CN114231630A - EBF3和/或Vimentin在作为鼻咽癌预后标记物中的应用 - Google Patents
EBF3和/或Vimentin在作为鼻咽癌预后标记物中的应用 Download PDFInfo
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Abstract
本发明涉及癌症诊断与治疗领域,尤其涉及一种EBF3和/或Vimentin在作为鼻咽癌预后标记物中的应用。本发明提供了一种EBF3和/或Vimentin作为鼻咽癌预后标记物在制备用于鼻咽癌的早期诊断、风险评估或预后程度预测的试剂盒或检测试剂中的用途。本发明分析发现EBF3在鼻咽癌中的表达高于癌旁组织,EBF3在转移鼻咽癌患者组织以及高转移鼻咽癌细胞中表达上调,本发明同时发现EBF3与Vimentin联合可以更好地预测NPC患者预后。因此,本发明将EBF3和/或Vimentin作为鼻咽癌预后标记物,有利于鼻咽癌的早期诊断、风险评估或预后程度预测。
Description
技术领域
本发明涉及癌症诊断与治疗领域,尤其涉及一种EBF3和/或Vimentin在作为鼻咽癌预后标记物中的应用。
背景技术
鼻咽癌(Nasopharyngeal carcinoma,NPC)有其独特的生物学特性,我们把它分为四种类型,I型为放射敏感不易转移型,单纯放疗可达到根治性效果;II型是放射抗拒不易转移型,常常是局部区域复发导致治疗失败;III型为放射敏感易转移型,单纯放疗时由于远处转移导致治疗失败;IV型为放射抗拒易转移型,约占5%左右,此型鼻咽癌疗效最差。近年,由于治疗技术的进步,在规范化治疗的基础上,开展多学科的诊治,使鼻咽癌得到更加合适的治疗包括个体化和精准治疗,II、III型鼻咽癌的疗效明显改进,使鼻咽癌总的5年生存率达到85-90%以上。但是IV型鼻咽癌疗效仍不满意,5年生存率不超过10%。它是影响鼻咽癌成为根治性疾病治疗进程中的瓶颈,是亟待解决的临床问题。
在小鼠、人类和其他脊椎动物的基因组中,有4个EBF家族的同源基因(EBF1-4)。EBF家族参与了多种发育途径,包括B细胞分化、神经发生和骨发育。与其他DNA结合转录因子类似,EBF家族蛋白可以直接结合到具有5′-CCCNNGGG-3′序列的DNA上,作为同型或异型二聚体从而发挥功能。而在EBF家族蛋白的DNA结合域上,有一个EBF家族的特征序列,即非典型的锌指序列(H-X3-C-X2-C-X5-C),这个序列也是DNA结合所必须的。据报导,转录因子EBF1在B细胞发育中起关键作用,分别与B细胞谱系程序性激活和选择性谱系潜能不可逆性丧失有关,缺乏EBF1基因的小鼠无法产生功能性B细胞和免疫球蛋白。EBF1可以在B细胞发育的不同时期选择性激活或抑制不同的基因,有报道称EBF1可以通过直接抑制GATA3或促进CD53的表达来促进B细胞谱系的形成。EBF家族在中脑到脊髓的有丝分裂后早期神经元和胚胎前脑的特定部位表达,提示它们可能调节中枢神经系统(CNS)中神经元的成熟。同时EBF2可以维持骨内稳态,调节破骨细胞(Ocs)的造血骨吸收和成骨细胞(Obs)的间充质骨形之间的相互作用,从而达到骨内平衡。在人和小鼠模型中的联合研究表明,EBF2也是调节脂肪形态、脂肪分解和胰岛素抵抗的重要分子。
据报导,EBF1基因的基因组缺失或突变与急性淋巴细胞白血病(ALL)的发病、耐药和复发有关。EBF和/或PAX5的突变将激活STAT5,通过加重B细胞分化增殖期的分化阻滞,增加了B细胞前体的突变,这些B细胞前体的突变促进了白血病转化。同时EBF1参与了对DNA损伤修复和细胞存活相关基因的调控,EBF1基因在人类白血病中频繁丢失,将导致包括RAD51在内的DNA损伤修复基因的表达减少。同时研究发现EBF1可以与TET2发生相互作用,从而形成一种调节DNA甲基化的特异性机制,而高甲基化导致异柠檬酸脱氢酶基因1和2(IDH1和IDH2)的变异,这种变异会促进急性髓系白血病(AML)、低级别胶质瘤和肝内胆管癌的发生发展。EBF1在慢性淋巴细胞白血病(CLL)、经典霍奇金淋巴瘤(cHL)和骨髓增生异常综合征(MDS)也均有报道。EBF2在骨肉瘤中高表达,导致骨保护素(osteoprote-gerin,OPG)的水平升高,并且EBF2的上调将会抑制骨肉瘤细胞凋亡,促进骨肉瘤细胞的迁移和侵袭。有关EBF与转移的报导较少,在胆管上皮癌(CCA)中,长时间的氧化应激抑制了EBF1的表达,降低的EBF1促进了肿瘤的发生,同时提升了细胞的侵袭能力。
