CN111206101A - circRRM2B基因作为新靶点在筛选维罗非尼耐药的黑色素瘤治疗药物中的应用 - Google Patents

circRRM2B基因作为新靶点在筛选维罗非尼耐药的黑色素瘤治疗药物中的应用 Download PDF

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CN111206101A
CN111206101A CN202010168534.0A CN202010168534A CN111206101A CN 111206101 A CN111206101 A CN 111206101A CN 202010168534 A CN202010168534 A CN 202010168534A CN 111206101 A CN111206101 A CN 111206101A
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程琼
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Abstract

本发明提供了circRRM2B基因作为新靶点在筛选维罗非尼耐药的黑色素瘤治疗药物中的应用。所述药物以circRRM2B基因为靶点，抑制或者沉默circRRM2B基因的表达。本发明还提供了抑制或沉默circRRM2B基因表达的试剂在制备用于抑制黑色素瘤药物中的应用。本发明通过芯片筛选，发现了circRRM2B与黑色素瘤维罗非尼耐药相关，是筛选维罗非尼耐药的黑色素瘤治疗药物的新靶点，对于筛选新的药物具有积极的意义。同时，新靶点的发现将为耐药黑色素瘤的治疗提供了一种新思路。

Description

circRRM2B基因作为新靶点在筛选维罗非尼耐药的黑色素瘤 治疗药物中的应用
技术领域
本发明属于生物工程领域，涉及黑色素瘤，具体来说是以circRRM2B基因作为靶点在筛选用于抑制黑色素瘤药物中的应用。
背景技术
1.1维罗非尼耐药是黑色素瘤治疗中的难题
黑色素瘤是一种黑色素细胞来源的恶性肿瘤，传统治疗效果差、死亡率高。约40-60％黑色素瘤患者携带BRAFV600E突变，这个位点突变能激活MEK-ERK通路，促进肿瘤细胞不断分裂、增殖。针对BRAFV600E突变的靶向药物维罗非尼(Vemurafenib PLX4032)可以明显延长患者无进展生存和总生存率。然而临床发现维罗非尼治疗1年内几乎所有的患者都会出现耐药。主要的获得性耐药机制包括：MEK-ERK通路再活化(BRAFV600E基因表达上调，NRAS或MEK等多个点突变的产生)、RTK或PI3K-AKT通路代偿激活和肿瘤微环境改变等。采用BRAF抑制剂联合用药方案，包括联合MEK抑制剂、PI3K抑制剂等可以降低耐药性，然而多种药物联合应用价格昂贵，且研究发现联合应用亦会通过激活代偿通路，再次产生耐药。因此深入研究黑色素瘤维罗非尼的耐药机理，寻找新的耐药靶点，对减少黑色素瘤维罗非尼耐药具有重要的现实意义。
1.2外泌体介导的circRNA转运是肿瘤耐药的新机制
外泌体是一类由细胞分泌的膜性囊泡，直径约40-100nm，内含蛋白质、脂质、非编码RNA等物质，是细胞间通讯的重要介质。非编码RNA是指不编码蛋白质的RNA，包括LncRNA、miRNA和circRNA等。circRNA是一种新型的非编码RNA。它们通过共价键形成闭合环，结构稳定，难以被RNA酶降解，在外泌体中表达十分丰富。近年来一些学者发现外泌体通过将circRNA转移到受体细胞，调控相应基因表达，参与肿瘤耐药。越来越多的研究也支持circRNA在细胞耐药方面显示出强大的生物学功能是肿瘤耐药的新靶点。
1.3 circRRM2B--黑色素瘤维罗非尼耐药的新靶点
circRRM2B是我们通过芯片筛选到的环状RNA。circRRM2B的circbase ID：hsa_circ_0003794，基因长度973bp,位于人类的第8条染色体上。序列为：caaaagtagattttctatctgctatccatcgcaaggcccaatctgcttttttcttaacatagggcatggtttcaattgcattaaataaaaattccctgtaaaaacaaaagaatgaacagcaaagttattcacttgtttttctttttttttttttgagacagagtctcgctctgttgcccaggctggagtgcagtggcacgatctcggctcactgcaagctccacctcccgggttcatgccattctcctgcctcagcctcccgagtagctaggacgacaggtgcccgccaccacgcccggctagtatttttagtagagacgtggtttcactgtgttagccaggatggtctcaatctcctgacctcgtgatccacctgcttcggcctcccaaggtgctgggattacagccatgagccaccatgccttggcctcacttgtttttcttaattggactaaacttaatcagagataataattgtaactctacggtatgctaccagatctgtagtttttatacatttttacatgtccatagaacagaaataaaactcaaattattggtttgaatctggtctcatacaaaaccagctaaatttgagtattcaatttctaaacagaagatgctactgaacagttcttaaagataaaatatctaaaggttaactggttctataacaagttttttttaaaacccaatacattattaagcaatagaaaatattatgctcagaaacttccatacttgaataatctttccttaacattgagttttggaataaattctgatctgaacataaccaagccgtaagcaatattttgtaaataaaatcccaacaataccttttcttgggatctctgatgtaagtgtctatcagcaaactgtacatctctgagtgaacattctcgatgagaatttgaaagccatagaaacagcgagcctctggaacctgcacctcctgactaaagcgctccac。由于circRNA的研究处在起步阶段，目前尚没有circRRM2B生物学功能的研究报道。而circRNA和其对应的线性基因有一定关联，因此circRNA可能具有和线性基因相关的功能。查circbase发现circRRM2B(hsa_circ_0003794)对应的线性基因是RRM2B。RRM2B基因又被称为P53R2，是黑素瘤的预后因子，沉默P53R2可以增强黑色素瘤细胞对尼莫司汀的敏感性。我们在实验中使用黑色素瘤细胞株(维罗非尼耐药株和敏感株)：耐药株来源的外泌体和敏感株共培养,增加了敏感株对药物的抗性。随后采用circRNA芯片筛选耐药株和敏感株外泌体中表达差异最显著的10个环状RNA，qRT-PCR验证发现circRRM2B在耐药株及其外泌体中表达明显增高。耐药株分泌的外泌体和敏感株共培养后敏感株中circRRM2B的表达也明显升高。说明circRRM2B被包裹在外泌体中，通过囊泡传递到敏感株，增加了细胞的耐药表型。而在耐药株中抑制circRRM2B的表达可以增加耐药株对维罗非尼的敏感性。这提示circRRM2B基因可以作为黑色素瘤维罗非尼耐药治疗的新靶点。
发明内容
针对现有技术中的上述技术问题，本发明提供了circRRM2B基因作为靶点在筛选用于抑制黑色素瘤的药物中的应用，所述的这种应用解决了现有技术中黑色素瘤维罗非尼耐药的技术问题。
本发明提供了circRRM2B基因作为靶点在筛选用于抑制黑色素瘤药物中的应用，所述药物以circRRM2B基因为靶点，抑制或者沉默circRRM2B基因的表达。
本发明还提供了抑制或沉默circRRM2B基因表达的试剂在制备用于抑制黑色素瘤药物中的应用。
circRRM2B(hsa_circ_0003794)是我们通过circRNA芯片筛选到的。在pubmed上尚未查到其生物学功能的研究报道。我们通过实验发现：在黑色素瘤维罗非尼耐药的细胞株中，抑制circRRM2B表达可以增加耐药株对药物的敏感性；而在敏感株中增加circRRM2B表达可以增强细胞的抗药性。故提示circRRM2B基因可以作为黑色素瘤维罗非尼耐药治疗的新靶点。
本发明和已有技术相比，其技术进步是显著的。现有的解决黑色素瘤维罗非尼耐药方案为多种靶向药物联合应用。对人体毒副作用大，且价格昂贵。本发明通过芯片筛选，发现了circRRM2B与黑色素瘤维罗非尼耐药相关，是筛选用于抑制黑色素瘤的药物的新靶点，对于筛选新的药物具有积极的意义。同时，新的靶点的发现将为耐药黑色素瘤的治疗提供了一种新的思路。
附图说明
图1:各组黑色素瘤细胞株对维罗非尼(PLX)的IC50图。黑色素瘤细胞株共分三组：敏感株(A375S)+PBS、敏感株+耐药株(A375R)来源的外泌体(Exo)、敏感株+敏感株来源的外泌体。各组细胞培养48小时后检测细胞对PLX的IC50值。A375S+PBS组IC50值为27.4nM；A375S+A375RExo组IC50值为982.2nM；A375S+A375SExo组IC50值为30.9nM。
图2:circRNA芯片筛选出敏感株和耐药株外泌体中10个差异表达最明显的circRNA。circRNA芯片检测由康成生物公司完成，检测六个样本。A.散点图显示检测组和对照组之间circRNA差异表达情况。B.火山图显示检测组和对照组之间circRNA差异表达情况。C.层次聚类图分析样本间差异表达的circRNA。每列代表样品表达谱，每行代表circRNA。红色代表上调，绿色代表下调。
