CN113498440A - 新型胰腺癌上皮间质转化标记物 - Google Patents
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Abstract
为了阐明BACH1的胰腺癌恶性化机制,利用RNA序列法揭示了:在胰腺癌细胞株中的BACH1的表达量所引起的基因表达变化。进而,进行了体外(in vitro)的迁移能力、浸润能力以及体内(in vivo)的原位移植实验,结果示出了:BACH1能单独或与其下游调控因子FOXA1组合而用作胰腺癌的上皮间质转化的优异生物标志物。
Description
技术领域
本发明涉及一种用于评价胰腺癌的上皮间质转化(Epithelial mesenchymaltransitios,EMT)能力的方法、用于评价胰腺癌的转移能力或浸润能力的方法、用于预测胰腺癌的预后的方法、胰腺癌转移抑制剂、以及胰腺癌转移抑制剂的筛选方法。
背景技术
胰腺癌是主要发生于胰管上皮的癌症,诊断后的五年生存率在10%以下,是预后最差的癌症。只有外科切除是可以期待根治的治疗方法,但是从现状来看,很难在早期发现,诊断时80%的病例为无法手术,且恶性程度高,因此化疗也没有什么效果等,缺乏有效的诊断方法、治疗方法。
对于胰腺癌的发生机制的理解在不断地深入,从20世纪50年代开始,根据病变病理学观察,逐渐推想出多阶段致癌假说。近年来的强大的基因组突变解析揭示了与胰腺癌的致癌过程相对应的突变基因的积累,目前,因突变基因的积累而致癌的这一多阶段致癌假说(Genetic progression model)已被广泛接受。在该致癌过程中,已知在癌前病变的早期开始观察到的突变中有鼠类肉瘤病毒癌基因(kirsten rat sarcoma viral oncogene,KRAS)的突变,90%以上的胰腺癌具有KRAS突变。通常而言,作为对受体型酪氨酸激酶受体的外部刺激响应,KRAS与三磷酸鸟苷(Guanosine triphosphate,GTP)结合而活化,促进RAS(Rat Sarcoma Viral Oncogene Homolog,大鼠肉瘤病毒同源癌基因)/RAF(RapidlyAccelerated Fibrosarcoma,快速加速纤维肉瘤)/MEK(Mitogen-Activated ProteinKinase,促分裂原活化蛋白激酶)/ERK(Extracellular signal regulated kinase,细胞外信号调节激酶)的信号转导通路而引发细胞增殖、凋亡、分化之类的细胞应答。此外,其活性在GTP水解而变成二磷酸鸟苷(Guanosine diphosphate,GDP)时失活。但是,癌症中常见的KRAS基因突变大多会阻害该GTP的水解,始终保持活化状态,促进癌细胞的增殖、恶性化。除了胰腺癌以外,所有人类癌症中的约30%都包含该活化RAS突变。因此,迄今一直致力于研究RAS和GTP的竞争阻害剂之类的以RAS为靶标的阻害剂,但是,因细胞内存在高浓度的GTP、GDP等而无法得到充分的效果,均尚未实现临床应用。
因此,虽然进一步阐明胰腺癌恶性化机理是很重要的,但是,目前还尚未鉴定出对转移、复发具有特异性的基因突变。此外,作为转移能力获得中的原发性肿瘤中基因表达波动以及信号转导的变化、进而转移促进因子,考虑到癌细胞的自我复制、上皮间质转化以及癌周围环境的影响,但目前尚有许多不明之处。
在正常状态下,BACH1(BTB and CNC homology 1,BTB-CNC同源体1)会抑制血红素加氧酶-1(Heme oxygenase-1,HO-1)等的基因表达,该血红素加氧酶-1会减轻氧化应激,在氧化应激下,BACH1会被排出核外,由此抑制活性氧簇(Reactive oxygen species,ROS)的上升等,有助于细胞的稳态维持(非专利文献1)。此外,BACH1与癌抑制转录因子p53形成复合体,由此抑制其靶基因的部分表达,抑制细胞老化(非专利文献2)。在将已导入突变型Ras的小鼠胚胎成纤维细胞(Mouse embryonic fibroblasts,MEFs)移植到小鼠皮下的实验中,与野生型MEFs相比,Bach1缺陷型MEFs的肿瘤的形成、增殖受到了显著阻害(非专利文献3)。在BACH1与癌症的关系方面,有报告称:在具有BRAF突变的大肠癌、恶性黑色素瘤中,BACH1会促进CpG岛(island)的甲基化,抑制癌抑制基因的表达(非专利文献4)。此外,还有报告称:在乳癌中,BACH1会调控与转移相关的多个基因表达,由此起到促进骨转移的作用(非专利文献5)。
现有技术文献
非专利文献
非专利文献1:Nat Rev Immunol,2017.17(7):p.437-450
非专利文献2:Nat Struct Mol Biol,2008.15(12):p.1246-54
非专利文献3:Oncogene,2013.32(27):p.3231-45
非专利文献4:Proc Natl Acad Sci U S A,2016.113(5):p.1250-5
非专利文献5:J Biol Chem,2012.287(40):p.33533-44
发明内容
发明所要解决的问题
本发明的问题在于提供一种新型的胰腺癌上皮间质转化标记物、胰腺癌转移或浸润标记物、胰腺癌预后标记物、胰腺癌转移抑制剂、以及胰腺癌转移抑制剂的筛选方法。
用于解决问题的方案
本发明人等着眼于BACH1,采用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库,对BACH1的表达与胰腺癌的预后的关系进行了研究,得到的结果是:在BACH1高表达的胰腺癌中,预后显著很差。根据这些研究结果,可以认为:BACH1会导致胰腺癌的恶性化。进而,人胰腺癌组织检测样本中的BACH1的免疫染色结果也是:在BACH1高表达中,预后恶化。
因此,在本研究中,为了阐明BACH1的胰腺癌恶性化机制,利用RNA序列揭示了:在胰腺癌细胞株中的BACH1的表达量所引起的基因表达变化。着眼于上皮间质转化,开展了体外(in vitro)的迁移能力、浸润能力以及体内(in vivo)的原位移植实验。此外,示出了:BACH1能通过与其下游调控因子的组合而用作胰腺癌的上皮间质转化的优异生物标志物、胰腺癌的转移或浸润的优异生物标志物、以及用于胰腺癌的预后预测的优异生物标志物。
进而示出了:通过调控BACH1所引起的转移相关基因的表达,能够抑制胰腺癌转移,还示出了:能够抑制该胰腺癌转移的药剂的筛选方法。
基于上述研究结果,完成了本发明。
即,本发明为下述技术方案。
[1]一种用于在体外评价胰腺癌的上皮间质转化能力的方法(数据取得方法),其中,所述方法包括测定BACH1的表达量的工序。
[2]根据[1]所述的用于在体外评价胰腺癌的上皮间质转化能力的方法(数据取得方法),其中,所述方法还包括测定FOXA1的表达量的工序。
[3]一种用于在体外评价胰腺癌的转移能力或浸润能力的方法(数据取得方法),其中,所述方法包括测定BACH1的表达量的工序。
[4]根据[3]所述的用于在体外评价胰腺癌的转移能力和浸润能力的方法(数据取得方法),其中,所述方法还包括测定FOXA1的表达量的工序。
[5]一种用于在体外预测胰腺癌的预后的方法(数据取得方法),其中,所述方法包括测定BACH1的表达量的工序。
[6]根据[5]所述的用于在体外预测胰腺癌的预后的方法(数据取得方法),其中,所述方法还包括测定FOXA1的表达量的工序。
[7]一种筛选胰腺癌转移抑制剂的方法,其中,包括:向表达BACH1基因或连接于BACH1基因的启动子的报告基因的细胞中,添加医药候选物质的工序;测定BACH1基因或报告基因的表达量的工序;以及选择使所述表达量降低的物质的工序。
[8]一种胰腺癌转移抑制剂,其中,将使BACH1基因的表达降低的药剂作为有效成分。
[9]根据[8]所述的胰腺癌转移抑制剂,其中,所述胰腺癌转移抑制剂阻害胰腺癌细胞的上皮间质转化能力。
[10]根据[8]或者[9]所述的胰腺癌转移抑制剂,其中,所述药剂为针对BACH1基因的小干扰RNA(Small interfering RNA,siRNA)。
发明效果
根据本发明,能够取得用于评价胰腺癌的上皮间质转化能力的数据、用于评价胰腺癌的转移能力或浸润能力的数据、以及用于预测胰腺癌的预后的数据,能够对胰腺癌的预后进行诊断。此外,能够胰腺癌转移抑制剂和胰腺癌转移抑制剂的筛选。
附图说明
图1表示BACH1是胰腺癌的预后预测因子。图1的A中,根据基于BACH1的表达量的ROC曲线(Receiver operating characteristic curve,受试者工作特性曲线)求得的截断值(cutoff value),将附加有获取自TCGA数据库的临床信息的176例胰管癌病例的RNA序列的数据分为两组(左图),采用乘积极限法(Kaplan Meier method,KM法)在分好的两组间进行了总体生存期间的解析(右图)。图1的B中,采用抗人BACH1抗体对166例胰腺癌临床检测样本进行免疫组化学,根据染色比例分为三个组(弱阳性(weak):阳性率小于10%;中阳性(moderate):阳性率10%~50%;强阳性(strong):阳性率50%以上)。示出本分类中的代表性的染色图像(倍率,200倍)。需要说明的是,在之后的解析中,会将弱阳性和中阳性分类为BACH1低表达组,将强阳性分类为BACH1高表达组。图1的C中,在免疫组织化学的BACH1高表达组与低表达组中,采用乘积极限法对总体生存期间进行了解析。P值是通过对数秩检验求得的。
图2表示BACH1不影响胰腺癌细胞的体外增殖。图2的A中,表示在敲减(siBACH1)了BACH1的胰腺癌细胞株(AsPC1(人转移胰腺腺癌细胞)和SW1990(人胰腺癌细胞))及成为其对照组的细胞(siCont.)中,采用定量逆转录PCR法(Quantitative reversetranscription PCR,RT-qPCR)所检测到的BACH1的表达量。各实验独立进行3次以上,柱状图中,每个实验值以点示出,平均值以柱形示出,标准误差以条形示出。统计学上的显著性差异的检验通过学生t检验(Student's t test)来进行,并示出了P值(**:P<0.01)。图2的B中,每隔24小时对BACH1敲减(siBACH1)AsPC1和SW1990及成为其对照组的细胞(siCont.)的细胞数进行经时计测直至72小时,由此以折线图示出细胞增殖的变化。实验独立进行4次,平均值以折线示出,标准误差在各计时点以条形示出。统计学上的显著性差异的检验通过学生t检验来进行(n.s.:not significant(无显著性差异))。
图3表示BACH1促进胰腺癌细胞的间质系性状。图3的A中,以显微镜图像表示BACH1敲减(siBACH1)AsPC1的细胞形态,图3的B中,以显微镜图像表示过量表达了BACH1的胰腺癌细胞株(Panc1)的细胞形态。比例尺表示100μm。图3的C中,表示BACH1敲减(siBACH1)AsPC1和SW1990、BACH1过量表达(exBACH1)Panc1、以及它们的对照细胞(siCont.或者EV(EmptyVector,空白载体))中的上皮系基因(CDH1(Cadherin 1,钙黏蛋白1)、OCLN(Occludin,紧密连接蛋白)以及FOXA1(Forkhead Box A1,叉头框A1))与间质系基因(VIM(Vimentin,波形蛋白)以及SNAI2(Snail Family Transcriptional Repressor 2,蜗牛家族转录阻遏物2))的表达。采用RT-qPCR法检测各基因。各因子的mRNA表达量以β-肌动蛋白(β-actin,ACTB)的mRNA表达量进行了校正。实验独立进行3次,每个实验的平均值以柱形示出,标准误差以条形示出。统计学上的显著性差异的检验通过学生t检验来进行,并示出了P值(*:P<0.05;**:P<0.01)。图3的D中,表示BACH1敲减(siBACH1)AsPC1和SW1990、BACH1过量表达(exBACH1)Panc1、以及它们的对照细胞(siCont.或者EV)中的E-钙黏蛋白(E-cadherin)、BACH1及作为其内参蛋白的GAPDH(Glyceraldehyde 3-phosphate dehydrogenase,甘油醛-3-磷酸脱氢酶)或者ACTB的蛋白质印迹图(Western blot)(照片)。图3的E中,表示BACH1敲减时的E-钙黏蛋白的免疫荧光染色图像。比例尺表示25μm。
图4表示BACH1在体外使胰腺癌细胞株的迁移能力和浸润能力增强。图4的A中,表示BACH1敲减(siBACH1)AsPC1及其对照细胞(siCont.)的划痕实验(Scratch Assay)中具有代表性的显微镜图像以及所测定细胞移动度的柱状图,图4的B中,表示过量表达(exBACH1)Panc1及其对照细胞(EV)的划痕实验中具有代表性的显微镜图像及所计测的细胞的移动度的柱状图。图4的C中,表示BACH1敲减AsPC1和SW1990的迁移实验(Transwell assay)和浸润实验(Invasion assay)中具有代表性的显微镜图像以及迁移或者浸润的细胞数目的柱状图。各实验独立进行3次以上,柱状图中,每个实验值以点表示,平均值以柱形表示,标准误差以条形表示。统计学上的显著性差异的检验通过学生t检验来进行,并示出了P值(*:P<0.05;**:P<0.01)。
图5是表示BACH1敲除AsPC1细胞株的建立的图。图5的A中,表示基于两种向导RNA(guide RNA,gRNA)建立的各个克隆(sgBACH1-1和sgBACH1-2)的靶位点处的DNA序列结果。两种向导RNA分别以BACH1基因的外显子2内部序列作为其靶点,sgBACH1-1的设计目标是引入13bp的碱基缺陷,sgBACH1-2的设计目标是引入一个碱基的插入突变。需要说明的是,参考序列采用的是人源参考基因组hg19。图5的B中,表示BACH1敲除(sgBACH1)AsPC1及其对照细胞(sgCont.)的BACH1、E-钙黏蛋白及作为其内参蛋白的GAPDH的蛋白质印迹图(照片)。图5的C中,表示BACH1敲除AsPC1的RT-qPCR的结果。各因子的mRNA表达量以ACTB mRNA表达量进行了校正。实验独立进行3次,图中,每个实验值以点示出,平均值以柱形示出,标准误差以条形示出。统计学上的显著性差异的检验通过学生t检验来进行,并示出了P值(*:P<0.05;**:P<0.01,n.s.:not significant(无显著性差异))。图5的D中,表示采用向导RNAsgBACH1-2制成的BACH1敲除AsPC1的BACH1的免疫荧光染色图像,图5的E中,表示E-钙黏蛋白的免疫荧光染色图像。比例尺分别表示7.5μm和75μm。
