CN115927645A - Hnf4g在检测肺腺癌顺铂敏感性中的应用 - Google Patents
Hnf4g在检测肺腺癌顺铂敏感性中的应用 Download PDFInfo
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Abstract
本发明公开了HNF4G在检测肺腺癌顺铂敏感性中的应用。本发明首先基于生物信息学分析，揭示了HNF4G的高表达与顺铂耐药性显著正相关；随后经过一系列生物学实验证实了HNF4G表达与顺铂耐药性的相关性，进一步提出通过检测HNF4G表达来判断肺腺癌对顺铂的敏感性。本发明首次提出了HNF4G可作为生物标志物用于判断肺腺癌对顺铂的敏感性；通过检测HNF4G表达来判断肺腺癌对顺铂的敏感性，具有操作简便、高敏感性、特异性的优点，因此，具有临床推广应用价值。
Description
技术领域
本发明涉及HNF4G在检测肺腺癌顺铂敏感性中的应用，属于分子诊断技术领域。
背景技术
顺铂为金属铂类络合物，在细胞内与DNA结合形成DNA链间、DNA链内或蛋白质与DNA的交联，从而破坏的结构，阻断DNA复制与转录从而抑制肿瘤细胞增殖并引发程序性凋亡，广泛地应用于肺腺癌乃至其它肿瘤的临床治疗中。但是，肺腺癌患者接受治疗过程中容易产生顺铂耐药，影响治疗效果。顺铂耐药的分子机制复杂，除主要与耐药相关基因的改变、细胞解毒和DNA损伤修复基因的改变外，还与染色体改变、凋亡相关基因的改变、细胞骨架、血管形成及细胞外基质密度异常有关，涉及到细胞内的多个信号通路。预测患者顺铂治疗的敏感性对于肺腺癌患者治疗方案的制定，提升患者治疗效果哦极为重要。
肝细胞核因子4γ(hepatocyte nuclear factor 4gamma，HNF4G)是一种目前研究较少的转录因子。据报道HNF4G在肺腺癌中表达高于正常组织，且促进肺腺癌的增殖与转移。但目前在肺腺癌乃至其它肿瘤中均尚未报道HNF4G与顺铂敏感性的关系。
发明内容
本发明的目的是：提供一种新的生物标志物HNF4G作为评估肺腺癌顺铂敏感性的诊断标志物，通过检测肺腺癌HNF4G基因的表达量用于判断肺腺癌患者对顺铂治疗的敏感性，具有操作简便、高敏感性、特异性、高性价比和应用价值，有助于实现针对患者的精准医疗。
为了实现上述目的，本发明提供了一种检测试剂在制备用于评估顺铂治疗肺腺癌敏感性的试剂盒中的应用，所述检测试剂为检测肺腺癌样本中HNF4G基因表达量的试剂，所述检测试剂作为试剂盒实现判断肺腺癌对顺铂敏感性的唯一关键成分。
优选地，所述试剂盒内还包括说明书，所述说明书记载了HNF4G基因表达量的评估截断值，所述HNF4G基因表达量的单位为FPKM，且进行log2(FPKM+1)变换；当肺腺癌样本中HNF4G log2(FPKM+1)≤2.40，则判断为患者对顺铂敏感；当肺腺癌样本中HNF4G log2(FPKM+1)>2.40，则判断为患者对顺铂耐药。
优选地，所述肺腺癌样本为肺腺癌细胞系或肺腺癌新鲜组织肿瘤样本。
优选地，所述检测样本为肺腺癌细胞系或肺腺癌新鲜组织肿瘤样本。
与现有技术相比，本发明的有益效果在于：
本发明首次提出了HNF4G可作为生物标志物用于判断肺腺癌对顺铂的敏感性；本发明通过生物信息学分析揭示了HNF4G的高表达与顺铂耐药性显著正相关，经过一系列生物学实验证实了HNF4G表达与顺铂耐药性的相关性，进一步提出通过检测HNF4G表达来判断肺腺癌对顺铂的敏感性，具有操作简便、高敏感性、特异性，为临床上评估肺腺癌患者对顺铂治疗的敏感性提供了一种新的诊断途径。
附图说明
图1：生物信息学分析揭示HNF4G的高表达与顺铂耐药性显著正相关：(A)HNF4G表达最高的50个细胞系和HNF4G表达最低的50个肿瘤细胞系对顺铂的耐药性；(B)50种对顺铂最耐药的细胞系和50种对顺铂最敏感的细胞系中的HNF4G表达；(C)不同HNF4G表达的接受顺铂化疗的肺腺癌患者的生存曲线；***p<0.001；
图2：HNF4G促进肺腺癌细胞对顺铂的耐药性(A)qRT-PCR和(B)A549和HCC827细胞中顺铂处理后HNF4G表达的western blot结果；(C)HNF4G过表达和敲低细胞中HNF4G表达的qRT-PCR结果；(D)HNF4G过表达和敲低细胞的顺铂敏感性曲线；*p<0.05，**p<0.01，**p<0.001；
