CN114164274A - 外泌体环状rna101093作为肺腺癌诊断标志物 - Google Patents
外泌体环状rna101093作为肺腺癌诊断标志物 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域,具体是外泌体环状RNA101093作为肺腺癌诊断标志物,本发明首次证实外泌体环状RNA101093可作为肺腺癌的诊断标志物以及外泌体环状RNA101093可抑制肺腺癌铁死亡敏感性,表明抑制外泌体环状RNA101093生成的功能的药物可以提高铁死亡药物对肺腺癌病人的临床疗效,为肺腺癌患者提供了一种新的治疗药物,有很好的应用前景。
Description
技术领域
本发明涉及医药技术领域,具体地说,是外泌体环状RNA101093作为肺腺癌诊断标志物。
背景技术
外泌体是由活细胞分泌的直径约为30-150nm的小囊泡,存在于细胞培养上清液、血清、血浆、唾液、尿液、羊水以及其它生物体液中[1];外泌体携带有多种蛋白质、脂类、RNA等重要信息,其中环状RNA是外泌体中所含的重要内容物[2]。环状RNA的共价闭环结构不易被核酸外切酶降解,因而具有较高的稳定性[3]。有研究表明环状RNA与肺腺癌的发生发展过程密切相关[4]。
根据2020年全球最新癌症数据[5],由于新发病例数的快速增长,乳腺癌取代肺癌成为全球第一大癌症。然而,肺癌死亡病例仍居所有癌症之首。在我国,肺癌的发病率和死亡率均位于癌症之首。肺腺癌是最常见的亚型,约占所有肺癌病例的40%[6]。虽然手术切除是早期肺腺癌最有效的治疗方法,但晚期患者可能受益于辅助细胞毒治疗[7,8]。然而,化疗耐药往往是肺腺癌患者复发的主要原因[6]。2012年,哥伦比亚大学Stockwell实验室报道erastin等一类小分子抗肿瘤化合物能够诱导大量的细胞死亡,该类型细胞死亡依赖于细胞内的铁离子和脂质过氧化物,并将之命名为ferroptosis,即铁死亡,其在形态学、生物学及基因水平上均明显不同于凋亡、坏死、自噬等其他形式的细胞死亡[9]。最近,有研究表明顺铂耐药的肺腺癌细胞对铁死亡敏感,诱导铁死亡的疗法可以为顺铂治疗失败的肺腺癌患者提供新的治疗方案[10]。与其他类型的癌症相似,肺腺癌对铁死亡的敏感性可能有所不同,是否存在某种环状RNA可以预示肺腺癌细胞或患者样本对铁死亡的敏感程度尚不清楚。铁死亡敏感性一定程度与肿瘤抗氧化能力有关,所以铁死亡敏感性标志物也可作为肿瘤早期诊断标志物,从肿瘤抗氧化水平提升角度预测肿瘤早期发病。
中国专利申请:CN202110024523.X公开了一种肺腺癌铁死亡敏感性标志物ADCY10及其应用,该专利首次实验发现肺腺癌铁死亡敏感性标志物:ADCY10,该专利还包括检测所述标志物表达量的试剂在制备评估肺腺癌铁死亡敏感性的试剂盒中的应用。实验结果表明(1)与肺腺癌I期原代细胞相比,ADCY10表达较高的肺腺癌III期原代细胞对铁死亡促进剂erastin处理更为敏感。(2)与亲本细胞系相比,铁死亡促进剂erastin和sorafenib对高水平表达ADCY10的AZD9291(第三代EGFR-TKI)耐药肺腺癌细胞具有更强的抑制作用,提示铁死亡相关治疗也可能是第三代EGFR-TKI耐药肺腺癌患者的一种选择。中国专利申请:CN202110966027.6公开了涉及下调RBMS1表达的试剂在制备治疗肺癌的药物中的应用,属于诊断试剂盒技术领域。该专利提供了下调RBMS1表达的试剂在制备治疗肺癌的药物中的应用,有助于实现治疗肺癌的药物的制备。但是关于本发明外泌体环状RNA101093作为肺腺癌诊断标志物目前还未见报道。
发明内容
本发明的目的是针对现有技术的不足,提供外泌体环状RNA101093作为肺腺癌诊断标志物。
为实现上述目的,本发明采取的技术方案是:
第一方面,本发明提供了外泌体环状RNA101093的抑制剂在制备治疗肺腺癌的药物中的应用。