图3:A.PCR图，用qRT-PCR技术检测circRRM2B在耐药株、敏感株、耐药株外泌体和敏感株外泌体中的表达。B.PCR图，用qRT-PCR技术检测circRRM2B在：敏感株+PBS、敏感株+耐药株外泌体、敏感株+敏感株外泌体中的表达。
图4:A.耐药株+阴性对照组培养48h后PLX5uM治疗，用流式细胞仪检测细胞周期和凋亡。细胞凋亡率为6.17％。G1期:44.52％,G2期:28.22％,S期:27.25％。B.耐药株+si-circRRM2B培养48h后PLX5uM治疗，用流式细胞仪检测细胞周期和凋亡。细胞凋亡率为32.23％。G1期:48.74％,G2期:16.28％,S期:34.98％。
具体实施方式
实施例1耐药株来源的外泌体和敏感株共培养，可以增加敏感株对维罗非尼的抗性。
1-1)培养多株黑色素瘤细胞,维罗非尼治疗后测IC50值,选取敏感株(A375S)。使用药物浓度递增法建立相应的耐药株(A375R)。
1-2)培养耐药株和敏感株，收集细胞上清液，110000×g离心2小时，除去上清液，PBS重悬沉淀。4℃，110000×g，离心70分钟。PBS重悬沉淀，4℃，110000×g离心70分钟(2次)，所获得沉淀重悬于PBS中，置-80℃保存。透射电镜观察外泌体形态。WB检测外泌体标志蛋白CD63、CD81。
1-3)敏感株分别与PBS、耐药株和敏感株来源的外泌体共培养48小时后检测细胞对维罗非尼的IC50值。
由图1可知：(耐药株来源的外泌体+敏感株)组的IC50值明显高于其他两组，提示细胞抗药性增强。
实施例2 circRNA芯片筛选出敏感株和耐药株外泌体中10个差异表达最明显的circRNA。
2-1)用Rnase R酶消化外泌体中总RNA，去除线性RNA，富集环状RNA。然后，利用随机引物法将标记的cRNA杂交到Arraystar Human circRNA Array V2(8x15K,Arraystar)上，65℃孵育17小时后洗涤芯片，用安捷伦G2505C扫描仪对阵列进行扫描。
2-2)使用Agilent Feature Extraction软件(version 11.0.1.1)对采集到的阵列图像进行分析。分位数归一化和后续数据处理使用R软件limma软件包进行。通过火山图筛选，鉴定两组间具有统计学意义的差异表达环状RNA。通过Fold Change filtering方法识别两个样本间差异表达的circRNA。采用层次聚类的方法，以显示样本间可区分的环状RNA表达模式。
由图2可知：根据FC值、p值等对差异表达的circRNA进行排序，我们选出差异最显著上升的10个circRNA。
circRNA Alias chrom GeneSymbol P-value FDR FC(abs) Regulation
hsa_circRNA_003794 hsa_circ_0003794 chr8 RRM2B 0.001051838 0.016073795 3.5065421 up
hsa_circRNA_082734 hsa_circ_0082734 chr7 NDUFB2 0.00498906 0.028860029 3.3808616 up
hsa_circRNA_089763 hsa_circ-0089763 chrM JA760600 0.004665964 0.02795357 3.0434903 up
hsa_circRNA_062143 hsa_circ-0062142 chr22 TPTEP1 0.009091084 0.037327505 2.90309 up
hsa_circRNA_007326 hsa_circ_0007326 chr14 CHMP4A 0.00142106 0.017853648 2.7200441 up
hsa_circRNA_089762 hsa_circ_0089762 chrM JA760602 0.000124927 0.012258661 2.5494241 up
hsa_circRNA_401262 chr14 PSMA3 0.00016464 0.012258661 2.5159626 up
hsa_circRNA_104484 hsa_circ_0082326 chr7 ZC3HC1 0.001620805 0.018710872 2.4930128 up
hsa_circRNA_044684 hsa_circ_0044684 chr17 TOM1L1 0.000101561 0.012258661 2.426205 up
hsa_circRNA_034093 hsa_circ_0034093 chr15 NIPA1 0.004072106 0.026320349 2.3932829 up
实施例3 qRT-PCR验证发现circRRM2B在耐药株及其外泌体中表达明显增高。耐药株分泌的外泌体和敏感株共培养后敏感株中circRRM2B的表达明显升高。
3-1)用TRIZOL提取RNA，测定RNA纯度和浓度，将RNA反转录为cDNA，将所有cDNA样品分别配置Realtime PCR反应体系。qRT-PCR检测耐药株，耐药株外泌体，敏感株及敏感株外泌体中circRRM2B的表达量。
