CN113278695B - Linc00969在肝癌诊断生物标志物及治疗靶点中的应用 - Google Patents
Linc00969在肝癌诊断生物标志物及治疗靶点中的应用 Download PDFInfo
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Abstract
本发明属于肿瘤分子生物学技术领域,涉及一种长链非编码RNA lncRNA LINC00969作为肝癌诊断生物标志物及治疗靶点的应用。本发明首次发现LINC00969可作为肝癌诊断生物标志物和药物治疗靶点。与健康人相比,LINC00969在肝癌患者的癌组织中显著下调。本发明的结果表明LINC00969在肝癌细胞中低表达,过表达LINC00969可以抑肝癌细胞的迁移和侵袭,表明LINC00969在肝癌的发生发展中发挥抑癌基因的作用,为临床治疗肝癌提供新的靶点。
Description
技术领域
本发明属于肿瘤分子生物学技术领域,涉及一种长链非编码RNA lncRNALINC00969作为肝癌诊断生物标志物及治疗靶点的应用。
背景技术
肝细胞癌(HCC)是世界上最常见的恶性肿瘤之一,其发病率近几年逐年上升,5年生存率仅为18%。侵袭转移是肝癌死亡的主要原因,免疫治疗是肝癌的新型治疗方法,但是目前没有明确简易且稳定的检测指标进行指导和预后监测。90%以上的死亡病例都是转移造成的,也是导致肝癌预后不良的重要因素。肝癌的早期诊断和及时正确的治疗,直接影响肝癌患者的预后。因此,探究一种新型高灵敏度和高特异度的肝癌诊断生物标志物和治疗靶点,提高肝癌的早期诊出率,是近年来关注的热点和难点。
早期肝癌通常缺乏明显的临床体征,主要通过钼靶X线、彩色多普勒超声等影像学检查获得早期诊断,但对于早期肝癌的诊断特异性和敏感性并不高。基于lncRNA在肝癌中的异常表达及生物学功能,确定新型lncRNA作为肝癌诊断生物标志物及治疗靶点并探究lncRNA在肝癌中的生物学调节功能,对于肝癌的诊断及治疗具有潜在的临床意义。
长链非编码RNA(long non-coding RNA,lncRNA)是一类转录本长度超过200个核苷酸且编码蛋白的潜力有限的RNA分子。根据在基因组中的相对位置及方向,lncRNA主要被分成以下几种:正义lncRNA、反义lncRNA、双向lncRNA、基因间lncRNA和基因内lncRNA。研究表明,lncRNA具有特定的空间结构和高度保守的序列原件,广泛存在于细胞的各个层面,其在遗传水平、转录及转录后水平、翻译及翻译后水平等多种层面调控重要的病理生理过程,如在染色质重塑、DNA甲基化、组蛋白修饰、RNA代谢和表观遗传特征的调节。近年研究发现,lncRNA广泛参与各种生物学过程,例如调控细胞增殖、细胞凋亡、细胞迁移、细胞侵袭等。文献报道,异常表达的lncRNAs与人类各种疾病尤其是恶性肿瘤(肝癌、乳腺癌、胰腺癌等)的发生发展、转移及耐药等过程密切相关。这些特征显示lncRNA在生物学过程中发挥着重要作用,并逐渐成为临床肿瘤诊断、治疗及预后的全新靶点。
发明内容
本发明针对传统早期肝癌诊断和治疗中存在的问题提出LINC00969在肝癌诊断及治疗方面的应用。
为了达到上述目的,本发明是采用下述的技术方案实现的:
本发明的第一个目的是提供一个肝癌潜在诊断生物标志物和治疗靶点,其为LINC00969。
本发明的第二个目的是提供特异性识别LINC00969的引物对,包括上游引物和下游引物。上游引物的核苷酸序列LINC00969-F, 5’-TACAGGCCCGATTCCACCTA-3’;下游引物的核苷酸序列LINC00969-R ,5’-GTGGCAAGGAACATCAGGGA-3’。
本发明的第三个目的是公开LINC00969在肝癌患者标本及肝癌细胞中的表达情况。
本发明的第四个目的是公开LINC00969在肝癌细胞中发挥的生物学功能。
本发明公开了LINC00969作为一种新型潜在的肝癌诊断生物标志物和治疗靶点。本发明从数据库中提取组织标本库中选取肝癌及癌旁组织的数据,差异表达的lncRNA与TCGA分析数据进行联合分析,筛选出在肝癌组中显著变化且与预后相关的候选lncRNA分子。在体外细胞实验中通过qRT-PCR验证发现LINC00969在肝癌中表达显著下调,受试者工作曲线(ROC)显示LINC009691具备良好的诊断肝癌的潜能,且高表达的LINC00969与患者的不良预后相关;功能实验结果显示LINC00969可抑制肝癌细胞的迁移和侵袭。
与现有技术相比,本发明的优点和积极效果在于:
1.首次发现LINC00969可作为肝癌诊断生物标志物和药物治疗靶点。