图3：HNF4G促进MAPK6表达和MAPK6/Akt信号通路；(A)Encode数据库的ChIP-Seq数据显示MAPK6启动子中的HNF4G结合峰；(B)TCGA数据库中肺腺癌组织中HNF4G和MAPK6表达的相关性；(C)qRT-PCR检测HNF4G过表达和敲低细胞中的MAPK6表达；(D)采用western blot检测过表达或敲低HNF4G的细胞中HNF4G、MAPK6、p-MAPK6，Akt和p-Akt(S473)表达；(E)用或不用Akt抑制剂处理的对照和HNF4G过表达细胞的顺铂敏感性曲线；
图4：HNF4G结合MAPK6的启动子区以促进MAPK6表达；(A)预测HNF4G结合位点并设计MAPK6启动子中的引物位置；(B)HNF4G在MAPK6启动子中结合的ChIP-qPCR结果；(C)MAPK6启动子中潜在HNF4G结合位点的序列和相应的突变序列；(D)采用含有MAPK6启动子和突变启动子的双荧光素酶实验；
图5：检测HNF4G表达判断细胞系顺铂耐药性的敏感性和特异性ROC曲线。
具体实施方式
为使本发明更明显易懂，兹以优选实施例，并配合附图作详细说明如下。
实施例
(一)生物信息学分析揭示HNF4G的高表达与顺铂耐药性显著正相关：
首先从CCLE数据库获得了542个肺腺癌细胞系的包含HNF4G在内的基因表达数据(以log2(FPKM+1)为单位)，从CTRP数据库中获得了这542个细胞系对顺铂的耐药性数据(以半数抑制浓度IC50的自然对数为单位，即LN_IC50)。在分析细胞系中基因表达与顺铂耐药性的相互关系时，发现HNF4G高表达的细胞对顺铂更为耐药。如图1A所示，HNF4G表达最高的50个细胞系的LN_IC50显著高于HNF4G表达最低的50个顺铂细胞系的LN_IC50(p<0.001)，而50个顺铂最为耐药的细胞系中的HNF4G表达显著高于50个顺铂最为敏感的细胞系(p<0.001)(图1B)。
同时，在Kaplan-Meier plotter数据库中获得了19例接受顺铂化疗的肺腺癌患者的预后，发现高HNF4G表达的患者预后更差，尽管p值不显著，这可能是由于样本量过小的原因(图1C)。
(二)HNF4G促进肺腺癌细胞对顺铂的耐药性：
使用qRT-PCR(图2A)和western blot(图2B)检测了不同浓度顺铂处理后肺腺癌细胞系A549和HCC827中HNF4G的表达，发现在顺铂处理后HNF4G显著增加。采用慢病毒分别在A549和HCC827细胞中过表达和敲低了HNF4G的表达，其中采用两种不同的shRNA序列来减少脱靶效应对实验结果的影响(图2C)。实验结果表明，过表达HNF4G显著增强了A549和HCC827细胞对顺铂的耐药性，而敲低HNF4G则使细胞对顺铂更为敏感(图2D)。上述结果表明，HNF4G显著增强了肺腺癌细胞对顺铂的耐药性。
(三)HNF4G促进MAPK6表达和MAPK6/Akt信号通路：
作为一种转录因子，HNF4G可能与一些与顺铂耐药相关基因的转录启动子结合，以调节其表达和顺铂耐药。通过分析Encode数据库中ChIP-Seq数据中HNF4G的可能下游因子，寻找其中与顺铂耐药相关的靶基因。结果发现，在MAPK6转录起始位点(TSS)上游的-1000bp～200bp启动子区域中有多个HNF4G的结合峰(图3A)，而先前的研究表明，MAPK6磷酸化Akt的S473位点以激活Akt，而激活的Akt显著促进细胞对顺铂的抗性。同时，TCGA数据库的肺腺癌RNA-Seq数据显示，HNF4G的表达与肺腺癌患者中MAPK6的表达显著正相关，也表明HNF4G调节MAPK6表达(图3B)。
采用qRT-PCR(图3C)和western blot(图3D)，证实HNF4G过表达促进了A549和HCC827细胞中MAPK6的表达和磷酸化，以及Akt S473磷酸化，而HNF4G敲低抑制了MAPK6表达和MAPK6/Akt信号通路的激活。
采用1μM Akt特异性抑制剂MK-2206处理细胞。结果发现，抑制Akt活性后，过表达HNF4G的A549和HCC827细胞与对照细胞之间的顺铂耐药性不再存在显著差异(图3E)，表明MAPK6/Akt信号通路是HNF4G作用于顺铂耐药性的关键机制。