图6表示BACH1虽然在体外促进转移,但不影响肿瘤形成。图6的A中,分别示出了将BACH1敲除(sgBACH1-2)AsPC1或者其对照(sgCont.)细胞移植到NOG小鼠(BACH1野生型AsPC1:n=17;BACH1敲除AsPC1:n=18)的胰腺中,经5周后形成于胰腺的肿瘤、向肝转移、向肠系膜扩散的代表例。以白色线条圈起来的区域表示形成于胰腺的肿瘤,白色箭头表示转移巢。图6的B中,分别表示摘除的胰腺的重量、肝转移数目以及腹膜转移数目的盒须图。盒子的下端表示数据的25%,上端表示75%,中央的线表示中央值,须子分别表示最大值和最小值。统计学上的显著性差异的检验采用学生t检验,并计算出P值。
图7表示BACH1通过追加其功能评价而成为更加准确的胰腺癌的预后预测标记物。图7的A中,根据基于FOXA1的表达量的ROC曲线求得的截断值,将获取自TCGA数据库的176例检测样本的RNA序列的数据分为两组,图7的B中,根据基于BACH1的表达量和FOXA1的表达量的ROC曲线求得的截断值,将获取自TCGA数据库的176例检测样本的RNA序列的数据分为四组,采用乘积极限法在分好的组间进行了总体生存期间的解析。统计学上的显著性差异的检验通过对数秩检验进行,并示出了P值。
具体实施方式
<用于评价胰腺癌的上皮间质转化能力的方法>
本发明提供一种用于在体外评价胰腺癌的上皮间质转化能力的方法(数据取得方法),其中,所述方法包括测定BACH1的表达量的工序。
BACH1基因只要是来源于被检对象的基因即可,具体而言,可举例示出包含如下所示的碱基序列的基因。
在被检对象为人的情况下,BACH1基因的碱基序列可举例示出序列编号1所记载的碱基序列。此外,BACH1基因只要编码具有作为转录因子的功能的蛋白质,就可包括:具有序列编号1所记载的碱基序列的互补序列的DNA和在严格条件下杂交的DNA。在此,作为严格条件,例如可列举出:在0.1×SDS(Sodium Dodecyl Sulphate,十二烷基硫酸钠),0.1×SSC(Standard Sodium Citrate,标准柠檬酸钠盐),68℃的条件下进行清洗的条件。此外,在被检对象采用不同动物的情况下,以来源于该动物的同源基因为测定对象。
BACH1蛋白质只要是来源于被检对象的蛋白质,就没有限定,具体而言,可举例示出含有如下所示的氨基酸序列的蛋白质。而且,BACH1蛋白质中还包含:具有与该蛋白质同样的胰腺癌关联性的蛋白质片段、类似物以及突变体。
在被检对象为人的情况下,BACH1蛋白质的氨基酸序列可举例示出序列编号2所记载的氨基酸序列。此外,只要是具有作为转录因子的功能的蛋白质,也可以是具有这些氨基酸序列中置换、缺失、插入或者增加一个或者数个(例如1~20个)氨基酸而成的氨基酸序列的蛋白质。此外,在被检对象采用不同动物的情况下,以来源于该动物的同源蛋白质为测定对象。
本发明还可以包括上皮系细胞标记物的表达量的测定工序。
作为上皮系细胞标记物,例如可列举出:FOXA1(Forkhead Box Protein A1)、OCLN(Occludin)、PKP2(Plakophilin 2)、CLDN3(Claudin 3)、或者CLDN4(Claudin 4)。上皮系细胞标记物优选为FOXA1。
该工序可以是对选自由这些上皮系细胞标记物构成的组中的一个上皮系细胞标记物的表达量进行测定的工序,也可以是对其中两个以上上皮系细胞标记物的表达量进行测定的工序。
在被检对象为人的情况下,FOXA1的碱基序列可举例示出序列编号3所记载的碱基序列。此外,FOXA1基因只要编码具有作为转录因子的功能的蛋白质,就可包括:具有序列编号3所记载的碱基序列的互补序列的DNA和在严格条件下杂交的DNA。在此,作为严格条件,例如可列举出:在0.1×SDS,0.1×SSC,68℃的条件下进行清洗的条件。此外,在被检对象采用不同动物的情况下,以来源于该动物的同源基因为测定对象。
在被检对象为人的情况下,FOXA1的氨基酸序列可举例示出序列编号4所记载的氨基酸序列。此外,只要是具有作为转录因子的功能的蛋白质,也可以是具有这些氨基酸序列中置换、缺失、插入或者增加一个或者数个(例如1~20个)氨基酸而成的氨基酸序列的蛋白质。此外,在被检对象采用不同动物的情况下,以来源于该动物的同源蛋白质为测定对象。
测定BACH1和FOXA1的表达量没有特别限定,例如为测定其mRNA或者蛋白质的表达量。
BACH1基因和FOXA1基因的表达量可以采用例如定量PCR法、RT-PCR法、定量RT-PCR法、微阵列法、高通量序列法、Northern印迹法、分光光度法以及荧光光度法进行测定,此外,BACH1蛋白质和FOXA1蛋白质的表达量可以采用例如流式细胞法(Flow cytometricanalysis)、蛋白质印迹法、ELISA法(Enzyme Linked Immunosorbent Assay,酶联免疫吸附剂测定)以及其他免疫化学法进行测定。
可以利用BACH1基因或者FOXA1基因的编码区域的碱基序列、即序列编号1或者序列编号3所记载的序列来设计或者取得基因表达解析用的引物、探针等。所述碱基序列可以与序列编号1所记载的碱基序列或者序列编号3所记载的碱基序列分别具有90%以上、优选95%以上、更优选98%以上的同源性。此外,所述引物、探针等只要能够与所述碱基序列特异性结合,可以是与所述碱基序列的互补序列具有90%以上、优选95%以上、更优选98%以上的同源性的引物、探针等。
定量PCR法可以采用常规方法进行,没有限定,可以采用使用嵌入剂的方法或者使用荧光标记探针的方法进行。例如,可以采用SYBR(注册商标)Green I作为嵌入剂。
用于测定BACH1蛋白质或者FOXA1蛋白质的表达量的抗体可以采用市售的抗体,也可以采用序列编号2或者序列编号4所记载的BACH1蛋白质或者FOXA1蛋白质的一部分氨基酸序列作为抗原而制成的抗体。所述氨基酸序列可以是与序列编号2所记载的氨基酸序列或者序列编号4所记载的氨基酸序列分别具有90%以上、优选95%以上、更优选98%以上的同源性的氨基酸序列。此外,所述抗体等只要能够与所记载的氨基酸序列特异性结合,可以是与所述氨基酸序列的互补序列具有90%以上、优选95%以上、更优选98%以上的同源性的抗体。
抗体可以是单克隆抗体、多克隆抗体中的任意种,但是,为了稳定地供应稳定的质量的抗体,优选为单克隆抗体。也可以是Fab'或者F(ab')2等单克隆抗体的片段。
此外,各抗体可以采用常用的来源于小鼠、大鼠、兔、山羊、绵羊、鸟的抗体等,但不限于此,只要是与BACH1蛋白质或者FOXA1蛋白质特异性结合的抗体,可以使用任意种。该抗体可以被标记化,或者也可以采用标记化第二抗体。
在使用标记化第二抗体的情况下,只要识别第一抗体,就可以没有特别限定地使用。例如,在第一抗体为兔抗体的情况下,可以采用标记化抗兔IgG抗体作为第二抗体,在第一抗体为小鼠抗体的情况下,可以采用标记化抗小鼠IgG抗体作为第二抗体。
标记物质可列举出:酶、放射线同位元素、荧光物质、发光物质、金溶胶等。
其中,从灵敏度以及操作简便性的观点考虑,优选为酶,更优选为过氧化物酶(peroxidase,PO)、辣根过氧化酶(Horseradish Peroxidase,HRP)、碱性磷酸酶(AlkalinePhosphatase,AP)、葡萄糖氧化酶(Glucose oxidase,GOD)等。在采用HRP作为标记物质的情况下,可以采用TMB(3,3',5,5'-四甲基联苯胺)等作为基质,在采用AP的情况下,可以采用AMPPD(3-(2'-螺旋金刚烷)-4-甲氧基-4-(3”-磷酰氧基)苯-1,2-二氧杂环丁烷二钠盐)、9-(4-氯苯硫代磷酰氧基亚甲基)-10-甲基吖啶二钠盐等作为基质。此外,作为标记物质,还可以采用异硫氰酸荧光素(fluorescein isothiocyanate,FITC)、罗丹明等荧光色素等。
测定对象物质的检测及定量方法会根据不同的标记方法而不同,可以采用本领域技术人员公知的惯用方法进行,没有特别限定。例如,在采用PO、HRP、AP、GOD等作为标记物质的情况下,可以通过添加发色基质、发光基质,测定吸光度、发光强度的变化,从而对测定对象物质进行定量。此外,在采用荧光物质作为标记物质的情况下,可以通过测定其荧光强度来对测定对象物质进行定量。此外,在采用放射性同位元素作为标记物质的情况下,可以通过测定放射能来对测定对象物质进行定量。此外,在采用金溶胶作为标记物质的情况下,可以通过测定吸光度来对测定对象物质进行定量。
进行定量时,例如可以预先采用已知浓度的试样绘制标定曲线(标准曲线),通过将测定值与标定曲线进行对照来计算出试样中的BACH1蛋白质或者FOXA1蛋白质表达量。
对于抗体溶液的浓度,只要不妨碍抗原-抗体反应,且相对于检测样本中的BACH1蛋白质或者FOXA1蛋白质表达量不是过少量,就没有特别限定。
本发明对于进行抗原-抗体反应的时间、实施本发明的方法的温度、试样和试剂的稀释液以及清洗液的组成、pH等没有特别限定,可以采用常规的蛋白质的定量方法所适用的条件。
被检对象只要是表达BACH1的哺乳类即可,没有特别限定,但优选为人。
作为测定的对象试样,例如为:从被检对象或者健全对象获得的生物试样。
生物试样是指,例如可以是胰腺的细胞或者组织、胰腺周边的细胞或者组织、以及胰腺癌可能转移到的其他所有部位的细胞或者组织等。此外,生物试样可以是可能含有胰腺癌细胞的血液、淋巴液等体液,也可以是血中循环癌细胞。血中循环癌细胞没有特别限定,例如可以通过由识别胰腺癌的抗体编码得到的磁珠作用于血液,依靠磁力的正向选择来进行收集。
上皮间质转化是指,上皮细胞失去了其细胞粘接能力,变成了具有迁移能力的间质系的细胞。
对于上皮间质转化能力,例如,可以通过下述方法进行评价。利用由癌症基因组图谱(The Cancer Genome Atlas,TCGA)的数据库获得的胰腺癌临床检测样本的临床数据制成受试者工作特性(Receiver Operating Characteristic,ROC)曲线,通过该ROC曲线计算出BACH1的表达量的截断值,在由被检对象获得的生物试样中的BACH1的表达量大于该截断值的情况下,可以评价为胰腺癌的上皮间质转化能力高,在为该截断值以下的情况下,可以评价为胰腺癌的上皮间质转化能力低。
进而,可以通过组合作为上皮系细胞标记物的FOXA1的表达量,更准确地评价胰腺癌的上皮间质转化能力。与BACH1同样地,利用由TCGA的数据库获得的胰腺癌临床检测样本的临床数据制成受试者工作特性(Receiver Operating Characteristic,ROC)曲线,通过该ROC曲线计算出FOXA1的表达量的截断值。然后,在由被检对象获得的生物试样中的FOXA1的表达量大于该截断值,且BACH1的表达量为该截断值以下的情况下,可以评价为胰腺癌的上皮间质转化能力低,另一方面,在由被检对象获得的生物试样中的FOXA1的表达量为该截断值以下,且BACH1的表达量大于该截断值的情况下,可以评价为胰腺癌的上皮间质转化能力高。
<用于评价胰腺癌的转移能力或浸润能力的方法>
本发明提供一种用于在体外评价胰腺癌的转移能力或浸润能力的方法(数据取得方法),其中,所述方法包括测定BACH1的表达量的工序。
胰腺癌的转移能力或浸润能力例如可以采用下述方法进行评价:利用由癌症基因组图谱(The Cancer Genome Atlas,TCGA)的数据库获得的胰腺癌临床检测样本的临床数据制成受试者工作特性(Receiver Operating Characteristic,ROC)曲线,通过该ROC曲线计算出BACH1的表达量的截断值,在由被检对象获得的生物试样中的BACH1的表达量大于该截断值的情况下,可以评价为胰腺癌的转移能力或浸润能力高,在为该截断值以下的情况下,可以评价为胰腺癌的转移能力或浸润能力低。
进而,可以通过组合作为上皮系细胞标记物的FOXA1的表达量,更准确地评价胰腺癌的转移能力或浸润能力。与BACH1同样地,利用由TCGA的数据库获得的胰腺癌临床检测样本的临床数据制成受试者工作特性(Receiver Operating Characteristic,ROC)曲线,通过该ROC曲线计算出FOXA1的表达量的截断值。然后,在由被检对象获得的生物试样中的FOXA1的表达量大于该截断值,且BACH1的表达量为该截断值以下的情况下,可以评价为胰腺癌的转移能力或浸润能力低,另一方面,在由被检对象获得的生物试样中的FOXA1的表达量为该截断值以下,且BACH1的表达量大于该截断值的情况下,可以评价为胰腺癌的转移能力或浸润能力高。
<用于预测胰腺癌的预后的方法>
本发明提供一种用于在体外预测胰腺癌的预后的方法(数据取得方法),其中,所述方法包括测定BACH1的表达量的工序。
本发明中,预后是指,在一般情况下,对疾病的未来展望。在预后预测中,例如,胰腺癌得到缓解或者得到改善的情况、长期的生存期间、长期的无恶化期间的情况为预后良好,另一方面,例如,胰腺癌复发、死灰复燃、或者转移的情况、短期的生存期间、短期的无恶化期间的情况为预后不良。
具体而言,例如,利用由癌症基因组图谱(The Cancer Genome Atlas,TCGA)的数据库获得的胰腺癌临床检测样本的临床数据制成受试者工作特性(Receiver OperatingCharacteristic,ROC)曲线,通过该ROC曲线计算出BACH1的表达量的截断值,在由被检对象获得的生物试样中的BACH1的表达量大于该截断值的情况下,可以预测为预后不良,在为该截断值以下的情况下,可以预测为预后良好。
进而,可以通过组合作为上皮系细胞标记物的FOXA1的表达量,更准确地进行预后预测。与BACH1同样地,利用由TCGA的数据库获得的胰腺癌临床检测样本的临床数据制成受试者工作特性(Receiver Operating Characteristic,ROC)曲线,通过该ROC曲线计算出FOXA1的表达量的截断值。然后,在由被检对象获得的生物试样中的FOXA1的表达量大于该截断值,且BACH1的表达量为该截断值以下的情况下,可以预测为预后良好,另一方面,在由被检对象获得的生物试样中的FOXA1的表达量为该截断值以下,且BACH1的表达量大于该截断值的情况下,可以预测为预后不良。
可以基于如上所述的预后预测的结果来确定治疗方针。例如,可以确定是采取外科治疗、放射线治疗、化疗以及内分泌疗法(激素疗法)中的任意种,此外,还可以确定作为内分泌疗法使用其他任意种的内分泌药物。
<筛选胰腺癌转移抑制剂的方法>
本发明提供一种筛选胰腺癌转移抑制剂的方法,其中,包括:向表达BACH1基因或连接于BACH1基因的启动子的报告基因的细胞中,添加医药候选物质的工序;测定BACH1基因或报告基因的表达量的工序;以及选择使所述表达量降低的物质的工序。
