CN113151457B - 胆固醇转运体基因和/或其编码的蛋白的新应用 - Google Patents
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Abstract
本发明公开了胆固醇转运体基因和/或其编码的蛋白在制备急性髓系白血病治疗药物中的新应用。本发明通过筛选急性髓系白血病(AML)诊断与预后相关分子标志物,筛选出与AML患者预后密切相关且在AML中呈差异表达的胆固醇转运体基因(GRAMD1C);AML患者体内高表达GRAMD1C,GRAMD1C与AML患者FAB分型和细胞遗传学危险分层具有相关性,细胞遗传学危险度越高,GRAMD1C表达量越高;GRAMD1C高表达提示AML患者预后不良;GRAMD1C可能通过参与Wnt信号通路、调节转录因子活性等参与AML的疾病进程。GRAMD1C可应用在AML的诊断和预后研究制剂中。
Description
技术领域
本发明属于生物医药领域,具体涉及胆固醇转运体基因和/或其编码的蛋白的新应用。
背景技术
急性髓系白血病(Acute myeloid leukemia,AML)是一种起源于造血干/祖细胞的恶性克隆性疾病,主要表现为髓系原始和幼稚细胞增殖失控、凋亡受阻、分化停滞,进而抑制正常造血,并引起髓外浸润。AML发病机制复杂、临床预后差,尽管联合化疗使大多数患者可获得完全缓解(Complete remission,CR),但只有少数特殊类型的AML患者能够长期存活,大部分患者在CR后的3年内发生疾病复发,且难治或复发患者化疗效果差,因此针对AML发生发展中关键分子为靶点的个体化治疗将成为AML治疗的发展趋势。目前关于AML的机制研究仍不充分,现有的分子靶向药物难以满足临床治疗的需要,因此挖掘和寻找AML发生发展中新的关键致病分子和潜在干预靶点,为诊疗分层和预后评估提供新的依据具有至关重要的临床意义。
发明内容
联合化疗是急性髓系白血病的主要干预策略,但由于化疗的无选择性不可避免地会伤害正常细胞,引起毒副作用,因此针对AML发生发展中关键分子为靶点的精准靶向治疗将成为AML治疗的新趋势。目前肿瘤的分子靶向治疗已取得巨大进步,如酪氨酸激酶抑制剂、CD20单抗等分子靶向药物已显示良好的临床疗效。然而,AML的发生发展是一个多因素、多阶段、多步骤的过程,涉及到大量分子参与的复杂网络调控,现有的分子靶向药物难以满足临床治疗的需要。因此,挖掘AML发生发展新的节点分子,确定其做为AML干预的潜在靶点具有十分重要的价值。此外,目前基于细胞遗传学的AML风险分层仍然不够精确,尽管大多数研究已经在特定的AML亚群中进行,但引入新的遗传和表观遗传标志物有助于缩小这一差距并提高风险分层的特异性。
随着生物技术的发展,尤其是以信息学为手段的分析方法的推陈出新,让人们对于数据的收集、处理、分析及使用有了更大的需求和更深的理解,而利用生物标志物进行诊断和治疗也日益受到关注。同时,现代生物技术的进步可以使得研究者从不同的层面全方位地了解肿瘤的发生、发展,作为一种初步定位标记物,分析、筛选相应的分子靶标,甚至是相关药物筛选、临床应用探究的工具意义重大,为人类寻求多水平的治疗手段提供了依据,人们可以根据癌症患者肿瘤相关基因和分子的变异情况设计出个体化的治疗程序。因此,利用生物信息学的方法快速寻找和定位全新的AML诊断和预后标记物具有重大意义。
胆固醇转运体(GRAMD1C)定位于3号染色体长臂近端,是嘌呤生物合成中的必须酶,介导胆固醇从质膜(PM)到内质网(ER)的非囊泡转运,其结构包含用于结合胆固醇和质膜的独特结构域,从而充当胆固醇从质膜转移到内质网的分子桥,在胆固醇的体内平衡中起着至关重要的作用,并具有基于膜胆固醇水平定位于质膜的独特能力:在脂质不足的情况下定位于内质网膜,通过GRAM域介导将质膜中过量的胆固醇募集到内质网-质膜接触点(EPCS);在EPCS中,固醇结合的VASt/ASTER结构域与质膜中的胆固醇结合,并促进其从质膜转移至内质网。已有报道证实GRAMD1C与肝细胞铁过载密切相关,但GRAMD1C在血液系统疾病中的作用尚不明确,本专利基于对TCGA数据库和GEO数据库的数据分析发现AML患者相对正常对照组体内GRAMD1C表达升高,且GRAMD1C高表达组AML患者具有更差的预后,提示其可能参与AML发生发展。