2.与健康人相比,LINC00969在肝癌患者的癌组织中显著下调。
3.本发明的结果表明LINC00969在肝癌细胞中低表达,过表达LINC00969可以抑肝癌细胞的迁移和侵袭,表明LINC00969在肝癌的发生发展中发挥抑癌基因的作用,为临床治疗肝癌提供新的靶点。
附图说明
图1A为TCGA数据挖掘分析结果,显示LINC00969在不同肿瘤中的差异(foldchange>2或<0.5,p<0.001)。图1B显示LINC00969在肝癌及癌旁组织中差异表达。图1C为TCGA公共数据库中LINC00969在肝癌组织中的与患者预后相关情况。
图2为TANRIC数据集上分析LINC00969所调控的mRNA和miRNA。
图3使用Co-LncRNA在线工具识别LINC00969的CEGs影响的GO和KEGG通路。
图4为LINC00969抑制HLF细胞活力。
图5为 LINC00969抑制HLF肝癌细胞的迁移和侵袭。
图6为肿瘤通路中与LINC00969相关的标记基因。
具体实施方式
为了能够更清楚地理解本发明的上述目的、特征和优点,下面结合具体实施例对本发明做进一步说明。需要说明的是,在不冲突的情况下,本申请的实施例及实施例中的特征可以相互组合。
在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是,本发明还可以采用不同于在此描述的其他方式来实施,因此,本发明并不限于下面公开说明书的具体实施例的限制。
在本发明中所使用的术语,除非另有说明,一般具有本领域普通技术上人员通常理解的含义。
在以下实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1
本实施例提供LINC00969在肝癌中的表达、预后及诊断效能方面的研究情况。
1、实验材料与方法
1.1数据库数据提取
运用网络分析工具,GEPIA (http://gepia.cancer-pku.cn/),使用GEPIA分析LINC00969的表达和总存活率,包括TCGA和GTEx的转录组数据。在基因表达分析中参数采用,对数尺度采用log2(TPM + 1), |Log2FC| Cutoff=1, p值Cutoff=0.01。总生存期分析采用Log-rank检验,即Mantel-Cox检验进行假设检验。
1.2相关基因分析
利用Co-LncRNA在线工具Co-lncRNA (http://bio-bigdata.hrbmu.edu.cn/Co-LncRNA/)鉴定了LINC00969共表达蛋白编码基因(CEGs)影响的GO分析和KEGG通路。选择一个命名为TCGA LIHC正常vs肿瘤的数据集,其中包括65例肝细胞癌样本。采用线性回归方法进行相关分析。
在TANRIC (https://ibl.mdanderson.org/tanric/_design/basic/main.html)上分析获得LINC00969和LINC00969在细胞系中表达的相关mRNA和miRNA。TANRIC使用TCGA和CCLE程序的RNA_seq数据,用Spearman相关系数计算进行相关分析。
利用基因集富集分析(Gene Set Enrichment Analysis, GSEA)在LmmLnc在线分析工具 LmmLnc (http://bio-bigdata.hrbmu.edu.cn/ImmLnc)中分析LINC00969参与的免疫相关通路。用LmmLnc观察linc00969免疫细胞浸润相关性(B细胞、CD4 T细胞、CD8 T细胞、巨噬细胞、中性粒细胞和树突状细胞)。
1.3 细胞系及培养
10株人肝癌细胞系HLF、SNU-387、SNU-475、SNU-423、SK-HEP-1、SNU-398、SNU-478、SNU-1196、SNU-245和SNU-761,均购买于中国科学院上海生命科学研究院。肝癌细胞均培养在含有10%胎牛血清(Gibco)的DMEM(Gibco)培养基中,并添加100ng/ml的霍乱毒素、20ng/ml EGF、0.5μg/ml的氢化可的松和10μg/ml的胰岛素。所有细胞系都培养在37℃和5%CO2的培养箱中。
1.4 lncRNA 差异基因表达谱
从TCGA数据挖掘组织标本库中选取肝癌369例及癌旁正常组织160例。分析肝癌及正常组织数据进行比对(设置差异显著基因的默认阈值为:p≤0.001且Fold change≤0.5或≥2.0),得到LINC00969在13种不同癌症中的表达差异及在肝癌中的表达差异。
1.5 RNA提取及荧光实时定量PCR(qRT-PCR)
