CN111012913B - Ilf3检测试剂在制备结直肠癌诊断试剂中的应用 - Google Patents
Ilf3检测试剂在制备结直肠癌诊断试剂中的应用 Download PDFInfo
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Abstract
本发明属于生物医药领域,更具体地,ILF3检测试剂在制备结直肠癌诊断试剂中的应用,以及一种结肠直肠癌预后诊断试剂/试剂盒。本发明研究发现ILF3在原发性CRC患者标本中过表达,并且与不良预后相关,从临床水平提示了该基因可能与CRC的恶性表型相关。通过分子生物学手段,干扰ILF3可以显著地抑制CRC的增殖,从而显示ILF3在结直肠癌发生发展中具有重要功能。另外,本发明还首创式地发现ILF3通过直接调节SGOC基因的mRNA稳定性,增加SGOC基因的表达从而促进肿瘤生长,即ILF3通过调节SGOC途径从而影响肿瘤。研究表明,SGOC抑制剂可用于ILF3过表达的CRC患者的治疗,具有重要的临床意义。
Description
技术领域
本发明属于生物医药领域,更具体地,ILF3检测试剂在制备结直肠癌诊断试剂中的应用,以及一种结肠直肠癌预后诊断试剂/试剂盒。
背景技术
结直肠癌(Colorectal Cancer,CRC),是消化系统最常见的肿瘤之一。据最新全球癌症调查报告显示,结直肠癌是世界上仅次于乳腺癌和肺癌的发病率与死亡率均位列第三的肿瘤。随着中国社会经济的飞速发展和居民生活习惯、饮食结构的改变,我国结直肠癌发病率和死亡率依然在不断升高。丰富的历史研究已经沉淀出许多CRC恶性进展相关的关键基因与重要通路,这些通路包括WNT,RAS-MAPK,PI3K,TGF-β,P53和DNA错配修复通路。然而现在CRC的治疗仍然难令人满意。
目前,临床上使用单克隆抗体西妥昔单抗进行CRC的治疗,其是通过靶向细胞外结构域抑制EGFR的活性起作用,在转移性CRC的疾病缓解和生存方面具有临床上有意义的。但是,只有一部分接受西妥昔单抗治疗的患者可以从该药物中获益。
SGOC途径(Serine-Glycine-One-Carbon)即丝氨酸-甘氨酸-一碳循环,是一条代谢信号通路,为葡萄糖和谷氨酰胺合成丝氨酸甘氨酸的代谢通路。
发明内容
本发明目的在于提供一种ILF3抑制剂在制备SGOC活性调控剂方面的应用。
本发明的另一个目的在于提供一种ILF3抑制剂在制备SGOC的负向调控剂方面的应用。
本发明的另一个目的在于提供一种ILF3抑制剂在制备结直肠肿瘤药物方面的应用。
本发明的另一个目的在于提供一种ILF3检测试剂在制备结直肠肿瘤诊断试剂/试剂盒中的应用。
本发明的另一个目的在于提供一种结直肠肿瘤的诊断试剂/试剂盒。
本发明的另一个目的在于提供一种结肠直肠肿瘤的诊断系统。
本发明的还有一个目的在于提供一种SGOC代谢通路抑制剂在制备结直肠肿瘤药物方面的应用。
发明通过以下技术方案实现上述目的:
发明人通过研究发现,ILF3在临床CRC样本中显著地高表达。
ILF3,也称为NF90/NF110,编码一种双链RNA(dsRNA)结合蛋白,该蛋白与其他蛋白质,mRNA,小的非编码RNA和dsRNA形成复合物,从而调节基因表达并稳定 mRNAs。ILF3首先是在一个IL-2启动子的复合物中被纯化鉴定出来的。进一步地研究发现 ILF3可以结合并提高IL-2mRNA的稳定性。ILF3除了在T细胞中被发现具有许多功能外,它还与其它许多生物学过程相关,包括RNA加工,蛋白质翻译,DNA损伤修复,宿主对病毒等的抵抗以及细胞的有丝分裂等等。
本发明研究发现,CRC中ILF3的频繁过度表达会导致丝氨酸生物合成中的代谢重编程表型,从而促进肿瘤生长,球体形成,并与不良的癌症生存率相关。
发明人通过抑制ILF3或抑制丝氨酸生物合成可减轻体内肿瘤的生长。