例如,与未添加候选化合物的对照相比,在有候选化合物的存在下,BACH1基因或连接于BACH1基因的启动子的报告基因的表达量降低的情况下,具体而言,例如降低20%以上、优选50%以上、更优选90%以上的情况下,可以将该候选化合物选择为胰腺癌的治疗药的候选。
表达BACH1基因的细胞可以采用包含表达BACH1基因的细胞的生物试样、表达BACH1基因的培养细胞株、或者强制表达BACH1基因的培养细胞株中的任意种,优选采用强制表达BACH1基因的培养细胞株。
表达BACH1基因的培养细胞株只要是表达BACH1基因的细胞株,就没有特别限定,例如可列举出来源于胰腺癌细胞的细胞株。
强制表达BACH1基因的培养细胞株例如可列举出:将BACH1基因嵌入到用于向哺乳类细胞中导入基因的质粒、病毒载体等中,采用脂质体转染等常规方法将其转染至细胞中的培养细胞株。转染可以是瞬时转染,也可以是稳定转染。
对于表达连接于BACH1基因的启动子的报告基因的细胞,例如可以使用强制表达报告基因的培养细胞株,即,将这些报告基因连接于BACH1基因的启动子上,然后将其嵌入到用于向哺乳类细胞导入基因的质粒、病毒载体等中,通过已知的脂质体转染等常规方法将其转染至细胞的培养细胞株。转染可以是瞬时转染,也可以是稳定转染。
在采用连接于BACH1基因的启动子的报告基因的情况下,作为BACH1基因的启动子,优选为包含转录起点上游约1kbp的区域,更优选为包含上游约2kbp的区域。
报告基因可以采用荧光素酶基因、绿色荧光蛋白(Green fluorescent protein,GFP)基因、氯霉素乙酰转移酶(Chloramphenicol Acetyltransferase)基因等,可以优选采用荧光素酶基因或者GFP基因。
在本发明中,候选化合物可以是高分子化合物或者低分子化合物中的任意种,没有特别限定,作为高分子化合物,例如可列举出蛋白质、抗体、肽、非肽性化合物、核酸、或者RNA等。这些化合物可以是新型化合物,也可以是公知的化合物,也可以是包含这些化合物的发酵产物、细胞提取液、植物提取液、动物组织提取液等。
与不添加候选化合物的情况相比,从候选化合物中选择使BACH1基因的表达量降低的化合物,由此可以得到能够作为胰腺癌的治疗药的物质。
候选化合物的浓度添加浓度只要是能够确认到使BACH1基因的表达量降低的浓度,就没有特别限定。此外,添加方法、反应时间、反应温度等可以根据所用的被检样本进行适当选择。
<胰腺癌转移抑制剂>
本发明提供一种胰腺癌转移抑制剂,其中,将使BACH1基因的表达降低的药剂作为有效成分。
使BACH1基因的表达降低的药剂可以是高分子化合物或者低分子化合物中的任意种,没有特别限定,作为高分子化合物,例如可列举出蛋白质、抗体(抗BACH1抗体)、肽、非肽性化合物、核酸、或者RNA。优选为RNA,更优选为siRNA。
siRNA的碱基序列只要使BACH1基因的表达降低,就没有限定,例如可列举出序列编号5或者序列编号6所记载的碱基序列。
实施例
以下,通过实施例对本发明进行更详细地说明,但是本发明的范围显然并不仅限于实施例。
<实施例1>BACH1表达量与预后的关系的计算机模拟(in silico)研究
登记在癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库中的胰腺癌患者检测样本的BACH1的表达量与预后是否有关联,对此进行了调查。从TCGA数据库中获得了176位胰腺癌患者的RNA-序列临床数据,利用软件JMP pro v13.1.0,根据基于该临床数据的受试者工作特性(Receiver Operating Characteristic,ROC)曲线求得了截断值,基于该截断值分为BACH1低表达组(n=134)和高表达组(n=42)这两组(图1的A的左图),利用乘积极限法解析了总体生存率(Overall survival,OS)。
结果可知:在BACH1高表达组中,OS会显著降低(对数秩检验;P<0.0001,图1的A的右图)。这一结果给出的启示是BACH1可能作为胰腺癌恶性化因子发挥功能,本研究着眼于BACH1在胰腺癌中的功能而进行解析。
<实施例2>胰腺癌临床检测样本中的BACH1的表达的研究
为了调查BACH1蛋白质表达与预后的关系,利用在日本东北大学病院消化器外科进行过手术的胰腺癌的临床检测样本,进行了采用抗人BACH1单克隆抗体(9D11,自制抗体,稀释(dilution)1∶100)的免疫组织化学。胰腺癌的临床检测样本选取了从2007年至2014年在东北大学病院消化器外科进行过切除手术的116例胰腺癌病例检测样本作为对象。需要说明的是,该抗人BACH1单克隆抗体的特异性已通过利用敲减、敲除后的细胞的实验得到了确认(不揭示数据)。
采用抗人BACH1单克隆抗体进行免疫组织化学。将以10%多聚甲醛固定的石蜡包埋切片切成3μm薄片,将其粘接固定在有防剥离片涂层的载玻片上。切片用二甲苯进行脱石蜡处理后,用乙醇进行了脱水处理。采用TE(10mM Tris-HCl pH 8.0,1mM EDTA)煮沸30分钟来进行抗原激活。通过在1%过氧化氢/甲醇环境下反应10分钟来进行内源性过氧化物酶活性阻害。采用正常山羊血清(DakoCytomation,Glostrup,Denmark)进行封闭。第一抗体反应在4℃下进行24小时。第二抗体反应采用Histofine Simple Stain MAX-PO(M)(NichireiBiosciences Inc.,Tokyo,Japan)在室温下进行2小时。此后,采用溶解于0.1MTris缓冲液(buffer)的3,3'-二氨基联苯胺(3,3'-Diaminobenzidine)和过氧化氢进行5分钟发色,利用苏木素(Hematoxylin)对核进行染色。在显微镜观察中,以淋巴球为内标,根据染色强度,分为弱阳性(weak positive,阳性率小于10%)、中阳性(moderate positive,阳性率10~50%)、强阳性(strong positive,阳性率50%以上)这3阶段进行评价后,将强阳性分类为BACH1高表达组(n=28),将弱阳性以及中阳性分类为低表达组(n=88)(图1的B)。
<实施例3>BACH1的表达与总体生存率的关系
为了调查基于免疫组织化学分类的BACH1蛋白质的表达与预后的关系,采用乘积极限法对OS进行了解析。
结果发现:与利用登记在TCGA数据库中的临床数据的BACH1的表达与预后的关系一致,在BACH1蛋白质的高表达组中,OS显著降低(对数秩检验;P=0.0213),BACH1为胰腺癌的预后不良因子(图1的C)。
进行单变量解析的结果是:在OS中,淋巴结转移(P=0.0094)、远隔转移(P=0.0004)、BACH1表达量(P=0.0231)显示出作为预后因子的显著性。因此,在这些预后因子候选中追加了组织等级(P=0.0638),进行了基于Cox比例风险模型的多变量解析。结果是:在OS中,淋巴结转移(P=0.011)和BACH1表达量(P=0.0296)显示出独立作为预后因子的显著性(表1)。
[表1]
变量分析
<实施例4>BACH1的表达与细胞增殖的关系
为了调查BACH1表达对癌细胞增殖的影响,在胰腺癌细胞株AsPC1、SW1990中,进行了利用基于siRNA的RNA干扰法的BACH1的敲减。基于siRNA的敲减通过下述方法进行。采用BACH1的siRNA(Stealth RNAi(商标)siRNA双链寡核糖核苷酸(DuplexOligoribonucleotides),Invitrogen,CA,USA)。采用了Stealth RNAi(商标)siRNA阴性对照(Negative Control),Low GC(Thermo Fisher Scientific Inc.,MA,USA)作为对照。采用Lipofectamine RNAiMAX(Thermo Fisher Scientific Inc.),根据产品说明书以脂质体转染法导入了siRNA。采用的siRNA的序列如下。
siBACH1-1;5’-GGUCAAAGGACUUUCACAACAUUAA-3’(序列编号5)。
siBACH1-2;5’-GGGCACCAGGGAAGAUAGUAGUGUU-3’(序列编号6)。
其结果是,在AsPC1和SW1990这两种细胞类型中,均未观察到BACH1敲减对细胞增殖的影响(图2)。
<实施例5>BACH1敲减以及过量表达所造成的细胞的形态变化
如图3的A所示,按照与实施例4同样的方式进行了BACH1敲减后的胰腺癌细胞株AsPC1的细胞间的粘接增强,显示出上皮系的细胞形态(图3的A)。
因此,使BACH1蛋白质的表达量低于AsPC1的Panc1进行了BACH1过量表达。过量表达是采用作为市售的转染套装的Fugene(注册商标)HD,按照随附的产品说明书将质粒导入到在6cm培养皿中培养出的Panc1中。作为对照,导入了7.2μg作为市售的载体的pcDNA3.1(-)(Addgene),另一方面,作为过量表达,向作为市售的载体的pCMV2中导入了已嵌入序列编号1所记载的碱基序列即BACH1基因的载体pCMV2-BACH1 7.2μg以及用于药剂选择的pcDNA3.1(-)1μg,在添加了2000μg/ml的G418(Calbiochem,Germany)的Panc1用培养基中培养了两周。培养AsPC1的培养基为:向RPMI 1640medium(无血清细胞冻存基础培养基)(Sigma Aldrich,MO,USA)中添加了20%的牛胎儿血清(Fetal Bovine Serum,FBS,SigmaAldrich)、0.1mg/ml的青霉素/链霉素(GIBCO,NY,USA)、10mM的HEPES(羟乙基哌嗪乙硫磺酸,GIBCO)的培养基;培养SW1990、Panc1的培养基为:向RPMI 1640medium(Sigma Aldrich,MO,USA)中添加了10%FBS、0.1mg/ml青霉素/链霉素、10mM HEPES的培养基。培养后,在显微镜下分离出由获得药剂耐性而存活的细胞形成的群落,进行了克隆。
其结果是,与BACH1敲减AsPC1时相反,BACH1过量表达Panc1中的细胞间的粘接减弱,显示出伪足状的变形的细胞形态(图3的B)。就是说可以认为:BACH1会促进上皮间质转化(epithelial to mesenchymal transition,EMT)。
因此,采用定量RT-PCR法按下述步骤对上皮系基因(CDH1、OCLN、FOXA1)和间质系基因(VIM和SNAI2)的表达进行了确认。首先,使用RNeasy(注册商标)Plus Mini Kit(Qiagen,Germany)按照随附的产品说明书进行RNA提取。然后利用Omniscript ReverseTranscription kit(Qiagen)按照随附的产品说明书对提取的RNA进行逆转录反应来合成cDNA。逆转录反应使用1μg的RNA,200ng的随机引物(Random primer)(Invitrogen),在37℃下反应60分钟,通过在93℃下5分钟的热处理来停止逆转录反应。目标基因的表达量的测定利用了采用SYBR(注册商标)GreenI作为嵌入剂的定量PCR法。采用LightCycler(注册商标)Fast Start DNA Master SYBR GreenI(Roche,Swiss),按照随附的产品说明书,以cDNA为模板,利用各种基因特异性引物,在定量PCR机LightCycler(注册商标)Nano(Roche)上进行了测定。目标基因的mRNA的表达量通过内标基因的表达量进行校正,通过进行检测样本间的比较的相对定量来进行评价。内标基因采用的是β-actin的基因(ACTB)。各引物的序列如下。
ACTB
(正向)5’-ATTTGCGGTGGACGATGGAG-3’(序列编号7)。
(反向)5’-AGAGATGGCCACGGCTGCTT-3’(序列编号8)。
BACH1
(正向)5’-AATCGTAGGCCAGGCTGATG-3’(序列编号9)。
(反向)5’-AGCAGTGTAGGCAAACTGAA-3’(序列编号10)。
CDH1
(正向)5’-TCCTGGCCTCAGAAGACAGA-3’(序列编号11)。
(反向)5’-CCTTGGCCAGTGATGCTGTA-3’(序列编号12)。
OCLN
(正向)5’-GAGTTGACAGTCCCATGGCA-3’(序列编号13)。
(反向)5’-CTGAAGTCATCCACAGGCGA-3’(序列编号14)。
FOXA1
(正向)5’-GGTGGCTCCAGGATGTTAGG-3’(序列编号15)。
(反向)5’-CCCAGGCCTGAGTTCATGTT-3’(序列编号16)。
VIM
(正向)5’-GGACCAGCTAACCAACGACA-3’(序列编号17)。
(反向)5’-GGGTGTTTTCGGCTTCCTCT-3’(序列编号18)。
SNAI2
(正向)5’-CAACGCCTCCAAAAAGCCAA-3’(序列编号19)。
(反向)5’-ACAGTGATGGGGCTGTATGC-3’(序列编号20)。
其结果是,在BACH1敲减细胞(AsPC1、SW1990)中,与对照细胞相比,上皮系基因的表达上升,另一方面,间质系基因的表达显著降低。此外,在BACH1过量表达细胞(Panc1)中,上皮系基因的表达降低,间质系基因VIM的表达上升,但是SNAI2的表达降低(图3的C)。