采用RNA提取试剂盒fast2000(飞捷,上海)提取细胞总RNA。逆转录试剂盒采用PrimeScriptTM RT reagent Kit( TAKARA,大连);荧光定量PCR试剂盒采用TB Green TMPremix Ex taqTM Ⅱ( TAKARA,大连)。采用β-actin作为内参;采用2-ΔΔCt法计算RNA相对表达量;引物由济南博尚生物技术有限公司合成;引物序列见表1,qRT-PCR体系见表2。
表1 qRT-PCR使用的引物序列
表2 qRT-PCR使用的体系
1.6数据处理与分析
使用SPSS 20.0软件对数据进行统计分析,使用GraphPad Prism 7.0软件做统计图。根据需要采用t检验或Wilcoxon秩和检验比较样本间或组间差异,p<0.05被认为具有统计学差异。
2、实验结果
如图1所示,图1显示 LINC00969在人肝癌中表达下调。其中图1A利用GEPIA在线分析软件上的TCGA数据分析LINC00969在人类肿瘤中的表达情况。使用GEPIA在线数据集分析LINC00969在多种人肿瘤组织和正常对照组织中的表达水平。绘制了热图。LINC00969在13个人类肿瘤(ACC、BRCA、COAD、LIHC、LUAD、OV、PRAD、READ、SKCM、TGCT、THCA、UCEC和UCS)中表达下调,在2个人类肿瘤(KICH和THYM)中表达上调,差异有统计学意义。图1B中对369例肝癌组织和160例肝脏正常组织进行比较,发现在肝癌组织中LINC00969水平表达明显降低。我们使用log2(TPM + 1)作为对数尺度。| Log2FC |cutoff= 1。
结果显示,LINC00969在13种不同癌症中的表达差异及在肝癌中的表达差异,见图1。LINC00969在肝癌中表达显著下调,且其低表达与患者不良预后显著相关(p=0.027)。
TCGA数据挖掘组织标本库中选取肝癌369例及癌旁正常组织160例。分析肝癌及正常组织数据进行比对。结果显示,LINC00969在肝癌标本中表达显著降低,见图1B。表明其对乳腺癌具有较好的诊断价值。图1C 显示了高表达(上面的线)和低表达(下面的线)患者生存率,从图中可以看出,高表达人群生存率明显提高。
本发明检测人肝癌细胞系中LINC00969的表达,显示LINC00969在10种肝癌中低表达,见图4。
实施例2
本实施例探讨过表达LINC00969对肝癌细胞迁移和侵袭的影响。
1、实验材料与方法
1.1 细胞系及培养
同实施例1
1.2 细胞转染
靶向过表达LINC00969的特异性过表达质粒及阴性对照由吉玛基因(上海)设计合成;利用Lipofectamine 2000(Invitrogen, Carlsbad, CA, USA)将过表达质粒转染入肝癌细胞HLF中;过表达序列见表3。
表3 LINC00969过表达序列
1.3 细胞迁移实验
将24孔细胞池放入24孔板中,胰酶消化转染的细胞,以5×104个细胞/孔取出相应细胞量,用200μl的无血清培养基重悬,接种于24孔池上室中,下室加入含有20%的胎牛血清的培养基。37℃,5% CO2的环境中培养24h后,弃掉上下室中的液体,擦除上室未迁移的细胞,PBS洗2遍,4%的多聚甲醛固定1h。弃固定液,PBS洗2遍,使用吉姆萨染色液染1h。弃染色液,PBS洗2遍,将小室孔膜割下,中性树胶封于载玻片上。使用蔡司显微镜拍照并计数统计
1.4 细胞侵袭实验
将24孔细胞池放入24孔板中,上室加入60μl基质胶(BD Biosciences),置于细胞培养箱中1h待胶凝固。胰酶消化转染的细胞,以1×105个细胞/孔取出相应细胞量,用200μl的无血清培养基重悬,接种于24孔池上室中,下室加入含有20%的胎牛血清的培养基。37℃,5%CO2的环境中培养24h后,弃掉上下室中的液体,擦除上室未迁移的细胞,PBS洗2遍,4%的多聚甲醛固定1h。弃固定液,PBS洗2遍,使用吉姆萨染色液染1h。弃染色液,PBS洗2遍,将小室孔膜割下,中性树胶封于载玻片上。使用蔡司显微镜观察拍照并计数统计
1.6 数据处理与分析
数据处理过程同实施例1。
2.实验结果
2.1 本发明检测人肝癌细胞系中LINC00969的表达,显示LINC00969在10种肝癌中均低表达,过表达LINC00969可以抑制肝癌细胞增殖,见图4。