为解决现有技术上的不足,根据研究结果,本发明提供了胆固醇转运体基因和/或其编码的蛋白的新应用。
本发明是通过以下技术方案实现的:
胆固醇转运体基因和/或其编码的蛋白在制备急性髓系白血病治疗药物中的应用。
优选的,所述药物中包括胆固醇转运体基因和/或其编码的蛋白,以及一种或多种药用赋形剂或药用载体。
胆固醇转运体基因和/或其编码的蛋白在制备急性髓系白血病辅助诊断和/或预后判断的组合物中的应用。
优选的,所述的辅助诊断和/或预后判断的组合物包括:用于在PCR中合成胆固醇转运体基因DNA链和/或其cDNA链的PCR引物、或抗胆固醇转运蛋白的抗体。
本发明的有益效果是:本发明提供了一种新的急性髓系白血病遗传和表观遗传标志物,该标志物相关性高,可以应用在制备急性髓系白血病治疗药物,或应用在制备急性髓系白血病辅助诊断和/或预后判断的组合物中。
附图说明
图1是图示TCGA和GSE12417数据库中与AML患者预后相关的分子取得交集。
图2是图示AML患者高表达GRAMD1C。
图3是图示GRAMD1C高表达提示AML患者预后不良(B图中上面曲线表示GRAMD1CLOW,下面曲线表示GRAMD1CHIGH)
图4是GRAMD1C高低表达组差异基因分析及富集分析。
具体实施方式
实施例1急性髓系白血病诊断和预后标志分子GRAMD1C的筛选与验证
一、材料和方法
1生物信息学数据分析工具
1.1癌症和肿瘤基因图谱(The Cancer Genome Atlas,TCGA)
TCGA计划是由美国政府投资,旨在利用基因组测序技术,将人类的全部癌症基因组变异图谱绘制而出,并进行对比分析,研究RNA和蛋白表达、DNA拷贝数变化、与患者预后之间的关系。目前为止,TCGA数据库中已收录了超过30种人类肿瘤数据,对于包含AML在内的肿瘤诊断与治疗研究具有重要意义。
1.2基因表达汇编(Gene Expression Omnibus,GEO)数据库
GEO是一个收录高通量基因表达和其他功能性基因组学数据的国际公用数据库,由美国国家医学图书馆国家生物技术信息中心支持和维护,于2000年创建,收集来自全球范围内的基因研究内容,其中接受并包含原始或者已加工的实验信息,样本数据信息,基因表达数据信息等。GEO数据库不仅可以提供研究相关的信息,同时还拥有网络为基础的工具包、策略包,以帮助研究者收集、处理和分析数据,提高了信息的可视化。
1.3 R语言(Language R)
R语言是一种由R Foundation支持,用于统计学分析、编辑、绘图等的编程语言和自由开放的软件环境,在全基因组表达芯片及高通量测序的分析中具有广泛应用。
1.4统计产品与服务解决方案(Statistical Product and Service Solutions,SPSS)软件
SPSS最大的优点是数据录入、整理、分析功能于一身,自由地按照统计学规范的方法处理缺失值、比较值,进行回归分析、聚类分析、生存分析、均值比较和统计性描述等,同时可以根据整理的数据绘制各种图形。
1.5 Graphpad Prism医学绘图数据分析工具
Graphpad Prism是一款基础生物统计及绘图综合软件,集曲线适配和科学图表绘制与一体,帮助科研工作者处理和分析实验结果等。
1.6 DAVID(the Database for Annotation,Visualization and IntegratedDiscovery)数据库
DAVID是一个生物信息数据库,整合了生物学数据和分析工具,为大规模的基因或蛋白列表提供系统综合的生物功能注释信息,帮助用户从中提取生物学信息。
2生物信息学数据分析方法
2.1 TCGA和GEO数据库生存分析
利用TCGA和GEO数据库中AML患者预后数据信息,整合患者基因表达数据,分别进行单因素COX回归分析,取交集后得到与AML患者生存相关的基因作为候选分子。通过查阅相关文献,选取GRAMD1C作为目的基因。
2.2目的基因表达与临床特征联系分析
根据目的基因表达量高低进行分组,统计各组的临床特征,进行卡方检验,探究可能与候选分子表达水平具有相关性的临床因素。