优选地,如上所述抑制剂选自生物大分子或化合物小分子。
第二方面,本发明提供了外泌体环状RNA101093的抑制剂在制备提高肺腺癌铁死亡敏感性的药物中的应用。
优选地,如上所述抑制剂选自生物大分子或化合物小分子。
第三方面,本发明提供了检测外泌体环状RNA101093表达量的物质在制备评估肺腺癌铁死亡敏感性的产品中的应用。
优选地,如上所述的物质是基因测序试剂、基因特异性引物、基因特异性探针或抗体。
第四方面,本发明提供了一种预测肺腺癌铁死亡敏感性的产品,所述产品为试剂或试剂盒,所述产品包括检测外泌体环状RNA101093表达量的物质。
本发明优点在于:
1、本发明研究证实,在肺腺癌中,外泌体环状RNA101093高表达,且高表达的外泌体环状RNA101093会抑制肺腺癌铁死亡的敏感性。首次证实外泌体环状RNA101093与肺腺癌铁死亡的关系,表明外泌体环状RNA101093可作为临床上预测肺腺癌患者的分子标志物。
2、本发明通过实验验证了外泌体环状RNA101093可抑制erastin和RSL3诱导的铁死亡的发生,从而表明抑制外泌体环状RNA101093生成的功能的药物可以提高铁死亡药物对肺腺癌病人的临床疗效。
附图说明
附图1是血清cir93(RNA101093)及外泌体cir93(RNA101093)检验效能判定。
附图2是表明外泌体使肺腺癌细胞对铁死亡变得抵抗。
附图3是肿瘤细胞分泌的外泌体对于可以提高肺腺癌细胞内的cir93(RNA101093)的含量。
附图4是表明cir93(RNA101093)降低了体外肺腺癌细胞对铁死亡的敏感性。
附图5是表明cir93(RNA101093)降低了体内肺腺癌组织对铁死亡的敏感性。
附图6是cir93(RNA101093)及外泌体生成抑制剂的临床应用。
具体实施方式
下面结合具体实施方式,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明记载的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
一、材料与方法
1.1细胞、试剂和质粒
已建立的H1975和A549细胞系均购自上海富衡生物科技有限公司,细胞用DMEM+10%胎牛血清和1%青霉素/链霉素双抗培养。
细胞实验所用的试剂为:Erastin(Sigma,St Louis,MO,USA),RSL3(Sigma)、DFO(Sigma)、ferrostatin-1(Fer-1,Sigma)、GW4869(Sigma)、PI(Sigma),SYTOX Green(Invitgen,Carbsland,CA,USA),C11-BODIPY581/591(Invitrogen)。动物实验所用的试剂为PKE(MedChemExpress,Monmouth Junction,NJ,USA)和GW4869(Sigma)
表达cir93的质粒购自广州吉赛生物科技有限公司。Anti-cir93质粒购自上海生工生物工程股份有限公司。
1.2临床标本
标本收集于上海市胸科医院2013年5月至2020年12月。以上患者均获得知情同意书。男女比例1.13:1。肺腺癌患者由组织病理学分析确认。研究方案根据1975年赫尔辛基宣言伦理准则实行。
1.3定量RT-PCR(qPCR)
用Trizol(Ambion,Carlsad,CA,USA)试剂提取总RNA,并用PrimeScriptTM RT试剂盒(中国大连Takara)反转录成cDNA。对于实时qPCR,使用SYBR premix Ex Taq(Takara)试剂盒检测mRNA含量。
1.4免疫荧光(IF)、免疫组织化学(IHC)和原位杂交(ISH)技术