进而,在AsPC1中,通过蛋白质印迹法检测E-钙黏蛋白(E-cadherin)。用SDS样品缓冲液(0.0625M Tris-HCl(pH6.8)、2.2%SDS、10%甘油(glycerol)、0.01%BPB(Bromophenol Blue,溴酚蓝)、5%β-ME(β-Mercaptoethanol,β-巯基乙醇))使细胞悬浮,通过可溶化处理调整蛋白质后,在95℃下进行5分钟的变性处理。热变性后的细胞的全蛋白质提取液通过7.5%~12%的聚丙烯酰胺凝胶电泳(Polyacryamide Gel Electrophoresis,PAGE)按分子量大小展开。用湿(Wet)法从凝胶转印至聚偏氟乙烯膜(PolyvinylideneFluoride,PVDF膜,Millipore,Germany)。在加脱脂牛奶(Wako Jyun-Yaku Co.,Osaka,Japan)至终浓度为3%的T-TBS(含有0.05%Tween 20的TBS(25mM Tris-HCl(pH 7.4),137mM NaCl,3mM KCl))中室温振荡1小时,从而对转印后的PVDF膜进行封闭处理。对于第一抗体,使用上述封闭液对抗BACH1抗体(1∶1000,自制)、抗GAPDH抗体(1∶5000,ab8245,Abcam,England)、抗β-Actin抗体(1∶1000,GTX109639,GeneTeX,CA,USA)、抗E-钙黏蛋白抗体(1∶1000,ab1416,Abcam)进行稀释后,使其在4℃下反应一晚。准备好用上述封闭液稀释了HRP conjugated anti-mouse IgG blotting reagents(连接有辣根过氧化物酶的抗小鼠IgG印迹试剂)(1∶5000,GE Healthcare,NJ,USA)的试剂,添加至第一抗体反应后的PVDF膜中,使其在室温下反应60分钟。用清洗缓冲液(wash buffer)清洗后,通过利用了SuperSignal West Pico(Thermo Fisher Scientific Inc.)或者ECL Plus WesternBlotting Substrate(ECL Plus超敏发光液)(Thermo Fisher Scientific Inc.)的化学发光,对X射线胶片(GE Healthcare)进行感光来检测。其结果是,通过BACH1敲减,继基因表达(CDH1,图3的C)之后,蛋白质表达量也增加(图4的D的左图)。此外,在AsPC1和SW1990中均确认到了同样的效果(图3的D的中央图)。进而判明了:在BACH1过量表达Panc1中,E-钙黏蛋白的基因表达以及蛋白质表达会减少(图3的D的右图)。在此,考虑到E-钙黏蛋白是上皮细胞中具有代表性的标记蛋白质,作为细胞间粘接因子发挥功能(图3的E),可以得到的启示是:其可能是改变细胞形态的因素之一。这些结果给出的启示是:BACH1对于胰腺癌中的间质细胞性状的表达以及维持是重要的。
<实施例6>BACH1对迁移能力、浸润能力的影响
为了调查BACH1能否促进胰腺癌细胞的迁移能力、浸润能力,按照下述方式进行了划痕实验,确认其迁移能力。首先,在6孔板中融合(confluent)后的细胞上利用1000μl的移液枪枪头形成划痕(直线),通过对划痕刚刚形成时与形成24小时后的创伤部进行比较来计测细胞移动面积。此外,移动面积是通过Image J(NIH,https://imagej.nih.gov/ij/)软件来计测像素数,同样的实验独立进行3次以上。其结果是,与对照细胞相比,在BACH1敲减AsPC1中,迁移能力显著降低(图4的A),与对照细胞相比,在BACH1过量表达Panc1中,迁移能力显著增加(图4的B)。
进而,采用Boyden小室(chamber)法确认了迁移能力以及浸润能力。首先,向下部24孔板中添加含有血清且适合于所使用细胞的培养基(AsPC1为20%FBS;SW1990为10%FBS),然后在其上静置插件(Insert)后,将悬浮于无血清培养基中的细胞(AsPC1为2×105个;SW1990为1×105个)接种于所述插件中。在24小时后,用棉棒将存在于插件膜上表面的细胞全部去除后,将移动至插件膜下表面的细胞浸泡于结晶紫溶液(4.2%福尔马林,0.05%结晶紫,10%乙醇)中10分钟,从而进行固定和染色。染色后的膜用蒸馏水清洗干净后,进行干燥,然后在显微镜下以目测法计测迁移以及浸润的细胞数目。对于一次实验,对各检测样本重复两次,对于AsPC1,计测了整个膜的细胞数目。对于SW1990,分别在独立的5个视野下对细胞数目进行了计数并取平均。同样的实验独立进行3次以上。其结果是,在BACH1敲减AsPC1、SW1990中,确认到迁移能力、浸润能力显著降低(图4的C)。
上述结果判明了:在胰腺癌细胞中,BACH1会使迁移能力、浸润能力增强。
<实施例7>BAHC1敲除细胞株的建立
关于BACH1具有转移促进功能,为了通过小鼠移植实验进行体内的验证,采用CRISPR/CAS9系统制作了BACH1敲除胰腺癌细胞株。CRISPR/CAS9系统如下述方法进行制作:将下述向导RNA连接(Ligation)至用限制酶BsmB1(识别序列:5’CGTCTC3’)处理过的病毒载体lentiCRISPR v2(Addgene,MA,USA),制作了持有目标向导RNA的病毒载体。采用Fugene(注册商标)HD(Promega,WI,USA),按照产品说明书对作为来源于人胎儿的肾脏上皮细胞的293T细胞进行转染,两天后,收集培养上清作为病毒液。利用收集的病毒液使持有目标向导RNA的病毒感染AsPC1,在培养基中添加10μg/ml的嘌呤霉素(Sigma Aldrich),进行3周的药剂选择,然后将形成的群落在显微镜下进行分离而得到单一克隆。对于基因突变和蛋白质的表达消失,分别通过基因组序列和蛋白质印迹法进行了确认。单一向导RNA(sgRNA)以BACH1的下述序列为靶序列。
向导RNA-1;5’-CCGCGCUCACCGGUCCGUGCUGG-3’(序列编号21)。
向导RNA-2;5’-CCACUCAAGAAUCGUAGGCCAGG-3’(序列编号22)。
通过序列解析确认到:制作的BACH1敲除细胞在图5的A所示的参考序列中的两种向导RNA的靶序列区域含有作为目标的13个碱基的缺失突变(sgBACH1-1)或者1个碱基的插入突变(sgBACH1-2)(图5的A)。此外,通过蛋白质印迹法确认到:BACH1蛋白质表达的消失(图5的B)。进而,采用定量RT-PCR法,对BACH1敲除是否会与BACH1敲减时同样地导致上皮系基因的表达增强以及间质系基因的表达降低进行了确认,其结果是,虽然上皮系基因的表达呈现出显著增强,但未观察到间质系基因的表达降低(图5的C)。此外,采用蛋白质印迹法确认了E-钙黏蛋白的表达量,其结果是,虽然CDH1的表达量在sgBACH1-1细和sgBACH1-2细胞中均增加(图5的C),但是确认到:E-钙黏蛋白的表达量只有在sgBACH1-2细胞中与siRNA干扰时的结果同样地显著增加(图5的B)。进而,进行了免疫荧光染色,确认了BACH1蛋白质与E-钙黏蛋白的表达量的变化。免疫荧光染色如下述方法进行:将载玻片上培养的细胞用4%甲醛/PBS(Polybutylene succinate,聚丁二酸丁二醇酯)固定10分钟。将载玻片上的细胞浸泡到用1%牛血清白蛋白(Bovine Serum Albumin,BSA)/PBS将第一抗体BACH1(9D11,自制)、E-钙黏蛋白(ab1416,abcam)稀释了200倍的抗体液中,在37℃下反应1小时。用PBS清洗后,将细胞浸泡到用1%BSA/PBS将第二抗体(抗小鼠IgG抗体-FITC(F3008,SigmaAldrich))稀释了1000倍的抗体液中,在37℃下反应1小时。用PBS清洗后,用20μg/ml的Hoechst33342/PBS进行核染色,然后将采用VECTASHIELD封固剂(Mounting Medium)(Funakoshi,Tokyo,Japan)封入的细胞在作为荧光倒置显微镜的高速荧光显像系统AF6500(Leica,Germany)下观察。其结果是,在本细胞中确认到了BACH1的蛋白质的消失与E-钙黏蛋白的蛋白质表达量的增加(图5的D、E)。
<实施例8>BACH1对肿瘤的形成、转移能力的影响
为了解析小鼠个体内的BACH1的功能,向超免疫不全小鼠(NOG(NOD.Cg-PrkdcscidIl2rgtm1Sug/ShiJic)小鼠)的胰腺组织进行了BACH1敲除AsPC1及其对照细胞的原位癌细胞移植。实验采用的是6~8周龄的NOG小鼠。向小鼠腹腔给予3种混合麻醉药(美托咪啶0.3mg/kg,咪达唑仑4mg/kg,布托啡诺5mg/kg)后,采用BACH1野生型AsPC1与BACH1敲除AsPC1向胰腺进行原位移植。针对原位移植,对左上腹部进行1.5cm剖腹,将胰腺取出体外,然后用27G的注射针将104个(悬浮于100μl PBS)细胞移植到胰腺尾部的被膜下。移植后,将胰腺送回体内,用3-0的吸收线缝合腹部。5周后,通过解剖以目测法计测胰腺组织重量、向肝脏的转移数目以及作为腹膜播种的向肠系膜、横隔膜、腹膜的转移数目。图6的A表示解剖时具有代表性的胰腺、肝脏、肠系膜的图像。与体外的细胞增殖结果一致,在胰腺(移植巢)中未观察到肿瘤增殖能力有显著性差异(图6的B的左图)。但是,在BACH1敲除AsPC1中,肝转移、腹膜播种显著减少(图6的B的中央图和右图)。本结果示出:BACH1在胰腺癌细胞中虽然对原发性肿瘤形成没有影响,但是会使转移能力增强。
<实施例9>将BACH1与FOXA1组合的预后预测的研究
采用TCGA的胰腺癌患者的RNA-序列数据对FOXA1的表达与预后的关系进行了解析。结果是,FOXA1越高表达,则预后越好得显著(图7的A)。进而,通过进一步将BACH1的下游因子与BACH1的表达组合来进行解析,对BACH1在预后的功能进行了再评价。其结果是,在BACH1高度发挥其转录抑制功能的BACH1高表达且FOXA1低表达的组合中,预后最差,在BACH1丧失其转录抑制功能的BACH1低表达且FOXA1高表达的组合中,预后良好(图7的B)。本结果示出:BACH1通过组合考虑利用作为其下游基因的FOXA1基因的表达来进行功能评价,能够用作胰腺癌的预后预测用的优异生物标志物。此外,BACH1被认为是显示胰腺癌的转移倾向强度的指标。
SEQUENCE LISTING
<110> 国立大学法人东北大学
<120> 新型胰腺癌上皮间质转化标记物
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atg tct ctg agt gag aac tcg gtt ttt gcc tat gaa tct tct gtg cat 166
Met Ser Leu Ser Glu Asn Ser Val Phe Ala Tyr Glu Ser Ser Val His
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Ser Thr Asn Val Leu Leu Ser Leu Asn Asp Gln Arg Lys Lys Asp Val
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ctg tgc gat gtc acc atc ttt gtg gag gga cag cgg ttc cgc gct cac 262
Leu Cys Asp Val Thr Ile Phe Val Glu Gly Gln Arg Phe Arg Ala His
35 40 45
cgg tcc gtg ctg gcg gca tgc agc agt tac ttc cac tca aga atc gta 310
Arg Ser Val Leu Ala Ala Cys Ser Ser Tyr Phe His Ser Arg Ile Val
50 55 60
ggc cag gct gat gga gag ctg aac att act ctt cca gaa gag gtg aca 358
Gly Gln Ala Asp Gly Glu Leu Asn Ile Thr Leu Pro Glu Glu Val Thr
65 70 75 80
gtt aaa gga ttt gaa cct tta att cag ttt gcc tac act gct aaa ctg 406
Val Lys Gly Phe Glu Pro Leu Ile Gln Phe Ala Tyr Thr Ala Lys Leu
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att tta agt aaa gag aat gtg gat gaa gtg tgc aaa tgt gtg gag ttt 454
Ile Leu Ser Lys Glu Asn Val Asp Glu Val Cys Lys Cys Val Glu Phe
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tta agt gta cat aat att gag gaa tcc tgc ttt cag ttt ctg aaa ttt 502
Leu Ser Val His Asn Ile Glu Glu Ser Cys Phe Gln Phe Leu Lys Phe
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aag ttt ttg gac tcc act gca gac cag caa gaa tgc cca aga aaa aaa 550
Lys Phe Leu Asp Ser Thr Ala Asp Gln Gln Glu Cys Pro Arg Lys Lys
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tgc ttt tca tca cac tgt cag aaa aca gac ctt aaa ctt tca ctt ttg 598
Cys Phe Ser Ser His Cys Gln Lys Thr Asp Leu Lys Leu Ser Leu Leu
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gac cag agg gat cta gaa act gat gaa gtg gag gaa ttt ctg gaa aat 646
Asp Gln Arg Asp Leu Glu Thr Asp Glu Val Glu Glu Phe Leu Glu Asn
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Ala Lys Ala Ser Pro Pro Leu Gln Asp Ser Ala Ser Gln Thr Tyr Glu
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Ser Met Cys Leu Glu Lys Asp Ala Ala Leu Ala Leu Pro Ser Leu Cys
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ccc aaa tac aga aaa ttc caa aaa gca ttt gga act gac aga gtc cgt 838
Pro Lys Tyr Arg Lys Phe Gln Lys Ala Phe Gly Thr Asp Arg Val Arg