3-2)敏感株和耐药株来源的外泌体分别与敏感株共培养48小时后qRT-PCR检测细胞中circRRM2B的表达。
由图3可知：circRRM2B在耐药株及其外泌体中表达明显增高。耐药株分泌的外泌体和敏感株共培养后敏感株中circRRM2B的表达明显升高。
实施例4抑制耐药株中circRRM2B的表达可以增加耐药株对维罗非尼的敏感性。
4-1)使用Lipofectamine 3000(Invitrogen)在37℃条件下用si-circRRM2B(100nmol/L)或阴性对照转染耐药株48小时后，qRT-PCR检测细胞中circRRM2B的表达。
4-2)维罗非尼5uM加入转染si-circRRM2B或阴性对照的耐药株，流式检测细胞周期和凋亡。
由图4可知：抑制耐药株中circRRM2B的表达可以增加耐药株对维罗非尼的敏感性。
序列表
<110> 上海市东方医院（同济大学附属东方医院）
<120> circRRM2B基因作为新靶点在筛选维罗非尼耐药的黑色素瘤治疗药物中的应用
<160> 1
<170> SIPOSequenceListing 1.0
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<211> 973
<212> DNA
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 1
caaaagtaga ttttctatct gctatccatc gcaaggccca atctgctttt ttcttaacat 60
agggcatggt ttcaattgca ttaaataaaa attccctgta aaaacaaaag aatgaacagc 120
aaagttattc acttgttttt cttttttttt ttttgagaca gagtctcgct ctgttgccca 180
ggctggagtg cagtggcacg atctcggctc actgcaagct ccacctcccg ggttcatgcc 240
attctcctgc ctcagcctcc cgagtagcta ggacgacagg tgcccgccac cacgcccggc 300
tagtattttt agtagagacg tggtttcact gtgttagcca ggatggtctc aatctcctga 360
cctcgtgatc cacctgcttc ggcctcccaa ggtgctggga ttacagccat gagccaccat 420
gccttggcct cacttgtttt tcttaattgg actaaactta atcagagata ataattgtaa 480
ctctacggta tgctaccaga tctgtagttt ttatacattt ttacatgtcc atagaacaga 540
aataaaactc aaattattgg tttgaatctg gtctcataca aaaccagcta aatttgagta 600
ttcaatttct aaacagaaga tgctactgaa cagttcttaa agataaaata tctaaaggtt 660
aactggttct ataacaagtt ttttttaaaa cccaatacat tattaagcaa tagaaaatat 720
tatgctcaga aacttccata cttgaataat ctttccttaa cattgagttt tggaataaat 780
tctgatctga acataaccaa gccgtaagca atattttgta aataaaatcc caacaatacc 840
ttttcttggg atctctgatg taagtgtcta tcagcaaact gtacatctct gagtgaacat 900
tctcgatgag aatttgaaag ccatagaaac agcgagcctc tggaacctgc acctcctgac 960
taaagcgctc cac 973

Claims (2)

1.circRRM2B基因作为新靶点在筛选维罗非尼耐药的黑色素瘤治疗药物中的应用，其特征在于：所述药物以circRRM2B基因为靶点，抑制或者沉默circRRM2B基因的表达。
2.抑制或沉默circRRM2B基因表达的试剂在制备用于抑制黑色素瘤药物中的应用。
CN202010168534.0A 2020-03-12 2020-03-12 circRRM2B基因作为新靶点在筛选维罗非尼耐药的黑色素瘤治疗药物中的应用 Active CN111206101B (zh)

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