对于IF,PKH67(Sigma,MKCG5294)用以标记包装在A549或H1299细胞中的外泌体。对于IHC,研究中使用的一抗是抗4-HNE(Abcam,#ab48506)。对于ISH,研究中使用了地高辛(DIG)标记的cir93探针(上海生工生物工程股份有限公司)、抗DIG抗体(Abcam,#ab420)和HRP标记的二抗(CST)。
1.5细胞活力、细胞死亡、脂质活性氧生成及丙二醛(MDA)含量的测定
CellTiter-Glo luminescent cell viability assay kit(Promega,Madison,WI,USA)用以检测细胞活力,根据制造商的说明进行操作。SYTOX Green染色分析细胞死亡,随后采用流式细胞仪测定。在细胞收获前加入终浓度为2μM的荧光探针C11-BODIPY581/591,37℃下孵育30分钟,随后用流式细胞仪检测脂质活性氧阳性的细胞。MDA检测试剂盒购自Abcam公司,根据制造商的说明测定代谢物。
1.6透射电镜分析
对于外泌体观察,将外泌体重悬在4%的多聚甲醛溶液中,并使用JEM1230TEM(JEOL,Tokyo,Japan)拍摄图像。对于线粒体的形态学观察,将细胞以15,000个细胞/孔的密度接种到4孔室盖玻片(Thermo Scientific,Waltham,MA,USA)上。使用Olympus EM208STEM(HITACHI,Tokyo,Japan)捕获图像。
1.7外泌体分离及检测
外泌体通过三个连续的4℃离心步骤从细胞培养基或人的血浆中分离出来:1)500g离心15分钟去除细胞;2)10,000g离心30分钟去除细胞碎片;3)110,000g超速离心70分钟以沉淀外泌体。最后将沉淀重新悬浮在PBS中,并以110,000g离心70分钟以去除可溶性和分泌的蛋白质。使用Nanosight NS 300系统(NanoSight Technology,Malvern,UK)分析外泌体的浓度和大小。
1.8点击化学
将细胞在含有10%FBS、3%BSA±20mM花生四烯酸炔烃类似物(中国无锡药明康德)的DMEM中孵育2小时。之后,将处理培养基替换为含有3%BSA的新鲜DMEM再培养10小时,随后将细胞用4%的多聚甲醛溶液固定,并用含0.1%Triton-X的PBS溶液进行透化处理。随后,将细胞与点击化学反应缓冲液[0.1mM Azide-fluor 488(Cat#760765,Sigma)、1mMCuSO4、1mM TCEP]在潮湿暗盒中孵育1小时。最后,将细胞用1X PBS洗涤5次并用PBS-BT(1XPBS、3%BSA、0.1%Triton X-100、0.02%NaN3)在室温下封闭45分钟,随后用ConcanavalinA-Alexa Fluor 350和DAPI染色,使用共聚焦显微镜捕获图像。
1.9动物实验
将建立的肺腺癌细胞(5×106个)注射到6周龄的无胸腺裸鼠(上海杰思捷实验动物有限公司)的皮下以产生肿瘤细胞系移植模型(CDX)。为了产生H1975或A549细胞肺内移植瘤模型,我们在麻醉状态下对6周龄的无胸腺裸鼠进行肺内注射肺腺癌细胞(5×106个),3周后在鼻内给药腺相关病毒5(AAV5)颗粒(2×1012病毒颗粒/ml,上海吉满生物科技有限公司)。我们将2-3mm3的新鲜肺腺癌组织植入到六周龄的无胸腺裸鼠的皮下用以产生人源肿瘤异种移植模型(PDX)。成功传代后,PDX小鼠用于进一步研究。肿瘤体积计算公式为0.5×L×W2(L表示长度,W表示宽度)。动物研究得到了上海市胸科医院伦理委员会的批准。
1.10统计学方法
用于统计分析的检验方法有Student’s-t检验、one-way ANOVA、two-way ANOVA和Spearman相关性检验。生存分析采用Kaplan-Meier法估计生存率,采用log-rank检验比较生存曲线的差异。P<0.05表示有统计学意义。
二、结果
2.1血清cir93及外泌体cir93肺腺癌检验效能判定