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act ggg gaa tct agt gtc aaa gac att cat gct tct gtt cag cca aat 886
Thr Gly Glu Ser Ser Val Lys Asp Ile His Ala Ser Val Gln Pro Asn
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gaa agg tct gaa aat gaa tgc ctg gga gga gtc ccg gag tgt aga gat 934
Glu Arg Ser Glu Asn Glu Cys Leu Gly Gly Val Pro Glu Cys Arg Asp
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ttg cag gtg atg tta aaa tgt gac gaa agt aaa tta gca atg gaa cct 982
Leu Gln Val Met Leu Lys Cys Asp Glu Ser Lys Leu Ala Met Glu Pro
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gaa gaa acg aag aaa gat cct gct tct cag tgc cca act gaa aaa tca 1030
Glu Glu Thr Lys Lys Asp Pro Ala Ser Gln Cys Pro Thr Glu Lys Ser
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Glu Val Thr Pro Phe Pro His Asn Ser Ser Ile Asp Pro His Gly Leu
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tat tct ttg tct ctt tta cac aca tat gac caa tat ggt gac ttg aat 1126
Tyr Ser Leu Ser Leu Leu His Thr Tyr Asp Gln Tyr Gly Asp Leu Asn
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Phe Ala Gly Met Gln Asn Thr Thr Val Leu Thr Glu Lys Pro Leu Ser
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Gly Thr Asp Val Gln Glu Lys Thr Phe Gly Glu Ser Gln Asp Leu Pro
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Leu Lys Ser Asp Leu Gly Thr Arg Glu Asp Ser Ser Val Ala Ser Ser
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Asp Arg Ser Ser Val Glu Arg Glu Val Ala Glu His Leu Ala Lys Gly
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ttc tgg agt gac att tgc agc acg gac act cct tgc caa atg cag tta 1366
Phe Trp Ser Asp Ile Cys Ser Thr Asp Thr Pro Cys Gln Met Gln Leu
405 410 415
tca cct gct gtg gcc aaa gat ggc tca gaa cag atc tca cag aaa cgg 1414
Ser Pro Ala Val Ala Lys Asp Gly Ser Glu Gln Ile Ser Gln Lys Arg
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tct gag tgt ccg tgg tta ggt atc agg att agt gag agc cca gaa cca 1462
Ser Glu Cys Pro Trp Leu Gly Ile Arg Ile Ser Glu Ser Pro Glu Pro
435 440 445
ggt caa agg act ttc aca aca tta agt tct gtc aac tgc cct ttt ata 1510
Gly Gln Arg Thr Phe Thr Thr Leu Ser Ser Val Asn Cys Pro Phe Ile
450 455 460
agt act ctg agt act gaa ggc tgt tca agc aat ttg gaa att gga aac 1558
Ser Thr Leu Ser Thr Glu Gly Cys Ser Ser Asn Leu Glu Ile Gly Asn
465 470 475 480
gat gat tat gtt tca gaa ccc cag caa gaa cct tgc cca tat gct tgt 1606
Asp Asp Tyr Val Ser Glu Pro Gln Gln Glu Pro Cys Pro Tyr Ala Cys
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gtc att agc ttg gga gac gac tct gag acg gac acc gaa gga gac agt 1654
Val Ile Ser Leu Gly Asp Asp Ser Glu Thr Asp Thr Glu Gly Asp Ser
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gaa tcc tgt tca gcc aga gaa caa gaa tgt gag gta aaa ctg cca ttc 1702
Glu Ser Cys Ser Ala Arg Glu Gln Glu Cys Glu Val Lys Leu Pro Phe
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ttg aaa atg cac aag ctt act cca gaa cag ctg gat tgt atc cat gat 1798
Leu Lys Met His Lys Leu Thr Pro Glu Gln Leu Asp Cys Ile His Asp
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att cga aga aga agt aaa aac aga att gct gca cag cgc tgt cgc aag 1846
Ile Arg Arg Arg Ser Lys Asn Arg Ile Ala Ala Gln Arg Cys Arg Lys
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Arg Lys Leu Asp Cys Ile Gln Asn Leu Glu Ser Glu Ile Glu Lys Leu
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Cys Lys Glu Ala Ala Leu Ser Gln Glu Gln Ile Gln Ile Leu Ala Lys
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Tyr Ser Ala Ala Asp Cys Pro Leu Ser Phe Leu Ile Ser Glu Lys Asp
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Lys Ser Thr Pro Asp Gly Glu Leu Ala Leu Pro Ser Ile Phe Ser Leu
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Ser Asp Arg Pro Pro Ala Val Leu Pro Pro Cys Ala Arg Gly Asn Ser
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Glu Pro Gly Tyr Ala Arg Gly Gln Glu Ser Gln Gln Met Ser Thr Ala
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Thr Ser Glu Gln Ala Gly Pro Ala Glu Gln Cys Arg Gln Ser Gly Gly
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Ile Ser Asp Phe Cys Gln Gln Met Thr Asp Lys Cys Thr Thr Asp Glu
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cctttaaaac tcatgtttta aagaataata actctagtaa taactcttcc tgctattcag 2619
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tatggactct agaaagtctg gctacatgaa tagatttaag tgtcactttc cctccctgcc 3039
ccccgcttca gtctctacca tatctggtcc catcatggac ttcctatttc ctggcatttt 3099
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gcattatctc aggctcccta gaatctggag agcttaccaa catgtaaagc tgttcatttt 3219
tccaccgtgg gtcaccaatg ccagaaaacc agacatcacg gggaaagaat gttgcttact 3279
ttttaccagg agtgcagttc atttttttca ccctgttttt gaagtcgtat tattcacttg 3339
taaaaatgat tgtaacagat aaaaaatgta tctgcagcaa ctctgcaggt ttgtgaaata 3399
ggatgaaact caatcttttt ctattgtggg tttgcatttg aaaagcaggt tgaatccttg 3459
ctctcttctc caaatttggt gtggtataaa gacacacaaa tcattttaac ttggacattt 3519
aaagatcagt cttagtgttt gttcagtcct gttacaaaat agataactga gcacctatcg 3579
cataacattt tgcggtggct tttagccatg ctggggttag atgtgtttga gagtcaaatg 3639
aaagctatgg atcttctcag caattaaaaa aaatgcatat attcacattc acagaaacat 3699
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cagagggctg aaagagacac ttctatagac tgcatcctga gcctagtgca gggcttgtct 3819
agctaatgtg ggcagccacc acccactgtg tatgaacaag tctgaagcaa gttggccttg 3879
cccttgagag tatatgggga ccagtcttca tgtcttggag taatttgtca aatgttaccc 3939
tttttgatca gggtgtaggg ggaggatatt gctagtatat tttcagtggt ttgtatgttc 3999
tctctgtcac tgacttattt gtaagagaaa attagttgga cttgtttatt ttctagtagc 4059
ttttataagt acactcaaga atttgtcagg gagaataatt ctgatagtgc atcccatact 4119
gcaaaagaat ttgtgtgtgt gtgtgtgtgt gtgtgtgtgt atgtgtatgt atacatatat 4179
atctctccat ataggtattt ctttgatact tgtaatttta aatttcagct tcacgatata 4239
aaataatata agaacttctg gtttacaaaa tgtaaaatct taagccaatg gaacccttga 4299
tttcctacct cagtgtacac tcaactattg gttgtatcag tttgtgtatg tgcaaatgtc 4359
aaataatctt ttgctttaat tgctactgta cttgctttga aagattacct actattttat 4419
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ctctctacct ataaacagtt tagcattaag ggtttctatt aatgacacag aattattggc 4539
caagtgtaat ttcttaaaat ttagcattac tttaaatagc cagcatgtaa tacaagtaac 4599
tacactacct catatctaca tgattttcaa gttgtaatgc agatggacag ataaaaaaga 4659
ttttacgttt gtcttttggc cataagtggg aaagttttct gtatattgca tagcattaca 4719