一方面,本发明提供了ILF3抑制剂在制备SGOC活性调控剂方面的应用。
另一方面,ILF3抑制剂在制备SGOC的负向调控剂方面的应用。
另一方面,ILF3抑制剂在制备肿瘤药物方面的应用,所述肿瘤包括肾上腺皮质癌、膀胱尿路上皮癌、乳腺浸润癌、宫颈癌、胆管癌、淋巴瘤、食道癌、胶质母细胞瘤、头颈部鳞状细胞癌、肾染色体、肾脏肾透明细胞癌、肾肾乳头状细胞癌、急性髓性白血病、脑低级脑胶质瘤、肝肝细胞癌、肺腺癌、肺鳞状细胞癌、间皮瘤、卵巢浆液性囊腺癌、胰腺腺癌、嗜铬细胞瘤和副神经节瘤、前列腺腺癌、肉瘤、皮肤皮肤黑色素瘤、胃腺癌、睾丸生殖细胞肿瘤、甲状腺癌、胸腺瘤、子宫体子宫内膜癌、子宫癌肉瘤、结直肠肿瘤。
一些实施例中,所述肿瘤为结直肠肿瘤。
一些实施例中,所述的ILF3抑制剂为抑制ILF3蛋白活性的物质、或降解ILF3蛋白的物质、或降低ILF3蛋白水平的基因工具。
一些实施例中,所述的抑制ILF3蛋白活性的物质选自化合物。
一些实施例中,所述的降低ILF3蛋白水平的基因工具为RNA干扰、microRNA、基因编辑或基因敲除材料。
一些实施例中,所述的ILF3抑制剂为肿瘤靶向ILF3抑制剂。
另一方面,本发明提供了一种ILF3检测试剂在制备肿瘤诊断试剂/试剂盒中的应用,所述肿瘤包括肾上腺皮质癌、膀胱尿路上皮癌、乳腺浸润癌、宫颈癌、胆管癌、淋巴瘤、食道癌、胶质母细胞瘤、头颈部鳞状细胞癌、肾染色体、肾脏肾透明细胞癌、肾肾乳头状细胞癌、急性髓性白血病、脑低级脑胶质瘤、肝肝细胞癌、肺腺癌、肺鳞状细胞癌、间皮瘤、卵巢浆液性囊腺癌、胰腺腺癌、嗜铬细胞瘤和副神经节瘤、前列腺腺癌、肉瘤、皮肤皮肤黑色素瘤、胃腺癌、睾丸生殖细胞肿瘤、甲状腺癌、胸腺瘤、子宫体子宫内膜癌、子宫癌肉瘤、结直肠肿瘤。
一些实施例中,所述肿瘤为结直肠肿瘤。
一些实施例中,所述的诊断试剂/试剂盒为结直肠肿瘤预后用途的诊断试剂/试剂盒。
一些实施例中,所述检测试剂为检测ILF3的基因表达量。
一些实施例中,所述检测试剂为检测ILF3的基因表达量。
一些实施例中,所述检测试剂检测ILF3的mRNA表达量。
一些实施例中,所述检测试剂检测ILF3蛋白的表达量。
一些实施例中,所述检测试剂为荧光定量PCR染料、荧光定量PCR引物、荧光定量PCR探针、抗体、抗体功能性片段和偶联抗体中的一种或多种。
一些实施例中,所述的试剂盒选自qPCR试剂盒、免疫印迹检测试剂盒、免疫层析检测试剂盒、流式细胞分析试剂盒、免疫组化检测试剂盒、ELISA试剂盒、蛋白沉淀试剂盒、免疫荧光试剂盒和电化学发光检测试剂盒中的一种或多种。
一些实施例中,所述的试剂盒选自蛋白沉淀试剂盒、免疫荧光试剂盒、免疫印迹检测试剂盒、免疫组化检测试剂盒中的一种或多种。
另一方面,本发明提供了一种结直肠肿瘤的诊断试剂/试剂盒,所述诊断试剂/试剂盒包含ILF3的检测试剂。
一些实施例中,所述检测试剂为检测ILF3的基因表达量。
一些实施例中,所述检测试剂检测ILF3的mRNA表达量。
一些实施例中,所述检测试剂检测ILF3蛋白的表达量。
一些实施例中,所述检测试剂为荧光定量PCR染料、荧光定量PCR引物、荧光定量PCR探针、抗体、抗体功能性片段和偶联抗体中的一种或多种。
一些实施例中,所述的试剂盒选自qPCR试剂盒、免疫印迹检测试剂盒、免疫层析检测试剂盒、流式细胞分析试剂盒、免疫组化检测试剂盒、ELISA试剂盒、蛋白沉淀试剂盒、免疫荧光试剂盒和电化学发光检测试剂盒中的一种或多种。
一些实施例中,所述的试剂盒选自蛋白沉淀试剂盒、免疫荧光试剂盒、免疫印迹检测试剂盒、免疫组化检测试剂盒。
另一方面,本发明提供了一种结肠直肠肿瘤的诊断系统,所述的诊断系统含有:
检测构件:所述的检测构件用以检测ILF3的表达量;
结果判断构件:所述的结果判断构件用于根据检测构件所检测ILF3的表达量的结果,输出肿瘤患者疾病结果。