AUC-ROC分析表明,血清环状RNA101093(cir93)的ROC曲线下面积为0.732,诊断灵敏度和特异性分别为85.0%、55.5%,约登指数为0.405;而外泌体cir93的ROC曲线下面积为0.838,诊断灵敏度和特异性分别为86.5%、82.5%,约登指数为0.690(图1A)。丙二醛是脂质过氧化的产物和标志物,我们发现cir93的表达量和丙二醛含量(R=0.1844,p=0.0089)存在负相关性(图1B)。此外,外泌体cir93的表达量和丙二醛含量(R=0.0860,p=0.2241)存在负相关性(图1B)。以上结果说明外泌体cir93有潜力作为肺腺癌诊断标志物。
2.2外泌体使肺腺癌细胞对铁死亡变得抵抗
我们从健康个体和肺腺癌患者的血浆中提取了外泌体,并用透射电子显微镜观察到它们的直径在30-150nm之间,与以前的研究报道一致(图2A)。通过检测细胞活力、细胞死亡情况和脂质活性氧含量,我们发现在与肺腺癌患者血浆中的外泌体预孵育后,H1975细胞对铁死亡变得抵抗;而健康个体血浆中的外泌体没有这种作用(图2B)。同时,3D球体培养结合细胞死亡情况检测进一步验证这个结论:肺腺癌患者血浆中的外泌体能抑制H1975细胞球体中erastin和RSL3诱导的铁死亡的发生(图2C)。考虑到A549和H1975细胞对铁死亡敏感程度的差异,我们提出一个猜想:A549细胞分泌的外泌体是否能使H1975细胞对铁死亡变得抵抗。正如预期的猜测,与培养A549细胞的培养基或A549细胞中提取的外泌体预孵育后,H1975细胞对铁死亡变得抵抗,而新鲜培养基、培养H1975细胞的培养基和GW4869(外泌体生成抑制剂)处理的培养A549细胞的培养基对H1975细胞没有这个作用(图2D)。综上所述,外泌体增加了肺腺癌细胞对铁死亡的抵抗性。
2.3肿瘤细胞分泌的外泌体可以提高肺腺癌细胞内的cir93的含量
我们进一步探究了外泌体中的内容物。大量的研究表明外泌体circRNA在肿瘤的发生发展中具有重要作用,因此我们将研究重点转移到circRNA上。已有的circRNA-chip数据分析了肺腺癌和正常肺组织中circRNA的表达差异。朱、杨等人的研究[13]表明circRNA_101093(cir93)和circRNA_100934(cir34)在肺腺癌组织中均表达上调(图3A)。原位杂交和实时荧光定量PCR技术均证实:与邻近正常组织相比,cir93在肺腺癌组织中表达上调(图3B-C)。我们同时检测了肺腺癌病人和健康个体血浆中的外泌体cir93的水平,发现肺腺癌病人血浆中的外泌体cir93含量明显高于健康个体(图3D)。通过原位杂交技术,我们发现cir93主要在肺腺癌组织的肿瘤区域表达(图3E)。通过将一个细胞系与从另一个表达mCherry标记的cir93的细胞系中提取的PKH67标记的外泌体一起孵育,然后在荧光显微镜下追踪外泌体和cir93,我们进一步证实了A549和H1299细胞之间存在有效的外泌体介导的cir93传递(图3E)。
2.4 cir93降低了体外肺腺癌细胞对铁死亡的敏感性
接着,我们探究了是否是外泌体中的cir93增加了肺腺癌细胞对铁死亡的抵抗性。研究表明细胞发生铁死亡时,电镜下可以观察到细胞的线粒体变小且线粒体膜密度增高[9]。透射电镜下可以观察到erastin和RSL3处理后,H1975细胞有相同的形态改变,而过表达cir93的H1975细胞没有此形态改变(图4A)。借助荧光显微镜观察PI染色检测细胞死亡情况,可以观察到升高的cir93抑制了erastin和RSL3诱导的铁死亡的发生(图4B)。通过细胞活力的检测,我们发现过表达cir93和铁死亡抑制剂ferrostatin-1、DFO具有相同作用即抑制铁死亡的发生(图4C)。综上,可以得出一个结论:cir93降低了体外肺腺癌细胞对铁死亡的敏感性。