2.3目的基因表达差异及与疾病预后关系分析
在TCGA和GEO数据库中,分析目的基因在AML患者与正常人群、AML患者不同预后分层之间的表达差异,以及基因表达量与患者生存时间的关系。
2.4通路富集分析
将AML患者依据候选分子表达量由大到小的顺序进行排序,选取前50%作为高表达组,后50%作为低表达组,分析高低表达组患者的全基因组表达水平,得到差异基因,对差异性最具统计学意义的分子进行富集分析,探索候选分子参与AML疾病进程的机制。
二、结果
1 GRAMD1C与AML患者的预后密切相关
表1 TCGA和GSE12417数据库中与AML患者预后相关的分子
运用R语言对TCGA和GSE12417数据库中AML患者基因表达谱与生存信息进行单因素COX回归分析,得到一系列与AML患者预后相关的分子,选取HR>1的分子,取交集后得到与AML患者预后最密切相关的8个分子作为研究候选(见图1、表1)。通过查阅相关文献,GRAMD1C未在肿瘤中进行研究,因此选取此分子作为研究对象。
2 AML患者组高表达GRAMD1C
在GSE13159数据集中分析AML患者及正常对照者体内GRAMD1C表达水平,发现AML组(n=542)相较对照组(n=74)高表达(见图2中左侧图)。在GSE30029数据集中分析AML干细胞及正常干细胞GRAMD1C表达水平,发现AML组(n=46)相较对照组(n=31)高表达(见图2中右侧图)。结果显示,AML患者组高表达GRAMD1C。
3 GRAMD1C高表达提示AML患者预后不良
在TCGA数据库中,将AML患者依据FAB分型及细胞遗传学特征进行危险度分层,比较不同AML患者GRAMD1C表达水平,结果显示非M3及细胞遗传学危险度越高的患者体内GRAMD1C表达量越高(见图3A)。将GEO数据库(GSE12417-GPL96、GSE37642-GPL96)中AML患者依据GRAMD1C表达量高低分为两组,结合患者生存信息进行预后分析,结果显示在各个数据集中,GRAMD1C高表达组患者与低表达组相比具有更差的总生存时间(OS)(见图3B)。综上,GRAMD1C高表达提示AML患者预后不良。
4 GRAMD1C与AML患者FAB分型和RUNX1突变相关
表2 AML患者GRAMD1C表达与临床特征相关性检验
将TCGA数据库中AML患者依据GRAMD1C表达量的中位数分为高低两组,整合AML患者各项临床特征,用SPSS软件进行卡方检验,发现GRAMD1C表达水平与AML患者FAB分型以及相关(见表2)。
5 GRAMD1C可能通过参与Wnt信号通路、调节转录因子活性等参与AML的疾病进程
将ADSS高表达组和低表达组患者的全基因组表达水平用SangerBox进行分析,得到差异表达基因,并利用DAVID数据库对高低表达组差异基因进行富集分析,包括GeneOntology(GO)分析,Kyoto Encyclopedia of Genes and Genomes(KEGG)Pathway分析,结果提示,GRAMD1C可能通过参与Wnt信号通路、调节转录因子活性等参与AML的疾病进程(见图4)。
综上所述,基于生物信息学分析GRAMD1C在AML患者中的表达增加,提示GRAMD1C可能作为AML发生过程中的潜在癌基因。GRAMD1C的高表达与多种AML患者的临床和生物学特征相关,可能是AML患者新的诊断及预后评估潜在分子。因此,本专利提示GRAMD1C可能作为AML诊断、治疗、疾病进展监测及预后评估的靶点分子。
以上所述仅是本专利的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本专利技术原理的前提下,还可以做出若干改进和替换,这些改进和替换也应视为本专利的保护范围。
Claims (2)
1.检测胆固醇转运体基因的试剂在制备急性髓系白血病辅助诊断的组合物中的应用,与正常对照者相比急性髓系白血病患者体内胆固醇转运体基因高表达。
2.根据权利要求1所述的应用,所述的辅助诊断的组合物包括:检测胆固醇转运体基因DNA链和/或其cDNA链的PCR引物。
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