一些实施例中,所述ILF3的表达量为基因表达量、mRNA表达量和或蛋白表达量中的一种或多种。
一些实施例中,所述的结果判断构件含有输入模块、分析模块和输出模块;输入模块用于输入ILF3的表达量;分析模块用于根据ILF3的表达量,分析出肿瘤患者疾病风险结果的可能性;输出模块用于输出分析模块的分析结果。
一些实施例中,所述的检测构件含有qPCR试剂盒、免疫印迹检测试剂盒、免疫层析检测试剂盒、流式细胞分析试剂盒、免疫组化检测试剂盒、ELISA试剂盒、蛋白沉淀试剂盒、免疫荧光试剂盒、电化学发光检测试剂盒、qPCR仪、免疫印迹检测装置、流式细胞仪、免疫组化检测装置、ELISA检测装置、电化学发光检测装置、免疫荧光检测装置中的一种或几种。
一些实施例中,所述的试剂盒选自蛋白沉淀试剂盒、免疫荧光试剂盒、免疫印迹检测试剂盒、免疫组化检测试剂盒。
本发明中,所述ILF3的检测试剂的检测样品为组织、粪便或血液。
一些实施例中,所述的检测样品为组织。
一些实施例中,所述的检测样品为肠粘膜组织。
另一方面,本发明提供了SPOP促进剂在制备ILF3的负向调节剂方面的应用。
一些实施例中,所述的SPOP促进剂为促进SPOP蛋白活性的物质或提高SPOP蛋白水平的基因工具。
还有一方面,本发明提供了SGOC代谢通路抑制剂在制备结直肠肿瘤药物方面的应用。
一些实施例中,所述SGOC代谢通路抑制剂为抑制该通路中代谢起始物、或中间物、或终产物生成或者活性的物质。
一些实施例中,所述的抑制剂为酶抑制剂。
一些实施例中,所述的SGOC代谢通路抑制剂包括上游通路抑制剂和/或下游通路抑制剂。
一些实施例中,所述SGOC代谢通路抑制剂包括NCT-503。
一些实施例中,所述结直肠肿瘤为ILF3高表达的肿瘤。
本发明一些实施例中,所述的结直肠肿瘤为I、II、III、IV期结直肠癌、癌前腺瘤。
与现有技术相比,本发明其中一些实施例的有益效果:
(1)本发明研究发现ILF3在原发性CRC患者标本中过表达,并且与不良预后相关,从临床水平提示了该基因可能与CRC的恶性表型相关。
(2)通过分子生物学手段,干扰ILF3可以显著地抑制CRC的增殖,从而显示ILF3在结直肠癌发生发展中具有重要功能。
(3)另外,本发明还首创式地发现ILF3通过直接调节SGOC基因的mRNA稳定性,增加SGOC基因的表达从而促进肿瘤生长,即ILF3通过调节SGOC途径从而影响肿瘤。研究表明,SGOC抑制剂的可用于ILF3过表达的CRC患者的治疗,具有重要的临床意义。
附图说明
图1为使用qRT-PCR从34个配对的CRC和正常组织样本中相对ILF3 mRNA水平的瀑布图。
图2为在不同细胞系中ILF3蛋白表达水平的免疫印迹分析。
图3为ILF3在79对正常和CRC组织样品中的表达。
图4:4A-4C为基于ILF3在测试和验证队列的CRC组织中的表达的Kaplan-Meier生存曲线;ROC曲线用于定义cutoff值,对Log-rank用于检验显着性。
图5为人结肠癌和邻近正常结肠组织中ILF3 IHC染色的定量图像。比例尺,50μM。
图6为通过分离临床标本建立类器官模型观察ILF3对肿瘤恶性的影响;其中siLF3-1指的是敲低ILF3的一号片段;siLF3-2指的是敲低ILF3的二号片段;PDO-1指的是一号病人来的类器官;PDO-2指的是二号病人来的类器官;Scramble RNA指的是对照组。
图7为细胞用指定的shRNA感染或者通过转染siRNA,通过shRNA或者siRNA抑制细胞中ILF3的表达,从而测定细胞的增值率和小球形成能力:图7A、7B测量细胞增殖率,数据以平均值±标准差表示;图7C为第7天的代表性图像(左图)和对小球形成能力测定的定量(右图),比例尺,25μM,在感染了ILF3 shRNA的所示细胞中形成了瘤球;shILF3-31 指的是敲低ILF3的基因表达(1号片段);shILF3-32指的是敲低ILF3的基因表达(2号片段);Scramble指的是对照组。