EBF3在肿瘤中的作用存在两面性。有证据表明EBF3在多种癌症中有抑癌作用。EBF3在转移性前列腺癌中表达降低,在结肠癌、肝癌、头颈部鳞状细胞癌发生表观沉默,全外显子测序发现在多形性胶质母细胞瘤(GBM)和胰腺癌中EBF3基因存在破坏蛋白质功能的肿瘤特异性错义突变从而导致蛋白失活。EBF3调节有关细胞生长、增殖和凋亡的多种基因的表达,例如细胞周期蛋白依赖激酶抑制剂(CDKIs)的Cip/Kip家族,以及一些细胞周期蛋白和CDKs。在胶质瘤细胞和骨肉瘤细胞中,EBF3的高表达导致p21和p27的初始激活和进一步的显著抑制。并且在大多数高级别脑肿瘤中,EBF3丢失的频率与神经胶质瘤发生的关键抑制因子PTEN的丢失频率相似。亦有报导发现EBF3在其他癌症中发挥促癌作用,例如嗜铬细胞瘤、慢性淋巴细胞白血病。此外,EBF3在髓母细胞瘤干细胞或HepG2肝癌细胞中表达量升高,并且分别通过影响细胞增殖以及细胞周期从而发挥癌基因的作用。在恶性黑色素瘤中,EBF3被报道因为启动子区域超甲基化而高表达,并在黑色素瘤转移中起到驱动作用,但并未阐明其具体分子机制。
发明内容
本发明的目的在于克服现有技术的不足,提供一种EBF3和/或Vimentin在作为鼻咽癌预后标记物中的应用。
为实现上述目的,本发明采取的技术方案为:提供一种EBF3和/或Vimentin作为鼻咽癌预后标记物在制备用于鼻咽癌的早期诊断、风险评估或预后程度预测的试剂盒或检测试剂中的用途。
作为本发明所述用途的优选实施方式,所述试剂盒或检测试剂用于患者原位组织样品的检测。
作为本发明所述用途的优选实施方式,所述试剂盒中含有能特异性检测EBF3和/或Vimentin的mRNA或蛋白水平的分子。
作为本发明所述用途的优选实施方式,能够特异性检测EBF3和/或Vimentin的mRNA或蛋白水平的分子为核酸或蛋白质。
作为本发明所述用途的优选实施方式,所述核酸包括能扩增得到EBF3基因和/或Vimentin基因的引物。
作为本发明所述用途的优选实施方式,所述能扩增得到EBF3基因的引物序列如SEQ ID NO:1和SEQ ID NO:2所示,所述能扩增得到Vimentin基因的引物序列如SEQ ID NO:3和SEQ ID NO:4所示。
作为本发明所述用途的优选实施方式,所述蛋白质为抗体。
作为本发明所述用途的优选实施方式,所述抗体为多克隆抗体或单克隆抗体。
作为本发明所述用途的优选实施方式,所述EBF3的NCBI登录号为253738;所述Vimentin的NCBI登录号为7431。
本发明同时提供一种鼻咽癌的早期诊断、风险评估或预后程度预测的试剂盒,所述试剂盒包括检测EBF3和/或Vimentin的mRNA或蛋白水平的分子。
本发明的有益效果:
本发明分析发现EBF3在鼻咽癌中的表达高于癌旁组织,EBF3在转移鼻咽癌患者组织以及高转移鼻咽癌细胞中表达上调,本发明同时发现EBF3与Vimentin联合可以更好地预测NPC患者预后,且对患者生存期的研究也发现,EBF3与Vimentin同时高表达的患者预后最差。因此,本发明将EBF3和/或Vimentin作为鼻咽癌预后标记物,有利于鼻咽癌的早期诊断、风险评估或预后程度预测。
附图说明