(四)HNF4G结合MAPK6的启动子区以促进MAPK6表达：
从JASPAR网站，获得了MAPK6启动子区域中HNF4G的潜在结合位点，并设计了三对ChIP-qPCR引物，以检测HNF4G与MAPK6基因启动子的结合(图4A)。如图4B所示，ChIP qPCR结果表明，HNF4G与这三对引物扩增的序列周围的区域显著结合。
为了进行双荧光素酶实验，分别合成了含有MAPK6-1000～200bp区域的萤火虫荧光素素酶质粒、以及其中该区域中HNF4G的所有潜在结合位点均随机突变的萤火虫萤光素酶质粒(图4C)。实验结果表明：过表达HNF4G显著增加了含MAPK6启动子的萤火虫荧光素酶的活性(图4D)。但过表达HNF4G不能促进MAPK6启动子中HNF4G的所有可能结合位点均被突变掉的萤火虫荧光素酶的表达(图4D)。
(五)HNF4G检测顺铂敏感性的界值和肺腺癌患者组织中的验证：
对CCLE和CTRP数据库中的肺腺癌细胞系的HNF4G表达和顺铂的耐药性数据进行ROC曲线分析(图5)。分析结果表明，当HNF4G表达界值为2.40时，其敏感性为0.860，特异性为1-0.360＝0.640。特异性和敏感性之和最大。因此，考虑将2.40作为HNF4G判断肺腺癌顺铂敏感性的界值。
分析复旦大学附属中山医院胸外科数据库中接受术后顺铂化疗的肺腺癌患者信息，其中于1年内出现肿瘤原发灶复发或转移或肿瘤导致死亡的患者定义为顺铂耐药组，而随访5年及以上无复发或转移、肿瘤导致死亡的患者定义为顺铂敏感。各获得了15例顺铂耐药患者和15例顺铂敏感患者的冰冻的新鲜肺腺癌组织样本，进行基因测序。具体步骤如下：
①RNA抽提和文库构建：
采用TRIzol试剂依照说明书提取总RNA。使用NanoDrop 2000分光光度计(ThermoScientific,USA)鉴定RNA纯度和定量，使用Agilent 2100Bioanalyzer(AgilentTechnologies,Santa Clara,CA,USA)评估RNA完整性。使用VAHTS Universal V5 RNA-seqLibrary Prep试剂盒依照说明书构建转录组文库。
②采用llumina Novaseq 6000测序平台对文库进行测序，并生成150bp双端reads。采用fastp软件对fastq格式的raw reads进行处理，去除低质量reads后获得cleanreads用于后续数据分析。使用HISAT2软件进行参考基因组比对，进行基因表达量(FPKM)计算，并转换成Log2(FPKM+1)值。
③将样本按照HNF4G表达分为两组，大于2.40的预测为顺铂耐药，等于或小于2.40的预测为顺铂敏感，与实际患者的顺铂耐药结果相比较，计算灵敏度＝12/15＝80％，特异度＝10/15＝66.6％(表1)。
表1评分模型在收集的肺腺癌患者中预测的灵敏度与特异度
上述实施例仅为本发明的优选实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本技术领域的普通技术人员，在不脱离本发明的前提下，还将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。
Claims (4)
1.一种检测试剂在制备用于评估顺铂治疗肺腺癌敏感性的试剂盒中的应用，其特征在于，所述检测试剂为检测肺腺癌样本中HNF4G基因表达量的试剂，所述检测试剂作为试剂盒实现判断肺腺癌对顺铂敏感性的唯一关键成分。
2.如权利要求1所述的应用，其特征在于，所述试剂盒内还包括说明书，所述说明书记载了HNF4G基因表达量的评估截断值，所述HNF4G基因表达量的单位为FPKM，且进行log2(FPKM+1)变换；当肺腺癌样本中HNF4G log2(FPKM+1)≤2.40，则判断为患者对顺铂敏感；当肺腺癌样本中HNF4G log2(FPKM+1)>2.40，则判断为患者对顺铂耐药。
3.如权利要求2所述的应用，其特征在于，所述肺腺癌样本为肺腺癌细胞系或肺腺癌新鲜组织肿瘤样本。
4.一种用于评估顺铂治疗肺腺癌敏感性的试剂盒，其特征在于，至少包括特异性检测HNF4G基因表达量的试剂。
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