图8A:在小鼠体内,ILF3促进肿瘤细胞增殖;EV指的是对照组;ILF3指的是过表达组;图8B:敲低ILF3可以抑制小鼠肿瘤组织生长;#1-#4分别指的是来自不同小鼠的肿瘤组织(相当于生物学重复);shILF3-31指的是敲低ILF3的基因表达(1号片段);shILF3-32指的是敲低ILF3的基因表达(1号片段);Scramble RNA指的是对照组;图8C:在小鼠体内, ILF3促进SGOC基因表达;PHGDH等指的是SGOC通路代表性基因。
图9为在产生的皮下肿瘤组织中ILF3,PHGDH,Ki67和cleaved-Caspase-3染色的代表性IHC图像。比例尺代表50μm。
图10:靶向SGOC的抑制剂可以抑制PDX(结直肠肿瘤病人来源的组织移植模型)的增殖;A16025指的是代表PDX编号,为ILF3高表达;A08053指的是代表PDX编号,为 ILF3高表达;B00027指的是代表PDX编号,为ILF3低表达;B00012指的是代表PDX编号,为ILF3低表达。
图11A:ILF3可以结合SGOC基因的mRNA并且使他们稳定;lgG指的是阴性对照;ILF3指的是实验组;SNRNP70指的是阳性对照(已经被报道可以结合U6);PHGDH指的是 SGOC基因之一;PSAT1指的是SGOC基因之一;PSPH指的是SGOC基因之一;SHMT1 指的是SGOC基因之一;SHMT2指的是SGOC基因之一;图11B和图11C:ILF3可以调控DLD1细胞中的SGOC系列基因的mRNA的稳定性,从而影响其表达;PHGDH指的是 SGOC基因之一;PSAT1指的是SGOC基因之一;PSPH指的是SGOC基因之一;SHMT1指的是SGOC基因之一;SHMT2指的是SGOC基因之一;ActD指的是放线菌素D。
图12:SPOP可以调控ILF3的表达;SPOP过表达可以抑制ILF3表达;SPOP敲低可以促进ILF3的表达;HA为标签。
图13为临床样本分析得到的基因表达图。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案,具体实施例不代表对本发明保护范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。
结直肠癌:Colorectal cancer,CRC。
备注:实施例1-11为具体的实验方案;实施例12-13为对应的实验测试结果。
shILF3:指的是敲低ILF3。
Scramble:指的是对照,即乱序RNA。
实施例1患者和组织样本
从中山大学附属第六医院外科提取新鲜的成对冷冻的原发性结直肠癌和邻近正常结肠组织的样本。在收集样本时,所有患者均患有II期或III期疾病。
另外,从三个独立的CRC患者队列中获得了原发性结直肠腺癌(制备为TMA)的石蜡包埋样本:(1)中山大学附属第六医院的79名患者(测试队列);(2)270名患者来自中山大学附属第一医院(验证队列1);(3)来自中国人民解放军第150中心医院的134名患者 (验证队列2)。原始的免疫组织化学玻片由Aperio Versa(Leica Biosystems)扫描,后者捕获了免疫染色玻片的数字图像。Genie为病理学家选择的区域计算H分数。所有样本均在获得患者书面知情同意并获得研究中心机构审查委员会的批准后收集。
实施例2细胞培养、试剂和转染
所有细胞均获自ATCC,并保存处于37℃和5%CO2条件下。其中,DLD-1和HCT-8 细胞保存在含有10%(v/v)胎牛血清(FBS)的RPMI 1640培养基(RPMI)中。293T, RKO,HT29,WiDR和SW620细胞用DMEM培养基(含10%FBS)培养。质粒和siRNA 导入细胞系的所有瞬时转染均遵循脂质体2000转染试剂(Thermo Fisher,#11668019)的说明书。