2.5 cir93降低了体内肺腺癌组织对铁死亡的敏感性
为了验证体内实验是否有相同结论,我们利用腺相关病毒5载体构建了cir93/GFP过表达的H1975细胞裸鼠肺内移植瘤模型,并对其注射了体内更稳定的erastin的衍生物PKE。与对照相比,cir93过表达的移植瘤的4-HNE和MDA水平明显下降(图5A),这表明升高cir93的水平可以抑制体内铁死亡相关的脂质过氧化物的产生。为了研究anti-cir93是否会促进小鼠肺腺癌组织中质膜内脂质过氧化物的生成,我们利用了腺相关病毒5载体构建了anti-cir93过表达的A549细胞裸鼠肺内移植瘤模型。通过荧光探针C11-BODIPY581/591检测氧化型及非氧化型脂质,conA-AlexaF标记质膜,可以在激光共聚焦显微镜下观察到过表达anti-cir93显著增加了移植瘤中质膜内的氧化型脂质的生成(图5B)。利用花生四烯酸炔烃类似物和Fluro-488标记的叠氮化物间的点击化学反应,我们可以观察到插入到质膜中的花生四烯酸,而花生四烯酸插入到质膜这一过程对于铁死亡的发生十分重要[14]。借助激光共聚焦显微镜我们观察到过表达cir93可以抑制花生四烯酸插入质膜中(图5C-D)。以上结果表明:cir93降低了体内肺腺癌组织对铁死亡的敏感性。
2.6 cir93及外泌体生成抑制剂的临床应用
我们构建了人源肿瘤异种移植模型来验证cir93的临床应用。注射PKE后,cir93高表达的移植瘤模型的4-HNE水平明显低于cir93低表达的移植瘤模型(图6A-B)。借助荧光显微镜观察PI染色检测细胞死亡情况,可以观察到:与cir93低表达的移植瘤模型相比,cir93高表达的移植瘤模型对erastin诱导的铁死亡明显抵抗(图6C)。生存分析显示cir93高表达的移植瘤模型的总生存期低于cir93低表达的移植瘤模型(图6D)。对肺腺癌病人的生存分析可以得到相同结论:cir93水平低的病人总生存期更长(图6E)。以上结果表明高水平的cir93可以预测铁死亡抵抗和肺腺癌病人的生存预期差。同时,为了探究抑制外泌体生成是否能提高铁死亡的疗效,我们构建了A549细胞裸鼠移植瘤模型。与PKE单独治疗的小鼠相比,GW4869和PKE共同治疗的小鼠的肿瘤生长受损,而且总生存期更长(图6F-H)。GW4869和PKE共同治疗的小鼠移植瘤的MDA含量明显高于PKE单独治疗的小鼠。这些结果表明,抑制外泌体生成的功能的药物可以提高铁死亡药物对肺腺癌病人的临床疗效.
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明原理的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
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Claims (7)
1.外泌体环状RNA101093的抑制剂在制备治疗肺腺癌的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述抑制剂选自生物大分子或化合物小分子。
3.外泌体环状RNA101093的抑制剂在制备提高肺腺癌铁死亡敏感性的药物中的应用。
4.根据权利要求2所述的应用,其特征在于,所述抑制剂选自生物大分子或化合物小分子。
5.检测外泌体环状RNA101093表达量的物质在制备评估肺腺癌铁死亡敏感性的产品中的应用。
6.根据权利要求5所述的应用,其特征在于,所述的物质是基因测序试剂、基因特异性引物、基因特异性探针或抗体。
7.一种预测肺腺癌铁死亡敏感性的产品,其特征在于,所述产品为试剂或试剂盒,所述产品包括检测外泌体环状RNA101093表达量的物质。
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