图1为EBF3在初诊转移的NPC患者组织以及NPC转移细胞系中上调;其中,A:不转移患者原位组织原代细胞vs转移患者原位组织原代细胞中EBF3的FPKM比较;B:鼻咽癌患者活检组织EBF3 mRNA水平检测;C:鼻咽癌患者活检组织EBF3蛋白水平检测;D:诊断时无转移vs有转移的患者活检肿瘤组织EBF3 mRNA水平检测。E:鼻咽癌细胞系EBF3 mRNA水平检测;F:鼻咽癌细胞系EBF3蛋白水平检测;G:在108例石蜡包埋的鼻咽癌组织中进行IHC检测,根据EBF3蛋白水平分组后进行总生存曲线分析;H:ONCOMINE数据库的正常鼻咽部上皮组织和鼻咽癌组织的EBF3 mRNA水平比较。
图2为EBF3表达量影响鼻咽癌细胞转移能力;其中,A、B:对照以及过表达EBF3细胞的迁移以及侵袭实验;C、D:对照以及敲低EBF3细胞的迁移以及侵袭实验;E:小鼠体内足底-淋巴结转移模型建模示意图;F:对照以及过表达EBF3的HK1细胞构建小鼠模型后淋巴结大体图像;G:存在转移阳性淋巴结的小鼠数量;H:转移淋巴结阳性率;I:对照以及敲低EBF3的HONE1细胞构建小鼠模型后淋巴结大体图像;J:存在转移阳性淋巴结的小鼠数量;K:转移淋巴结阳性率。
图3为RNA-seq测序分析;其中,A:对照以及过表达EBF3的HK1细胞的差异基因热图;B:对照以及敲低EBF3的HONE1细胞的差异基因热图;C:对照以及过表达EBF3的HK1细胞的差异基因功能富集分析;D:对照以及敲低EBF3的HONE1细胞的差异基因功能富集分析。
图4为EBF3表达影响细胞形态以及Vimentin表达;其中,A、B:对照以及过表达EBF3细胞的mRNA表达水平分析;C、D:对照以及敲低EBF3细胞的mRNA表达水平分析;E、F:对照以及过表达EBF3细胞的蛋白表达水平分析;G、H:对照以及敲低EBF3细胞的蛋白表达水平分析;I、J:免疫荧光展示过表达或敲低EBF3细胞的形态变化。
图5为EBF3直接与Vimentin启动子结合并促进其活性;其中,A:在带有EBF3结合启动子的基因转录起始位点(TSS)的上游和下游3kb范围内EBF3结合峰的位置分布;B:CUT&Tag密度热图,在TSS前后3kb范围内,基因密度由高到低依次排列;C:EBF3结合位点富集的前4个基序;D:测序数据显示EBF3与Vimentin启动子结合;E、F:对转染了Vimentin启动子报告基因的细胞进行荧光素酶活性测定;G:使用Flag抗体或IgG抗体对稳定表达FLAG-EBF3的HK1细胞进行ChIP-qPCR分析;H:Vimentin启动子区域示意图(箭头表示转录起始位点;ATG,翻译开始密码子);I:野生型Vimentin启动子及其突变体示意图;J:用Vimentin启动子报告基因(野生型或突变型)转染对照或过表达EBF3细胞,然后进行荧光素酶活性测定。
图6为EBF3对鼻咽癌转移的促进作用依赖于Vimentin;其中,A、B、C:对相应细胞进行mRNA表达水平分析;D、E、F:对相应细胞进行蛋白表达水平分析;D:对应细胞构建小鼠模型后淋巴结大体图像;H:存在转移阳性淋巴结的小鼠数量;I:转移淋巴结阳性率;
图7为EBF3作为NPC预后标记物;其中,A:对上述108例石蜡包埋的鼻咽癌组织中进行IHC检测,根据Vimentin蛋白水平分组进行总生存曲线分析;B:这108例组织中EBF3与Vimentin表达的相关性;C:总生存的ROC曲线分析:EBF3[AUC=0.625,(95%CI,0.560-0.690)],Vimentin[AUC=0.693,(95%CI,0.634-0.753)],联合组[AUC=0.755(95%CI,0.701-0.809)]。AUC,曲线下的面积;D:29例EBF3高表达/Vimentin高表达组织和42例EBF3低表达/Vimentin低表达组织的总生存率比较。
具体实施方式
为更清楚地表述本发明的技术方案,下面结合具体实施例进一步说明,但不能用于限制本发明,此仅是本发明的部分实施例。
实施例1 EBF3在转移鼻咽癌患者组织以及高转移鼻咽癌细胞中表达上调