实施例3ILF3的shRNA敲低
本发明筛选了针对人ILF3转录本的四个发夹型shRNA,发现了两个独立的序列,可将mRNA水平降低>70%。所述shRNA在pLKO.1载体中(#31和#32)。#35的是以ILF3 的3’UTR为靶标进行设计的。
制备慢病毒颗粒的步骤为:将55cm2皿中的1×107个HEK293T细胞与10μg pLKO.1shRNA构建体,5μg psPAX2和5μgpMD2.G共转染。转染48和72小时后,收集含有病毒颗粒的上清液,并通过Millex-GP过滤器(0.45μm孔径,Millipore)过滤。为了用慢病毒感染癌细胞,将细胞用含有2mL慢病毒、200μL FBS和5mg/mL polybrene(Sigma)的培养基在37℃的条件下,感染24小时和48小时,共两次。为了提高敲低效率,对感染的细胞进行嘌呤霉素筛选几天。
实施例4异种移植结肠直肠癌模型
该研究得到中山大学动物伦理与福利委员会的批准。使用皮下移植异种移植模型确定用非靶向发夹或shILF3-31或shILF3-32转导的DLD1细胞的体内肿瘤生长。DLD1(5×106细胞/小鼠)细胞通过皮下接种到5周大的雌性BALB/c-nu/nu小鼠的后肢侧翼。6天后,出现明显的肿瘤将小鼠随机分为两组。8天后,肿瘤的平均大小达到~150mm3。将NCT-503(40毫克/千克/天)通过腹膜内注射给药。每周两次测量肿瘤的长度和宽度,并根据公式(长度×宽度2)/2计算体积。
对于患者衍生的异种移植物(PDX),PDX模型是从南京大学南京生物医学研究所和中山大学附属第六医院获得的。患者来源的肿瘤碎片(3-4mm3 0)通过手术异种移植在雄性NSG小鼠的皮肤下。当肿瘤达到约为100立方毫米时,将小鼠随机分为2/4个治疗组中的一个。
实施例5类器官培养
按照现有技术的方法(Roper J,Tammela T,Cetinbas NM et al.In vivo genomeediting and organoid transplantation models of colorectal cancer andmetastasis.Nat Biotechnol 2017;35:569- 576.),将人类癌症组织生长为类器官。将新鲜的CRC肿瘤组织样品切成小块,用冰冷的 PBS洗涤,然后用EDTA消化。在Matrigel聚合之后(在37℃下放置10分钟),在 Advanced DMEM/F12中补充青霉素/链霉素,10mM HEPES,2mMGlutaMAX,1×B27, 1×N2(生命技术),10nM胃泌素I(Biogems)和1mM N-乙酰半胱氨酸(Sigma)。并添加以下因子:50ng/mL重组EGF,100ng/mL重组Noggin(Peprotech),500nMA83-01 (Biogems),500ng/mL R-spondin-1(Peprotech),10μM Y-27632(Abmole),10mM烟酰胺 (Sigma)和10μMSB202190(Sigma)。
实施例6免疫组织化学实验
使用特异性抗体通过免疫组织化学表征肿瘤中ILF3,PHGDH,Cleaved-Caspase 3和Ki- 67的表达。步骤包括:将肿瘤切片(4μm)在二甲苯中脱蜡,以降浓度的乙醇水合,浸入0.3%H2O2-甲醇中30分钟,用磷酸盐缓冲液洗涤,并用单克隆抗ILF3(1:250)进行探测,抗PHGDH(1:200),抗Casped Caspase 3(1:100)或Ki-67抗体(1:100)或同种型对照在4℃过夜。洗涤后,将切片与生物素化的山羊抗兔或抗小鼠IgG在室温下孵育2小时。用链霉亲和素/过氧化物酶复合物和二氨基联苯胺可视化免疫染色,然后用苏木精复染色。