图4 显示LINC00969抑制HLF细胞活力。(A)从TANRIC获得10株HCC细胞株HLF、SNU-387、SNU-475、SNU-423、SK-HEP-1、SNU-398、SNU-478、SNU-1196、SNU-245和SNU-761的LINC00969水平。(B)转染LINC00969过表达质粒(LINC00969组)或pcDNA3.1(对照组)后,用qPCR检测LINC00969的表达水平。(C) CCK8法检测细胞活力。450nm处测OD值。结果显示LINC00969在肝癌中低表达,并可能在HCC的进展中发挥作用。LINC00969在10株肝癌细胞株HLF、SNU-387、SNU-475、SNU-423、SK-HEP-1、SNU-398、SNU-478、SNU-1196、SNU-245和SNU-761中表达,如图4A所示,LINC00969在HLF细胞中的表达最低。因此,我们在HLF细胞中过表达LINC00969,以研究其在肝癌中的具体作用(图4B)。从CCK8的结果来看,与对照细胞相比,过表达LINC00969后OD值明显受到抑制(图4C)。这些结果表明LINC00969可以抑制肝癌细胞的活力。
2.2 在实施例2中,本发明在人肝癌细胞HLF中转染过表达质粒后,能显著上调肝癌细胞中LINC00969的表达水平,见图4B。*代表p值<0.05
2.3 在实施例2中,本发明在人肝癌细胞HLF中转染过表达质粒后,细胞实验结果显示过表达LINC00969能显著抑制肝癌细胞的迁移和侵袭能力,见图5。
图5 LINC00969抑制HLF肝癌细胞的迁移和侵袭, (A) Transwell实验检测HLF细胞的迁移和侵袭。(B)显微镜下5个随机场计数迁移细胞数量。(C)显微镜下进行5个随机场的侵袭细胞计数。
肿瘤转移是肝癌患者死亡的主要原因之一。增强细胞的侵袭和迁移能力是肿瘤转移的必要条件。因此,我们使用transwell实验检测了HLF肝癌细胞的迁移和侵袭。如图5A和B所示,LINC00969过表达细胞与对照组相比迁移细胞数量明显减少50%以上。此外,过表达LINC00969后侵袭细胞数量也减少50%以上(图5A和C)。这些数据表明LINC00969可以抑制肝癌细胞的转移。
2.4 使用TANRIC数据集上分析LINC00969所调控的mRNA和miRNA。如图2所示。结果显示,在TCGA的LIHC样本中,SDHAP(图2A)、KIAA0319(图2B)和SDHAP1(图2C)为与LINC00969正相关的前3个mRNA, NMUR1(图2D)、CLDN5(图2E)和RASIP1(图2F)为与LINC00969负相关的前3个mRNA。然而,只有一个miRNA与LINC00969相关,且具有统计学意义。miR-1266在LIHC样本中与LINC00969水平呈正相关(图2G)。
图3利用Co-lncRNA在线工具分析了65例肝癌样本中LINC00969调控的蛋白编码基因(CEGs),共获得2786个基因。然后在Co-lncRNA 软件上对这2786个基因的生物过程(BP)、分子功能(MF)和细胞成分(CC)类中丰富的基因 (GO)进行分析。BP、MF和CC排在前20位如图3A-C所示。我们使用Co-lncRNA上的KEGG模块进一步分析了这2786个基因参与的通路。共获得了58条相关信号通路。重叠基因数量最多的是肿瘤信号通路,提示LINC00969可能参与了肿瘤相关信号通路(图3D显示前30条通路)。使用imlnc在线工具分析linc00969免疫细胞浸润的相关性。结果显示,LINC00969与树突状细胞(DC)浸润显著相关(P=0.013,表1)。接下来,我们分析了LINC00969细胞的免疫相关通路。如图3E所示,柱状图表示参与免疫通路的标记基因数量。LINC00969 CEGs与细胞因子(0.001032)和抗原处理递呈(P=0.008333)通路显著相关。
2.3 肿瘤通路中与LINC00969相关的标记基因。红框(原图为有色彩的图)中的基因与lINC00969显著相关。
见图6和表4。
表4 linc00969免疫细胞浸润相关性分析
表4说明linc00969与免疫治疗相关,对免疫治疗的预后有明显检测指示作用。
上述结果表明LINC00969在肝癌组织、细胞中低表达且与预后不良相关,体外实验显示LINC00969抑制肝癌细胞的迁移及侵袭能力,表明LINC00969在肝癌中发挥抑癌基因的作用,且与免疫系统有显著相关性。LINC00969有望成为一种新型肝癌诊断生物标志物和治疗靶点。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例应用于其它领域,但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
SEQUENCE LISTING
<110> 山东大学第二医院
<120> LINC00969在肝癌诊断生物标志物及治疗靶点中的应用