对收集到的10例患者原代细胞进行RNA-seq测序,得到不转移患者原位组织vs转移患者原位组织中的差异基因,分析发现转录因子EBF3在转移患者原位组织中显著上调(图1A)。提取鼻咽癌患者活检组织进行mRNA以及蛋白水平检测,发现与正常鼻咽组织相比鼻咽癌组织中EBF3水平上调(图1B、C)。取诊断时无转移vs有转移的患者原位肿瘤组织提取RNA,发现EBF3在诊断时有转移的患者组织中表达上调(图1D)。在不同转移特性的NPC细胞系检测EBF3的mRNA以及蛋白水平,其在低转移特性细胞系HK1、S26、6-10B表达量较高转移特性细胞系S18、5-8F表达量低(图1E、F)。在108例鼻咽癌石蜡切片中进行EBF3的IHC检测,发现其在细胞核表达,并且高表达EBF3的患者预后更差(图1G)。网络数据库数据分析发现EBF3在鼻咽癌中的表达高于癌旁组织(图1H)。
实施例2 EBF3表达量影响鼻咽癌细胞转移能力
在NPC细胞系HK1以及S26中过表达EBF3,能够显著促进NPC细胞的迁移以及侵袭能力(图2A、B),而在HONE1以及S18细胞中敲低EBF3明显抑制NPC细胞的迁移以及侵袭能力(图2C、D)。小鼠体内足底-淋巴结转移模型证实了EBF3在体内的功能(图2E),过表达EBF3显著促进NPC细胞从足底转移到淋巴结(图2F-H),敲低EBF3显著抑制NPC细胞的转移能力(图2I-K)。
实施例3 RNA-seq测序发现EBF3与转移相关
本发明将HK1对照和稳定过表达EBF3细胞系,以及HONE1对照和稳定敲低EBF3细胞系送RNA-seq测序,得到差异基因(图3A、B),并对差异基因进行GO分析,发现存在血管生成、细胞形态细胞间黏附以及其他与转移相关的通路富集(图3C、D)。
本发明进一步对有差异的转移相关标记物进行mRNA、蛋白水平以及免疫荧光检测,发现EBF3对Vimentin的调控最为显著(图4A-H)。同时免疫荧光检测细胞形态,我们发现在细胞系HK1中过表达EBF3,细胞形态发生明显变化,丝状伪足和片状伪足数量明显增长增多,敲低EBF3能使得HONE1细胞由细长变得椭圆,伪足数量明显减少(图4I-J)。
实施例4 EBF3直接与Vimentin启动子结合并促进其活性
我们使用Flag抗体对过表达Flag-EBF3的HK1细胞进行CUT&Tag测序分析,发现EBF3在基因转录起始位点附近显著富集(图5A、B)。同时我们对EBF3的DNA结合序列进行了鉴定(图5C),发现VIM基因启动子上存在EBF3的结合峰(图5D)。应用双荧光素酶报告基因实验发现过表达EBF3可特异性促进Vimentin启动子的活性,而敲低EBF3将使得Vimentin启动子的活性下降(图5E、F)。将Vimentin启动子分隔成300bp的片段设计引物,进行分段ChIP实验,我们发现EBF3与Vimentin启动子上+201bp至+400bp片段以及+601bp至+800bp片段存在结合(图5G、H)。由于已有报导发现EBF家族结合下游基因启动子上的回文序列“CCCNNGGG”,我们在上述ChIP验证的Vimentin启动子上找到5个相似序列,并将其进行突变,检测Vimentin启动子活性,发现MUT1和MUT2是EBF3在Vimentin启动子上的结合位点(图5I、J)。
实施例5 EBF3对鼻咽癌转移的促进作用依赖于Vimentin
内源性Vimentin的敲除逆转了EBF3过表达诱导的迁移和侵袭增强(图6A、D)。而Vimentin的过表达逆转了EBF3敲除引起的细胞迁移、侵袭和转移抑制(图6B、C、E-I)。这些结果表明EBF3结合Vimentin启动子并诱导其表达,从而导致鼻咽癌转移。
实施例6 EBF3联合Vimentin作为NPC预后标记物