实施例7免疫荧光实验
将石蜡包埋的样品切成4mm的厚度。用高压锅在0.01M柠檬酸盐缓冲液(pH 6.0)中进行抗原回收15-20分钟,以去除最初固定组织时形成的醛键。然后,在室温下将切片在含有10%驴血清或2%牛血清白蛋白的PBS中封闭1小时。室温下,将免疫荧光细胞用4%多聚甲醛固定15分钟,用PBS洗涤,再用0.2%Triton X-100的PBS渗透15分钟。此后,在室温下将细胞在含2%BSA的PBS中封闭1小时。封闭后,将样品与对兔抗人ILF3特异性的一抗(1:200)在4℃孵育过夜。将Alexa Fluor偶联的二抗(Invitrogen)在室温下孵育 1小时。然后使用DAPI对细胞核进行染色。对于TUNEL分析,将玻片在37℃下使用原位细胞死亡检测试剂盒(POD)染色30分钟,然后在室温下与Alexa Fluor偶联的二抗 (Invitrogen)孵育1小时。
实施例8RNA免疫沉淀与稳定性分析
按照产品说明书,使用Magna RIP RNA结合蛋白免疫沉淀试剂盒(17-701,Millipore) 进行RNA免疫沉淀。用加扰或ILF3 shRNA处理DLD1细胞,然后用放线菌素D(10mg/mL)处理0、3、6、9或12小时,然后用Trizol RNA提取。进行定量qRT-PCR分析,并使用2-ΔΔCt方法进行相对mRNA分析。校准mRNA水平,并与0时间点进行比较。其中放线菌素D是抑制转录的。
实施例9
测试队列包括来自79例患者的配对CRC和正常结肠组织样本。验证队列包括来自270 位患者和134位患者的CRC样本。ILF3高表达与晚期临床阶段呈正相关(表S1)。此外,多因素Cox回归分析显示ILF3表达是生存不良的独立预后因素(表S2):测试队列包括来自79例患者的配对CRC和正常结肠组织样本。验证队列包括来自270位患者和134位患者的CRC样本。ILF3高表达与晚期临床阶段呈正相关(表S1)。此外,多因素Cx回归分析显示ILF3表达是生存不良的独立预后因素(表S2)。
表S1 ILF3的临床病理相关性分析
表S2单一变量和多变量结直肠癌病人不同预后参数分析
实施例10实验结果分析
使用qRT-PCR对34个配对的结肠癌组织和邻近的正常黏膜样本进行了进一步分析,相对ILF3 mRNA水平的瀑布图如图1所示(相应样本和试剂如实施例1和实施例2所示)。
为了验证ILF3在不同肠癌细胞中的表达情况,通过免疫印迹分析对不同细胞系中ILF3 蛋白表达水平进行分析,结果如图2所示,发现CRC表现出较高的ILF3水平。
以免疫组化的方法对ILF3在79对正常和CRC组织样品中的表达情况进行分析,结果如图3所示,表明,ILF3在结直肠癌种高表达。基于ILF3在测试和验证队列的CRC组织中的表达的生存分析(Kaplan-Meier分析)如图4显示,在三个独立的队列中,高ILF3水平与较差的总体生存率相关。即表明高ILF3水平与病人恶性预后相关(实验方法为实施例1 和实施例6和实施例9)。
组织芯片中ILF3的免疫组织化学染色(n=79),如图5所示,CRC中ILF3的表达高于正常组织(实验方法为实施例1和实施例6)。
另外,本发明发现SPOP过表达可以抑制ILF3表达,SPOP敲低可以促进ILF3的表达,如图12所示,SPOP是ILF3的E3连接酶,可以降解ILF3。SPOP缺失或者突变可以引起ILF3在肿瘤组织的堆积。(实验方法为实施例2)。
通过分离临床标本建立类器官模型观察ILF3对CRC肿瘤恶性的影响,类器官的培养方法按照实施例5进行,结果如图6所示,敲低ILF3可以显著的抑制CRC肿瘤类器官的形成能力和生长。
分子生物学方法(实施例2和实施例3)实验结果如图7A和图7B显示,敲低ILF3,从而抑制了这些结直肠癌细胞的细胞增殖和球形成能力。