catttatgcc tattttaaca ttaacttcta aagaagtttt ttctaagaaa atgtttcaag 4779
gcaatatttt ttttgaggct gccgaagaca aatgacagga ttatgagtat acagtgtatg 4839
ccttttcctt catgcagaat tttgaaatgt tttcagtttg tatattgcat attcacatga 4899
tcattgctca ctattttatg aactggcctt ctcaatgttt gatgattttt taaaagctgt 4959
tatgttgaat tcagtaaaat aacattacct tatttttttt cttattcaaa ttctggaact 5019
atagcaaata attcgttaaa ttgtcatatt caaaacaaat gtggatacag tcttggttct 5079
ccatctgtaa ttttttttaa cagtttgcta tagcttactg cttaactaat tttaaataag 5139
gaaataagta tgttagatgc agtagacgat acaggttgca tgtggacact cagtcacatt 5199
aacaacttgg gaaaaaaatg gcaatgttac ggtgaattct caggtgaact tttttcagtt 5259
ataaaacatc tattttgaat ctgtaaatat tttaaatgtt ttattaaggc atgtaataaa 5319
ctattctttg aaacttgttg ggtagaatga aaattaaagc cataatggta aaagatggca 5379
tactgattat aaaagaagca gaaaaacatt gattttttta tatctttcat aatataattt 5439
tctaacaatg caataaaacc actaaacttt tgtgtc 5475
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Met Ser Leu Ser Glu Asn Ser Val Phe Ala Tyr Glu Ser Ser Val His
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Ser Thr Asn Val Leu Leu Ser Leu Asn Asp Gln Arg Lys Lys Asp Val
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Leu Cys Asp Val Thr Ile Phe Val Glu Gly Gln Arg Phe Arg Ala His
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Arg Ser Val Leu Ala Ala Cys Ser Ser Tyr Phe His Ser Arg Ile Val
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Gly Gln Ala Asp Gly Glu Leu Asn Ile Thr Leu Pro Glu Glu Val Thr
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Val Lys Gly Phe Glu Pro Leu Ile Gln Phe Ala Tyr Thr Ala Lys Leu
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Ile Leu Ser Lys Glu Asn Val Asp Glu Val Cys Lys Cys Val Glu Phe
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Leu Ser Val His Asn Ile Glu Glu Ser Cys Phe Gln Phe Leu Lys Phe
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Lys Phe Leu Asp Ser Thr Ala Asp Gln Gln Glu Cys Pro Arg Lys Lys
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Cys Phe Ser Ser His Cys Gln Lys Thr Asp Leu Lys Leu Ser Leu Leu
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Asp Gln Arg Asp Leu Glu Thr Asp Glu Val Glu Glu Phe Leu Glu Asn
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Lys Asn Val Gln Thr Pro Gln Cys Lys Leu Arg Arg Tyr Gln Gly Asn
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Ala Lys Ala Ser Pro Pro Leu Gln Asp Ser Ala Ser Gln Thr Tyr Glu
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Ser Met Cys Leu Glu Lys Asp Ala Ala Leu Ala Leu Pro Ser Leu Cys
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Pro Lys Tyr Arg Lys Phe Gln Lys Ala Phe Gly Thr Asp Arg Val Arg
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Thr Gly Glu Ser Ser Val Lys Asp Ile His Ala Ser Val Gln Pro Asn
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Glu Arg Ser Glu Asn Glu Cys Leu Gly Gly Val Pro Glu Cys Arg Asp
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Leu Gln Val Met Leu Lys Cys Asp Glu Ser Lys Leu Ala Met Glu Pro
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Glu Glu Thr Lys Lys Asp Pro Ala Ser Gln Cys Pro Thr Glu Lys Ser
290 295 300
Glu Val Thr Pro Phe Pro His Asn Ser Ser Ile Asp Pro His Gly Leu
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Tyr Ser Leu Ser Leu Leu His Thr Tyr Asp Gln Tyr Gly Asp Leu Asn
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Phe Ala Gly Met Gln Asn Thr Thr Val Leu Thr Glu Lys Pro Leu Ser
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Gly Thr Asp Val Gln Glu Lys Thr Phe Gly Glu Ser Gln Asp Leu Pro
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Leu Lys Ser Asp Leu Gly Thr Arg Glu Asp Ser Ser Val Ala Ser Ser
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Asp Arg Ser Ser Val Glu Arg Glu Val Ala Glu His Leu Ala Lys Gly
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Phe Trp Ser Asp Ile Cys Ser Thr Asp Thr Pro Cys Gln Met Gln Leu
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Ser Pro Ala Val Ala Lys Asp Gly Ser Glu Gln Ile Ser Gln Lys Arg
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Ser Glu Cys Pro Trp Leu Gly Ile Arg Ile Ser Glu Ser Pro Glu Pro
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Gly Gln Arg Thr Phe Thr Thr Leu Ser Ser Val Asn Cys Pro Phe Ile
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Ser Thr Leu Ser Thr Glu Gly Cys Ser Ser Asn Leu Glu Ile Gly Asn
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Asp Asp Tyr Val Ser Glu Pro Gln Gln Glu Pro Cys Pro Tyr Ala Cys
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Val Ile Ser Leu Gly Asp Asp Ser Glu Thr Asp Thr Glu Gly Asp Ser
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Glu Ser Cys Ser Ala Arg Glu Gln Glu Cys Glu Val Lys Leu Pro Phe
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Asn Ala Gln Arg Ile Ile Ser Leu Ser Arg Asn Asp Phe Gln Ser Leu
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Leu Lys Met His Lys Leu Thr Pro Glu Gln Leu Asp Cys Ile His Asp
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Ile Arg Arg Arg Ser Lys Asn Arg Ile Ala Ala Gln Arg Cys Arg Lys
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Arg Lys Leu Asp Cys Ile Gln Asn Leu Glu Ser Glu Ile Glu Lys Leu
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Gln Ser Glu Lys Glu Ser Leu Leu Lys Glu Arg Asp His Ile Leu Ser
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Thr Leu Gly Glu Thr Lys Gln Asn Leu Thr Gly Leu Cys Gln Lys Val
610 615 620
Cys Lys Glu Ala Ala Leu Ser Gln Glu Gln Ile Gln Ile Leu Ala Lys
625 630 635 640
Tyr Ser Ala Ala Asp Cys Pro Leu Ser Phe Leu Ile Ser Glu Lys Asp
645 650 655
Lys Ser Thr Pro Asp Gly Glu Leu Ala Leu Pro Ser Ile Phe Ser Leu
660 665 670
Ser Asp Arg Pro Pro Ala Val Leu Pro Pro Cys Ala Arg Gly Asn Ser
675 680 685
Glu Pro Gly Tyr Ala Arg Gly Gln Glu Ser Gln Gln Met Ser Thr Ala
690 695 700
Thr Ser Glu Gln Ala Gly Pro Ala Glu Gln Cys Arg Gln Ser Gly Gly
705 710 715 720
Ile Ser Asp Phe Cys Gln Gln Met Thr Asp Lys Cys Thr Thr Asp Glu
725 730 735
<210> 3
<211> 3373
<212> DNA
<213> 智人
<220>
<221> CDS
<222> (142)..(1560)
<400> 3
ctcttcgccc gggtggcgtt gggcccgcgc gggcgctcgg gtgactgcag ctgctcagct 60
cccctccccc gccccgcgcc gcgcggccgc ccgtcgcttc gcacagggct ggatggttgt 120
attgggcagg gtggctccag g atg tta gga act gtg aag atg gaa ggg cat 171
