CN114392346A - 亨廷顿相互作用蛋白-1相关蛋白基因和/或其编码的蛋白的新应用 - Google Patents
亨廷顿相互作用蛋白-1相关蛋白基因和/或其编码的蛋白的新应用 Download PDFInfo
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Abstract
本发明通过筛选急性髓系白血病(AML)预后相关之分子标志物，筛选出与AML患者预后密切相关的亨廷顿相互作用蛋白‑1相关蛋白基因(HIP1R)；HIP1R高表达提示AML患者预后不良；HIP1R与AML患者FAB分型和细胞遗传学危险分层具有相关性；HIP1R可能通过PI3K‑AKT,TLR等多种途径参与AML的疾病进程。HIP1R应用在AML的预后研究制剂中。
Description
技术领域
本发明属于生物医药领域，具体涉及亨廷顿相互作用蛋白-1相关蛋白基因和/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。
亨廷顿相互作用蛋白-1(HIP1R)是哺乳动物体内目前已知唯一的与亨廷顿相互作用蛋白(HIP1)同家族的蛋白质，HIP1R和HIP1具有相似的蛋白结构。作为网格蛋白有被小窝与囊泡的组分之一，HIP1R与细胞内吞过程中肌动蛋白骨架的组装有关。HIP1R可通过其ENTH结构域参与配体介导的细胞内吞作用，稳定受体型酪氨酸激酶蛋白，从而促进细胞存活。最近的研究还发现HIP1R可以介导PD-L1在溶酶体内降解，通过降低PD-L1增强T细胞的杀伤作用，然而HIP1R在AML中的作用尚不清楚。由于目前尚无文献报导HIP1R与肿瘤的发生、发展以及预后有关。本专利基于对多个数据库的数据分析发现，HIP1R在AML患者中表达降低，HIP1R低表达组AML患者具有更差的预后，并进一步探索了可能的相关机制，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，本发明提供了亨廷顿相互作用蛋白-1相关蛋白基因和/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：
本专利基于生物信息学分析，HIP1R在AML患者中的表达升高，提示HIP1R可作为AML发生过程中的潜在促癌基因。HIP1R的高表达与多种AML患者的临床和生物学特征相关，可作为AML患者新的预后评估潜在分子。因此，本专利除提示HIP1R可能作为AML治疗以及预后评估的靶点分子以外，也提示HIP1R参与其他肿瘤疾病过程的可能性。因此HIP1R或其编码的蛋白可作为AML患者治疗药物中应用，或者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
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。
附图说明
图1是图示经过多数据库分析发现与AML预后相关分子HIP1R的流程。
图2是图示HIP1R在AML患者中低表达，且低表达提示AML患者预后不良。图中浅色曲线表示HIP1RLOW，深色曲线表示HIP1RHIGH。
图3为差异基因分布的火山图，以及其通过GO和KEGG聚类分析后得到的通路。
图4，是HIP1R高低表达组的GSEA富集分析。
具体实施方式
实施例1急性髓系白血病预后标志分子HIP1R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。
1.3BeatAML数据集
BeatAML计划利用全外显子组测序、RNA测序和体外药物敏感性分析等多种方法对来自562名AML患者的672个肿瘤样品进行大规模的功能基因组分析，发现了从未在AML中检测到的突变事件，突变状态会影响肿瘤样品对药物的反应情况。该项目的数据集大部分已发布于2018年10月的《自然》杂志上。
1.4R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。
1.5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。
1.6全基因组关联分析GWAS(Genome-wide association study)
GWAS是通过使用基因组中的单核苷酸多态性(SNP)为分子遗传标记，进行全基因组水平上的对照分析或相关性分析，经由比较发现影响复杂性状的基因变异的一种新策略。
1.7京都基因与基因组百科全书KEGG(Kyoto Encyclopedia of Genes andGenomes)
KEGG是一类数据库资源，可用于从分子水平的信息(尤其是通过基因组测序和其他高通量方法生成的大规模分子数据集)中了解生物系统(例如细胞，生物体和生态系统)的高级功能和实用功能。
2生物信息学数据分析方法
2.1多数据库COX生存分析