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<170> PatentIn version 3.5
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gaatggtgtg tgctgtgcta tccaggaaca catttattat cattatcaag tattgtgtac 60
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gtgtactgta cagaatgatg tgcgctgtgc tatccaggaa cacatttatt atcattatca 180
agtattgtgt actgtacaga atggtgtgcg ctgtgctatc caggaacaca tttattatca 240
ttatcaagta ttgtgtactg tacagaatgg tgtgcgctgt gctatccagg aacacattta 300
ttatcattat caagtattgt gtactgtaca gaatggtgtg cgctgtgcta tccaggaaca 360
catttattat cattatcaag tattgtgtac tgtacagaat ggtgtgcgct gtgcttttat 420
gcaagtggca gcacagtagc tttacacgag catcactaga cacatgagta gcattgcact 480
cggcaacagg aattttttca ggcccattat tataatctta tgggaccgca tcctatatgc 540
agtttgtcat tgaccaaaat gtccttatgc gatgcatgac tatatttgca aaggactagt 600
atctagaata catttaaaag tcttaaaata gtaacaaaac aaagaatgca attagaacat 660
gagcaaaaga tacaaagcaa catttcactg gagaagatat acagattgca aataagcaca 720
tgaaaagatg tttgatacca ttagggaaac gcttctttaa accaggagat atcaccacgt 780
gttagaatca acaaaataag gccaggcatg gtggctcaca cctgtaatcc caacactttg 840
ggaggctggg gcaggcagat cacatgagat caggaattca agaccaacct ggccaacatg 900
gcaaaaccct gtctctgctg aaaacacaaa aattagccag gtgtggtggc acacgcctgt 960
agtcctagca ccttgggagg ctgaggcaag ataattgctt aaacccagga gacggaggtt 1020
gcagtaagct gagatcatgc cactgcgctc cagcctgggc gacagagcaa gattatgtct 1080
caaaaaaaaa aaaaaaaaaa agaatcacca aaataaaaaa tagtaacaat actattgtca 1140
aggatgcaaa ggaactgtac cactcaatca ctgctgtgag aatttaaagt ggtgcagcca 1200
ctctgggaaa cagcttggct gttttttttt atgactgaat gtgcaactac tatatgatgc 1260
agtaatttca tttttgcaca tttatcccgg agaaatgaaa acatatattc acacaaaacc 1320
tgtatatgaa tgctaataaa agtcaattgg ccaggtgtgg tggctcatgc ctgtaatccc 1380
agcactttgg gaggctgagg cagtggatca cctgaggtca ggagtttgag accagcctgg 1440
ccaacgtggt gaaaactcgt ctctactaaa aatacagcaa ttagctgggt gtaatagtag 1500
ccacctgtaa tcccagctac tggggaggct gaagcagaag aacctcttga acccgggagg 1560
cagaggttgc agtgagctga gatcgtacca ctgcactcca gcctgggcga tagagtgaga 1620