Met Leu Gly Thr Val Lys Met Glu Gly His
1 5 10
gaa acc agc gac tgg aac agc tac tac gca gac acg cag gag gcc tac 219
Glu Thr Ser Asp Trp Asn Ser Tyr Tyr Ala Asp Thr Gln Glu Ala Tyr
15 20 25
tcc tcc gtc ccg gtc agc aac atg aac tca ggc ctg ggc tcc atg aac 267
Ser Ser Val Pro Val Ser Asn Met Asn Ser Gly Leu Gly Ser Met Asn
30 35 40
tcc atg aac acc tac atg acc atg aac acc atg act acg agc ggc aac 315
Ser Met Asn Thr Tyr Met Thr Met Asn Thr Met Thr Thr Ser Gly Asn
45 50 55
atg acc ccg gcg tcc ttc aac atg tcc tat gcc aac ccg ggc cta ggg 363
Met Thr Pro Ala Ser Phe Asn Met Ser Tyr Ala Asn Pro Gly Leu Gly
60 65 70
gcc ggc ctg agt ccc ggc gca gta gcc ggc atg ccg ggg ggc tcg gcg 411
Ala Gly Leu Ser Pro Gly Ala Val Ala Gly Met Pro Gly Gly Ser Ala
75 80 85 90
ggc gcc atg aac agc atg act gcg gcc ggc gtg acg gcc atg ggt acg 459
Gly Ala Met Asn Ser Met Thr Ala Ala Gly Val Thr Ala Met Gly Thr
95 100 105
gcg ctg agc ccg agc ggc atg ggc gcc atg ggt gcg cag cag gcg gcc 507
Ala Leu Ser Pro Ser Gly Met Gly Ala Met Gly Ala Gln Gln Ala Ala
110 115 120
tcc atg aat ggc ctg ggc ccc tac gcg gcc gcc atg aac ccg tgc atg 555
Ser Met Asn Gly Leu Gly Pro Tyr Ala Ala Ala Met Asn Pro Cys Met
125 130 135
agc ccc atg gcg tac gcg ccg tcc aac ctg ggc cgc agc cgc gcg ggc 603
Ser Pro Met Ala Tyr Ala Pro Ser Asn Leu Gly Arg Ser Arg Ala Gly
140 145 150
ggc ggc ggc gac gcc aag acg ttc aag cgc agc tac ccg cac gcc aag 651
Gly Gly Gly Asp Ala Lys Thr Phe Lys Arg Ser Tyr Pro His Ala Lys
155 160 165 170
ccg ccc tac tcg tac atc tcg ctc atc acc atg gcc atc cag cag gcg 699
Pro Pro Tyr Ser Tyr Ile Ser Leu Ile Thr Met Ala Ile Gln Gln Ala
175 180 185
ccc agc aag atg ctc acg ctg agc gag atc tac cag tgg atc atg gac 747
Pro Ser Lys Met Leu Thr Leu Ser Glu Ile Tyr Gln Trp Ile Met Asp
190 195 200
ctc ttc ccc tat tac cgg cag aac cag cag cgc tgg cag aac tcc atc 795
Leu Phe Pro Tyr Tyr Arg Gln Asn Gln Gln Arg Trp Gln Asn Ser Ile
205 210 215
cgc cac tcg ctg tcc ttc aat gac tgc ttc gtc aag gtg gca cgc tcc 843
Arg His Ser Leu Ser Phe Asn Asp Cys Phe Val Lys Val Ala Arg Ser
220 225 230
ccg gac aag ccg ggc aag ggc tcc tac tgg acg ctg cac ccg gac tcc 891
Pro Asp Lys Pro Gly Lys Gly Ser Tyr Trp Thr Leu His Pro Asp Ser
235 240 245 250
ggc aac atg ttc gag aac ggc tgc tac ttg cgc cgc cag aag cgc ttc 939
Gly Asn Met Phe Glu Asn Gly Cys Tyr Leu Arg Arg Gln Lys Arg Phe
255 260 265
aag tgc gag aag cag ccg ggg gcc ggc ggc ggg ggc ggg agc gga agc 987
Lys Cys Glu Lys Gln Pro Gly Ala Gly Gly Gly Gly Gly Ser Gly Ser
270 275 280
ggg ggc agc ggc gcc aag ggc ggc cct gag agc cgc aag gac ccc tct 1035
Gly Gly Ser Gly Ala Lys Gly Gly Pro Glu Ser Arg Lys Asp Pro Ser
285 290 295
ggc gcc tct aac ccc agc gcc gac tcg ccc ctc cat cgg ggt gtg cac 1083
Gly Ala Ser Asn Pro Ser Ala Asp Ser Pro Leu His Arg Gly Val His
300 305 310
ggg aag acc ggc cag cta gag ggc gcg ccg gcc ccc ggg ccc gcc gcc 1131
Gly Lys Thr Gly Gln Leu Glu Gly Ala Pro Ala Pro Gly Pro Ala Ala
315 320 325 330
agc ccc cag act ctg gac cac agt ggg gcg acg gcg aca ggg ggc gcc 1179
Ser Pro Gln Thr Leu Asp His Ser Gly Ala Thr Ala Thr Gly Gly Ala
335 340 345
tcg gag ttg aag act cca gcc tcc tca act gcg ccc ccc ata agc tcc 1227
Ser Glu Leu Lys Thr Pro Ala Ser Ser Thr Ala Pro Pro Ile Ser Ser
350 355 360
ggg ccc ggg gcg ctg gcc tct gtg ccc gcc tct cac ccg gca cac ggc 1275
Gly Pro Gly Ala Leu Ala Ser Val Pro Ala Ser His Pro Ala His Gly
365 370 375
ttg gca ccc cac gag tcc cag ctg cac ctg aaa ggg gac ccc cac tac 1323
Leu Ala Pro His Glu Ser Gln Leu His Leu Lys Gly Asp Pro His Tyr
380 385 390
tcc ttc aac cac ccg ttc tcc atc aac aac ctc atg tcc tcc tcg gag 1371
Ser Phe Asn His Pro Phe Ser Ile Asn Asn Leu Met Ser Ser Ser Glu
395 400 405 410
cag cag cat aag ctg gac ttc aag gca tac gaa cag gca ctg caa tac 1419
Gln Gln His Lys Leu Asp Phe Lys Ala Tyr Glu Gln Ala Leu Gln Tyr
415 420 425
tcg cct tac ggc tct acg ttg ccc gcc agc ctg cct cta ggc agc gcc 1467
Ser Pro Tyr Gly Ser Thr Leu Pro Ala Ser Leu Pro Leu Gly Ser Ala
430 435 440
tcg gtg acc acc agg agc ccc atc gag ccc tca gcc ctg gag ccg gcg 1515
Ser Val Thr Thr Arg Ser Pro Ile Glu Pro Ser Ala Leu Glu Pro Ala
445 450 455
tac tac caa ggt gtg tat tcc aga ccc gtc cta aac act tcc tag 1560
Tyr Tyr Gln Gly Val Tyr Ser Arg Pro Val Leu Asn Thr Ser
460 465 470
ctcccgggac tggggggttt gtctggcata gccatgctgg tagcaagaga gaaaaaatca 1620
acagcaaaca aaaccacaca aaccaaaccg tcaacagcat aataaaatcc caacaactat 1680
ttttatttca tttttcatgc acaacctttc ccccagtgca aaagactgtt actttattat 1740
tgtattcaaa attcattgtg tatattacta caaagacaac cccaaaccaa tttttttcct 1800
gcgaagttta atgatccaca agtgtatata tgaaattctc ctccttcctt gcccccctct 1860
ctttcttccc tctttcccct ccagacattc tagtttgtgg agggttattt aaaaaaacaa 1920
aaaaggaaga tggtcaagtt tgtaaaatat ttgtttgtgc tttttccccc tccttacctg 1980
accccctacg agtttacagg tctgtggcaa tactcttaac cataagaatt gaaatggtga 2040
agaaacaagt atacactaga ggctcttaaa agtattgaaa gacaatactg ctgttatata 2100
gcaagacata aacagattat aaacatcaga gccatttgct tctcagttta catttctgat 2160
acatgcagat agcagatgtc tttaaatgaa atacatgtat attgtgtatg gacttaatta 2220
tgcacatgct cagatgtgta gacatcctcc gtatatttac ataacatata gaggtaatag 2280
ataggtgata tacatgatac attctcaaga gttgcttgac cgaaagttac aaggacccca 2340
acccctttgt cctctctacc cacagatggc cctgggaatc aattcctcag gaattgccct 2400
caagaactct gcttcttgct ttgcagagtg ccatggtcat gtcattctga ggtcacataa 2460
cacataaaat tagtttctat gagtgtatac catttaaaga attttttttt cagtaaaagg 2520
gaatattaca atgttggagg agagataagt tatagggagc tggatttcaa aacgtggtcc 2580
aagattcaaa aatcctattg atagtggcca ttttaatcat tgccatcgtg tgcttgtttc 2640
atccagtgtt atgcactttc cacagttgga catggtgtta gtatagccag acgggtttca 2700
ttattatttc tctttgcttt ctcaatgtta atttattgca tggtttattc tttttcttta 2760
cagctgaaat tgctttaaat gatggttaaa attacaaatt aaattgttaa tttttatcaa 2820
tgtgattgta attaaaaata ttttgattta aataacaaaa ataataccag attttaagcc 2880
gtggaaaatg ttcttgatca tttgcagtta aggactttaa ataaatcaaa tgttaacaaa 2940
agagcatttc tgttattttt tttcacttaa ctaaatccga agtgaatatt tctgaatacg 3000
atatttttca aattctagaa ctgaatataa atgacaaaaa tgaaaataaa attgttttgt 3060
ctgttgttat aatgaatgtg tagctagtaa aaaggagtga aagaaattca agtaaagtgt 3120
ataagttgat ttaatattcc aagagttgag atttttaaga ttctttattc ccagtgatgt 3180
ttacttcatt tttttttttt tttttgacac cggcttaagc cttctgtgtt tcctttgagc 3240
cttttcacta caaaatcaaa tattaattta actacctttc ctccttcccc aatgtatcac 3300