利用TCGA和GEO以及BeatAML(Tyner et al.,Nature,2018)数据库中AML患者预后数据信息，整合患者基因表达数据，将AML患者按照高低表达量进行分组，使用survival包作单因素COX生存分析。分别在各个数据库中得到一组与AML患者生存相关的基因。按P值从小到大排列，然后取交集，将取得交集的分子作为候选分子。
2.2多数据库Kaplan-Meier生存分析
选取之前交集中的一个分子，利用已有的将AML患者按照高低表达量进行分组所得到的预后信息，使用survival包作Kaplan-Meier生存分析，进行Log-Rank检验分析并绘制生存曲线图。
2.3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。
2.4基于目的基因的差异富集分析和PPI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，用R语言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进行富集分析，包括Gene Ontology(GO)分析，Kyoto Encyclopedia of Genes and Genomes(KEGG)Pathway分析，Gene Set EnrichmentAnalysis(GSEA)分析,Genome-wide association study(GWAS)分析，观察这些蛋白可以被注释于哪些生物学功能通路和疾病谱中。
二、结果
1 HIP1R与AML患者的预后密切相关。
表1 TCGA，BeatAML，GEO数据集中预后(上)和表达差异(下)分析
通过对TCGA，GEO，BeatAML数据库中AML患者基因表达谱与生存信息的综合分析，得到若干与AML患者预后相关的分子(流程见图1)，将四个数据集取交集，得到4个与AML患者作为研究候选(见表1)，经过文献检索发现，HIP1R从未在AML中报道过，故选取HIP1R作为研究对象。
3 HIP1R低表达提示AML患者预后不良
将GEO数据库(GSE71014-GPL10558)、TCGA数据库以及BeatAML数据库中的AML患者依据HIP1R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，HIP1R高表达组患者与低表达组相比具有更差的总生存(OS)(见图2)。
5 HIP1R与AML患者年龄，FAB分型以及NPM1突变相关
表2 TCGA中HIP1R经过高低表达分组后病人的基线资料差异
将TCGA数据库中AML患者依据HIP1R表达量的中位数分为高低两组，整合AML患者各项临床特征，计数资料行卡方检验，计量资料行Wilcoxon检验，发现HIP1R表达水平与AML患者年龄，白细胞数量，FAB分型以及NPM1突变有关(见表2)。
6 HIP1R可能通过多种途径参与AML发生
将HIP1R高表达组和低表达组患者的全基因组表达水平用R语言进行分析，得到差异表达基因(图3)，并对高低表达组差异基因进行GO,KEGG,GSEA富集分析，分析结果表明HIP1R可能通过参与模式识别受体，snRNA(小核苷酸RNA)，凋亡，mTORC1,Notch,活性氧(Reactive Oxygen Species)通路等途径参与AML发生与发展(图4)。
综上所述，基于生物信息学分析HIP1R在AML患者中的表达升高，提示HIP1R可能作为AML发生过程中的潜在促癌基因。HIP1R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患者新的预后评估潜在分子。由于目前尚无文献报导HIP1R与肿瘤的发生、发展以及预后有关。因此，本专利除提示HIP1R可能作为AML治疗以及预后评估的靶点分子以外，也提示HIP1R参与其他肿瘤疾病过程的可能性。
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 (4)
1.亨廷顿相互作用蛋白-1相关蛋白基因和/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。
2.根据权利要求1所述的应用，所述药物中包括亨廷顿相互作用蛋白-1相关蛋白基因和/或其编码的蛋白，以及一种或多种药用赋形剂或药用载体。
3.亨廷顿相互作用蛋白-1相关蛋白基因和/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。
4.根据权利要求3所述的应用，所述的辅助诊断和/或预后判断的组合物包括：用于在PCR中合成亨廷顿相互作用蛋白-1相关蛋白基因DNA链和/或其cDNA链的PCR引物、或抗-亨廷顿相互作用蛋白-1相关蛋白的抗体。
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