ctctgtctca aaaaataaaa taaaataaat aaaaagatta gataatctgc aaagttcctg 1680
tgagcgctgt cattttgtca ctctggtttt tcagattctt cccctggagg ctggagtttc 1740
caggatgtca agattacctc tgcttgggtg agctatttca agcagctggg atacctgtgt 1800
cactcctgct gtctgccagt gactgcccag gtgtctgctg gttcctcccc aggagtaggg 1860
aggaaccagg tgggctggct gggatgggtg gatatttaaa gaccaggcct tggacgctgc 1920
agcacttcta tctctgcttg atgcctgctg ccacgtggct ggtcctcctc ctcctgctgt 1980
ggctgagcct tggggtgaag acagctgctc ccaaccccag aacctttgct gtcttgggac 2040
ggatcaccgc tgcaagaggg gaagttgcta ctgtgatgaa ttctgccatg tggcaccaga 2100
ctgccaccca gaccacagtg tcctctgcaa ccccggtaac tcacatacag gcccgattcc 2160
acctacagca aagctggatg cgatggctgg cagaggcaaa ccctttgcct gcactgcagg 2220
ccaaagccgg gatgtggcct agatggttcc taaggtccct gacaatcctg agatcttgca 2280
tcttgtctat ttcaggtcaa aggtgcctac atgctccctc tagctttgtt tccctgatgt 2340
tccttgccac ctgctactcc tctctgagct acttttccag gttccacagg gagaggttca 2400
gctgtccgtg gtagacatga gggtagagaa tgaggtggtt gggttccact tacctttcta 2460
tcatcttgca gtatggatgt ctcttgactg gtaccgtgta gacttttgag ggcacacagg 2520
agtctgcaga gagatactgg ggacattgag cagcagcagt ggggttggga ggcagaaatg 2580
aggacaggaa catttacctt gtgtttctct cagcttctca gatgaccaag atggtgctgc 2640
agatggtgct gaggatggag aacccaccaa gccccgctag gagccaccta gactggatgc 2700
agagcatggt tcagcgagtt ctccaaacca gcctcccagg aatgccattc accatggctg 2760
tgaggagaat aaagaagaga gcctgactcc tctcctgagg ccccttcccc accctgagcc 2820
agcaggatcc acggagcaga ggtcatctgt ccccagcttg gcccactgag gccagcatgg 2880
ctgggcccag gatgcttgtc tctcagctcc catcctgtgt acttccacat tggtttaacc 2940
agaggaaaac cgaaatctac aattgtcata aacacattta aatgtgcgta gaatcagcca 3000
tacaaattgt gaaacat 3017
<210> 2
<211> 40
<212> DNA
<213> 未知
<400> 2
tacaggcccg attccaccta gtggcaagga acatcaggga 40
<210> 3
<211> 37
<212> DNA
<213> 未知
<400> 3
cccgagccgt gtttcctgtc ccagttggtg acgatgc 37
Claims (1)
1.过表达LINC00969的物质在制备抑制肝癌细胞的迁移和侵袭药物中的应用。
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