盒，其特征在于，除hsa_circ_0135404的引物外，还含有从胶质瘤组织中提取RNA并进行逆转录及荧光定量PCR的所有试剂。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009102729A1 (en) * | 2008-02-11 | 2009-08-20 | Historx, Inc. | Association of biomarkers with patient outcome |
| WO2009106065A2 (de) * | 2008-02-29 | 2009-09-03 | Meyer Helmut E | Biomarker für die diagnose von hirntumor |
| WO2015035146A2 (en) * | 2013-09-05 | 2015-03-12 | Memorial Sloan-Kettering Cancer Center | Ddx43 as a biomarker of resistance to mek1/2 inhibitors |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009102729A1 (en) * | 2008-02-11 | 2009-08-20 | Historx, Inc. | Association of biomarkers with patient outcome |
| WO2009106065A2 (de) * | 2008-02-29 | 2009-09-03 | Meyer Helmut E | Biomarker für die diagnose von hirntumor |
| WO2015035146A2 (en) * | 2013-09-05 | 2015-03-12 | Memorial Sloan-Kettering Cancer Center | Ddx43 as a biomarker of resistance to mek1/2 inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| RYBAK-WOLF A.等: "Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed", 《MOLECULAR CELL》 * |
| WU S.等: "A novel integrated gene coexpression analysis approach reveals a prognostic three-transcription-factor signature for glioma molecular subtypes", 《BMC SYSTEMS BIOLOGY》 * |
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