为了确定ILF3在肿瘤发生中的体内作用贡献,本发明进行了CRC异种移植小鼠模型实验(实施方法见实施例4和实施例6)。具体为将过表达ILF3的DLD1和HCT-116细胞系皮下植入裸鼠。实验结果如图8A-8C所示,其中图8A显示了过度表达ILF3的荷瘤细胞加速了肿瘤的生长,同时在肿瘤组织中SGOC基因的表达增加。此外,图8B显示了,用ILF3 敲低抑制ILF3表达可显着降低体内肿瘤的生长。相应地,图8C显示了,ILF3促进SGOC 基因表达;PHGDH等指的是SGOC通路代表性基因。这些肿瘤在SGOC基因表达,细胞增殖和凋亡增加方面均表现出明显的降低。
为了验证ILF3敲低确实可以抑制肿瘤增殖,本发明通过取材动物体内肿瘤组织,进行免疫组化染色(方法如实施例6)。如图9所示,结果表明敲低ILF3可以显著抑制细胞恶性指标Ki67和PHGDH的表达,促进细胞凋亡指标cleaved-caspase3的表达。
为了验证靶向SGOC可以抑制肿瘤增殖,本发明通过取材PDX(结直肠肿瘤病人来源的肿瘤组织移植模型)肿瘤组织,进行免疫组织荧光染色(方法如实施例4和实施例7)。如图10所示,结果表明,SGOC抑制剂NCT-503可显著促进ILF3高表达的PDX(结直肠肿瘤病人来源的肿瘤组织移植模型)的细胞凋亡(TUNEL阳性细胞数目),但是对ILF3低表达的PDX无显著影响。
为了阐明ILF3如何调控SGOC基因表达,本发明通过ILF3抗体拉下来ILF3蛋白,进而检测ILF3结合的mRNA(方法如实施例8)。结果如图11A、图11B和图11C所示,结果表明,ILF3可以结合到SGOC的mRNA,稳定mRNA,促进基因的表达,从而促进肿瘤的发生发展。
另外,本发明研究发现ILF3在除了CRC中升高以外,还在一些其他肿瘤也会升高,结果如图13所示,包括肾上腺皮质癌、膀胱尿路上皮癌、乳腺浸润癌、宫颈癌、胆管癌、淋巴瘤、食道癌、胶质母细胞瘤、头颈部鳞状细胞癌、肾染色体、肾脏肾透明细胞癌、肾肾乳头状细胞癌、急性髓性白血病、脑低级脑胶质瘤、肝肝细胞癌、肺腺癌、肺鳞状细胞癌、间皮瘤、卵巢浆液性囊腺癌、胰腺腺癌、嗜铬细胞瘤和副神经节瘤、前列腺腺癌、肉瘤、皮肤皮肤黑色素瘤、胃腺癌、睾丸生殖细胞肿瘤、甲状腺癌、胸腺瘤、子宫体子宫内膜癌、子宫癌肉瘤。总之,本发明研究表明,ILF3在CRC中高表达,并且与较差的存活率相关,其对细胞生长和球形成的积极影响将增加其致癌作用。在体内,ILF3具有激活SGOC通路从而促进肿瘤发生的作用。本发明还阐明了癌症形成过程中ILF3表达水平和SGOC网络之间的调控。本发明基于转录组和IHC分析的临床数据表明,ILF3是与预后相关的标志物,在结肠癌中被上调。ILF3在CRC中过表达与SGOC基因有关。
Claims (7)
1.NCT-503在制备治疗结直肠肿瘤药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述的结直肠肿瘤为I、II、III、IV期结直肠癌或癌前腺瘤。
3.一种试剂,其特征在于,包含ILF3检测试剂和SGOC代谢通路抑制剂,所述SGOC代谢通路抑制剂为NCT-503。
4.如权利要求3所述的试剂,其特征在于,所述检测试剂为检测ILF3的基因表达量。
5.如权利要求3所述的试剂,其特征在于,所述检测试剂检测ILF3的mRNA表达量。
6.如权利要求3所述的试剂,其特征在于,所述检测试剂检测ILF3蛋白的表达量。
7.如权利要求3-6任一所述的试剂,其特征在于,所述检测试剂为荧光定量PCR染料、荧光定量PCR引物、荧光定量PCR探针、抗体、抗体功能性片段和偶联抗体中的一种或多种。
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