进一步对上述108例NPC石蜡切片组织进行IHC染色分析,我们发现Vimentin高表达的患者预后更差(图7A)。同时我们发现EBF3与Vimentin的表达存在明显正相关(图7B),并且ROC曲线发现联合EBF3与Vimentin的曲线下面积大于单指标,表示EBF3与Vimentin联合可以更好地预测NPC患者预后(图8C)。并且对患者生存期的研究也发现,EBF3与Vimentin同时高表达的患者预后最差(图8D)。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
SEQUENCE LISTING
<110> 中山大学肿瘤防治中心(中山大学附属肿瘤医院、中山大学肿瘤研究所)
<120> EBF3和/或Vimentin在作为鼻咽癌预后标记物中的应用
<130> 2021.12.10
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<170> PatentIn version 3.3
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Claims (10)
1.EBF3和/或Vimentin作为鼻咽癌预后标记物在制备用于鼻咽癌的早期诊断、风险评估或预后程度预测的试剂盒或检测试剂中的用途。
2.根据权利要求1所述的用途,其特征在于,所述试剂盒或检测试剂用于患者原位组织样品的检测。
3.根据权利要求1所述的用途,其特征在于,所述试剂盒中含有能特异性检测EBF3和/或Vimentin的mRNA或蛋白水平的分子。
4.根据权利要求3所述的用途,其特征在于,能够特异性检测EBF3和/或Vimentin的mRNA或蛋白水平的分子为核酸或蛋白质。
5.根据权利要求4所述的用途,其特征在于,所述核酸包括能扩增得到EBF3基因和/或Vimentin基因的引物。
6.根据权利要求5所述的用途,其特征在于,所述能扩增得到EBF3基因的引物序列如SEQ ID NO:1和SEQ ID NO:2所示,所述能扩增得到Vimentin基因的引物序列如SEQ ID NO:3和SEQ ID NO:4所示。
7.根据权利要求4所述的用途,其特征在于,所述蛋白质为抗体。
8.根据权利要求7所述的用途,其特征在于,所述抗体为多克隆抗体或单克隆抗体。
9.根据权利要求1所述的用途,其特征在于,所述EBF3的NCBI登录号为253738;所述Vimentin的NCBI登录号为7431。
10.一种鼻咽癌的早期诊断、风险评估或预后程度预测的试剂盒,其特征在于,所述试剂盒包括检测EBF3和/或Vimentin的mRNA或蛋白水平的分子。
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WO2017219062A1 (en) * | 2016-06-23 | 2017-12-28 | The University Of Sydney | Methods for differentiating cells into cells with a muller cell phenotype, cells produced by the methods, and methods for using the cells |
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SHIRONG DING 等: "EBF3 reactivation by inhibiting the EGR1/EZH2/HDAC9 complex promotes metastasis via transcriptionally enhancing vimentin in nasopharyngeal carcinoma", 《CANCER LETTERS》, vol. 527, pages 49, XP086945996, DOI: 10.1016/j.canlet.2021.12.010 * |
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