ttttctttat ctgagaattc ttccaatgaa aataaaatat cagctgtggc tgatagaatt 3360
aagttgtgtc caa 3373
<210> 4
<211> 472
<212> PRT
<213> 智人
<400> 4
Met Leu Gly Thr Val Lys Met Glu Gly His Glu Thr Ser Asp Trp Asn
1 5 10 15
Ser Tyr Tyr Ala Asp Thr Gln Glu Ala Tyr Ser Ser Val Pro Val Ser
20 25 30
Asn Met Asn Ser Gly Leu Gly Ser Met Asn Ser Met Asn Thr Tyr Met
35 40 45
Thr Met Asn Thr Met Thr Thr Ser Gly Asn Met Thr Pro Ala Ser Phe
50 55 60
Asn Met Ser Tyr Ala Asn Pro Gly Leu Gly Ala Gly Leu Ser Pro Gly
65 70 75 80
Ala Val Ala Gly Met Pro Gly Gly Ser Ala Gly Ala Met Asn Ser Met
85 90 95
Thr Ala Ala Gly Val Thr Ala Met Gly Thr Ala Leu Ser Pro Ser Gly
100 105 110
Met Gly Ala Met Gly Ala Gln Gln Ala Ala Ser Met Asn Gly Leu Gly
115 120 125
Pro Tyr Ala Ala Ala Met Asn Pro Cys Met Ser Pro Met Ala Tyr Ala
130 135 140
Pro Ser Asn Leu Gly Arg Ser Arg Ala Gly Gly Gly Gly Asp Ala Lys
145 150 155 160
Thr Phe Lys Arg Ser Tyr Pro His Ala Lys Pro Pro Tyr Ser Tyr Ile
165 170 175
Ser Leu Ile Thr Met Ala Ile Gln Gln Ala Pro Ser Lys Met Leu Thr
180 185 190
Leu Ser Glu Ile Tyr Gln Trp Ile Met Asp Leu Phe Pro Tyr Tyr Arg
195 200 205
Gln Asn Gln Gln Arg Trp Gln Asn Ser Ile Arg His Ser Leu Ser Phe
210 215 220
Asn Asp Cys Phe Val Lys Val Ala Arg Ser Pro Asp Lys Pro Gly Lys
225 230 235 240
Gly Ser Tyr Trp Thr Leu His Pro Asp Ser Gly Asn Met Phe Glu Asn
245 250 255
Gly Cys Tyr Leu Arg Arg Gln Lys Arg Phe Lys Cys Glu Lys Gln Pro
260 265 270
Gly Ala Gly Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser Gly Ala Lys
275 280 285
Gly Gly Pro Glu Ser Arg Lys Asp Pro Ser Gly Ala Ser Asn Pro Ser
290 295 300
Ala Asp Ser Pro Leu His Arg Gly Val His Gly Lys Thr Gly Gln Leu
305 310 315 320
Glu Gly Ala Pro Ala Pro Gly Pro Ala Ala Ser Pro Gln Thr Leu Asp
325 330 335
His Ser Gly Ala Thr Ala Thr Gly Gly Ala Ser Glu Leu Lys Thr Pro
340 345 350
Ala Ser Ser Thr Ala Pro Pro Ile Ser Ser Gly Pro Gly Ala Leu Ala
355 360 365
Ser Val Pro Ala Ser His Pro Ala His Gly Leu Ala Pro His Glu Ser
370 375 380
Gln Leu His Leu Lys Gly Asp Pro His Tyr Ser Phe Asn His Pro Phe
385 390 395 400
Ser Ile Asn Asn Leu Met Ser Ser Ser Glu Gln Gln His Lys Leu Asp
405 410 415
Phe Lys Ala Tyr Glu Gln Ala Leu Gln Tyr Ser Pro Tyr Gly Ser Thr
420 425 430
Leu Pro Ala Ser Leu Pro Leu Gly Ser Ala Ser Val Thr Thr Arg Ser
435 440 445
Pro Ile Glu Pro Ser Ala Leu Glu Pro Ala Tyr Tyr Gln Gly Val Tyr
450 455 460
Ser Arg Pro Val Leu Asn Thr Ser
465 470
<210> 5
<211> 25
<212> RNA
<213> 人工序列
<220>
<223> siRNA BACH1-1
<400> 5
ggucaaagga cuuucacaac auuaa 25
<210> 6
<211> 25
<212> RNA
<213> 人工序列
<220>
<223> siRNA BACH1-2
<400> 6
gggcaccagg gaagauagua guguu 25
<210> 7
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> ACTB primer forward
<400> 7
atttgcggtg gacgatggag 20
<210> 8
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> ACTB primer reverse
<400> 8
agagatggcc acggctgctt 20
<210> 9
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> BACH1 primer forward
<400> 9
aatcgtaggc caggctgatg 20
<210> 10
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> BACH1 primer reverse
<400> 10
agcagtgtag gcaaactgaa 20
<210> 11
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> CDH1 primer forward
<400> 11
tcctggcctc agaagacaga 20
<210> 12
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> CDH1 primer reverse
<400> 12
ccttggccag tgatgctgta 20
<210> 13
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> OCLN primer forward
<400> 13
gagttgacag tcccatggca 20
<210> 14
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> OCLN primer reverse
<400> 14
ctgaagtcat ccacaggcga 20
<210> 15
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> FOXA1 primer forward
<400> 15
ggtggctcca ggatgttagg 20
<210> 16
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> FOXA1 primer reverse
<400> 16
cccaggcctg agttcatgtt 20
<210> 17
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> VIM primer forward
<400> 17
ggaccagcta accaacgaca 20
<210> 18
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> VIM primer reverse
<400> 18
gggtgttttc ggcttcctct 20
<210> 19
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> SNAI2 primer forward
<400> 19
caacgcctcc aaaaagccaa 20
<210> 20
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> SNAI2 primer reverse
<400> 20
acagtgatgg ggctgtatgc 20
<210> 21
<211> 23
<212> RNA
<213> 人工序列
<220>
<223> guide RNA BACH1-1
<400> 21
ccgcgcucac cgguccgugc ugg 23
<210> 22
<211> 23
<212> RNA
<213> 人工序列
<220>
<223> guide RNA BACH1-2
<400> 22
ccacucaaga aucguaggcc agg 23
<210> 23
<211> 65
<212> DNA
<213> 人工序列
<220>
<223> hg19
<400> 23
ccgcgctcac cggtccgtgc tggcggcatg cagcagttac ttccactcaa gaatcgtagg 60
ccagg 65
<210> 24
<211> 52
<212> DNA
<213> 人工序列
<220>
<223> sgBACH1-1
<400> 24
ccgcgctcac cggcatgcag cagttacttc cactcaagaa tcgtaggcca gg 52
<210> 25
<211> 66
<212> DNA
<213> 人工序列
<220>
<223> sgBACH1-2
<400> 25
ccgcgctcac cggtccgtgc tggcggcatg cagcagttac ttccactcaa agaatcgtag 60
gccagg 66
Claims (10)
1.一种用于在体外评价胰腺癌的上皮间质转化能力的方法,其中,
所述方法包括测定BACH1的表达量的工序。
2.根据权利要求1所述的用于在体外评价胰腺癌的上皮间质转化能力的方法,其中,
所述方法还包括测定FOXA1的表达量的工序。
3.一种用于在体外评价胰腺癌的转移能力或浸润能力的方法,其中,
所述方法包括测定BACH1的表达量的工序。
4.根据权利要求3所述的用于在体外评价胰腺癌的转移能力和浸润能力的方法,其中,
所述方法还包括测定FOXA1的表达量的工序。
5.一种用于在体外预测胰腺癌的预后的方法,其中,
所述方法包括测定BACH1的表达量的工序。
6.根据权利要求5所述的用于在体外预测胰腺癌的预后的方法,其中,
所述方法还包括测定FOXA1的表达量的工序。
7.一种筛选胰腺癌转移抑制剂的方法,其中,包括:
向表达BACH1基因或连接于BACH1基因的启动子的报告基因的细胞中,添加医药候选物质的工序;
测定BACH1基因或报告基因的表达量的工序;以及
选择使所述表达量降低的物质的工序。
8.一种胰腺癌转移抑制剂,其中,
将使BACH1基因的表达降低的药剂作为有效成分。
9.根据权利要求8所述的胰腺癌转移抑制剂,其中,
所述胰腺癌转移抑制剂阻害胰腺癌细胞的上皮间质转化能力。
10.根据权利要求8或9所述的胰腺癌转移抑制剂,其中,
所述药剂为针对BACH1基因的siRNA。
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CN114225008A (zh) * | 2021-12-29 | 2022-03-25 | 中国医学科学院医学生物学研究所 | 转录因子btb-cnc同源体1在非霍奇金淋巴瘤治疗中的应用 |
CN115029351A (zh) * | 2022-06-29 | 2022-09-09 | 江南大学 | 一种shRNA或BACH1缺失巨噬细胞来源的EVs在制备治疗高血压的药物中的应用 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114225008A (zh) * | 2021-12-29 | 2022-03-25 | 中国医学科学院医学生物学研究所 | 转录因子btb-cnc同源体1在非霍奇金淋巴瘤治疗中的应用 |
CN114225008B (zh) * | 2021-12-29 | 2024-03-08 | 中国医学科学院医学生物学研究所 | 转录因子btb-cnc同源体1在非霍奇金淋巴瘤治疗中的应用 |
CN115029351A (zh) * | 2022-06-29 | 2022-09-09 | 江南大学 | 一种shRNA或BACH1缺失巨噬细胞来源的EVs在制备治疗高血压的药物中的应用 |
CN115029351B (zh) * | 2022-06-29 | 2023-12-08 | 江南大学 | 一种shRNA或BACH1缺失巨噬细胞来源的EVs在制备治疗高血压的药物中的应用 |
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