CN116855608B - Cited1在肺癌诊断、治疗及预后预测中的应用 - Google Patents
Cited1在肺癌诊断、治疗及预后预测中的应用 Download PDFInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/7023—(Hyper)proliferation
- G01N2800/7028—Cancer
Abstract
本发明公开了CITED1在肺癌诊断、治疗及预后预测中的应用,本发明发现了CITED1与肺癌的相关性,发现CITED1在肺癌中显著高表达,敲低CITED1能够抑制肺癌细胞的迁移和侵袭,并且发现CITED1与肺癌的生存期密切相关。本发明提供的CITED1标志物能够准确的诊断及有效的治疗肺癌,并且可以预测肺癌患者的预后,具有广阔的应用前景。
Description
技术领域
本发明属于生物医药领域,具体涉及CITED1在肺癌诊断、治疗及预后预测中的应用。
背景技术
肺癌是全球最常见的恶性肿瘤之一,发病率和死亡率呈持续上升趋势。主要原因是肺癌细胞具有高转移能力,一旦发生转移,患者将面临极大的死亡威胁。IV期肺癌患者的5年生存率仅为1%。因此,控制肺癌转移、提高肺癌治疗有效率是临床亟待解决的难题。
发明内容
为弥补现有技术的不足,本发明提供了CITED1在肺癌诊断、治疗及预后预测中的应用。
为实现上述目的,本发明采用如下技术方案:
本发明的第一方面提供了检测CITED1表达水平的试剂在制备诊断肺癌/预测肺癌预后的产品中的应用。
进一步,所述试剂选自特异性识别CITED1基因的探针、特异性扩增CITED1基因的引物或特异性结合CITED1基因编码的蛋白的结合剂。
进一步,所述试剂还包括可检测标记。
进一步,所述可检测标记包括放射性同位素、核苷酸发色团、酶、底物、荧光分子、化学发光部分、磁粒、生物发光部分。
进一步,所述产品包括芯片、试剂盒、试纸或核酸膜条。
进一步,所述芯片包括基因芯片、蛋白芯片,所述基因芯片包括用于检测CITED1基因转录水平的针对CITED1基因的寡核苷酸探针,所述蛋白芯片包括CITED1蛋白的特异性结合剂。
进一步,所述试剂盒包括基因检测试剂盒、蛋白检测试剂盒,所述基因检测试剂盒包括用于检测CITED1基因转录水平的试剂或芯片,所述蛋白检测试剂盒包括用于检测CITED1蛋白表达水平的试剂或芯片。
进一步,所述试剂盒还包括缓冲剂、防腐剂或蛋白质稳定剂。
进一步,所述试剂盒还包括说明书。
进一步,所述肺癌包括小细胞肺癌、非小细胞肺癌。
进一步,所述肺癌选自非小细胞肺癌。
本发明的第二方面提供了一种诊断肺癌/预测肺癌预后的产品,所述产品包括能够检测CITED1表达水平的试剂。
进一步,所述产品包括芯片、试剂盒、试纸或核酸膜条。
进一步,所述试剂盒还包括通过RT-PCR法、生物芯片检测法、DNA印迹法、原位杂交法、免疫印迹法检测CITED1基因或蛋白表达水平的试剂。
进一步,所述肺癌包括小细胞肺癌、非小细胞肺癌。
进一步,所述肺癌选自非小细胞肺癌。
本发明的第三方面提供了CITED1的抑制剂在制备治疗肺癌的药物组合物中的应用。
进一步,所述抑制剂抑制肺癌细胞的迁移。
进一步,所述抑制剂降低CITED1的表达水平。
进一步,所述抑制剂包括核酸抑制剂、蛋白抑制剂。
进一步,所述核酸抑制剂包括siRNA、shRNA、核酶、反义寡核苷酸。
进一步,所述蛋白抑制剂包括中和CITED1的抗体。
进一步,所述抑制剂为shRNA。
进一步,所述药物组合还包括药学上可接受的载体。
进一步,所述肺癌包括小细胞肺癌、非小细胞肺癌。
进一步,所述肺癌选自非小细胞肺癌。
本发明的第四方面提供了一种用于治疗肺癌的药物组合物,所述药物组合物包括CITED1的抑制剂。
进一步,所述抑制剂包括核酸抑制剂、蛋白抑制剂。
本发明的第五方面提供了CITED1作为靶标在筛选治疗肺癌的候选药物中的应用。
进一步,筛选治疗肺癌的候选药物的方法如下:用待筛选物质处理表达或含有CITED1基因或其编码的蛋白的培养体系;和检测所述体系中CITED1基因或其编码的蛋白的表达或活性;其中,当所述待筛选物质抑制CITED1基因的或其编码的蛋白的表达水平或活性时,该待筛选物质是治疗肺癌的候选药物。
进一步,所述肺癌包括小细胞肺癌、非小细胞肺癌。
进一步,所述肺癌选自非小细胞肺癌。
本发明的第六方面提供了一种筛选治疗肺癌的候选药物的方法,所述方法包括:用待筛选物质处理表达或含有CITED1基因或其编码的蛋白的培养体系;和检测所述体系中CITED1基因或其编码的蛋白的表达或活性;其中,当所述待筛选物质抑制CITED1基因的或其编码的蛋白的表达水平或活性时,该待筛选物质是治疗肺癌的候选药物。
进一步,所述肺癌包括小细胞肺癌、非小细胞肺癌。
进一步,所述肺癌选自非小细胞肺癌。
本发明的第七方面提供了CITED1在构建诊断肺癌/预测肺癌预后的模型中的应用。
进一步,所述肺癌包括小细胞肺癌、非小细胞肺癌。
进一步,所述肺癌选自非小细胞肺癌。
本发明的第八方面提供了CITED1在构建诊断肺癌/预测肺癌预后的系统/装置中的应用。
进一步,所述肺癌包括小细胞肺癌、非小细胞肺癌。
进一步,所述肺癌选自非小细胞肺癌。
本发明的优点和有益效果:
本发明发现了CITED1与肺癌的相关性,发现CITED1在肺癌中显著高表达,敲低CITED1能够抑制肺癌细胞的迁移和侵袭,并且发现CITED1与肺癌的生存期密切相关。本发明提供的CITED1标志物能够准确的诊断及有效的治疗肺癌,并且可以预测肺癌患者的预后,具有广阔的应用前景。
附图说明
图1是CITED1表达图,其中,1A是CITED1免疫印迹图,1B是CITED1蛋白水平图,1C是CITED1 mRNA表达水平图;
图2是CITED1与肺癌转移相关性图,其中,2A是敲低CITED1免疫印迹图,2B是敲低CITED1水平图,2C是划痕实验图,2D是细胞迁移率图,2E是Transwell实验图,2F是细胞迁移数量图;
图3是CITED1在A549细胞稳定下调表达的验证图,其中,3A是CITED1免疫印迹图,3B是CITED1 mRNA表达水平图;
图4是小鼠肺内转移灶情况图,其中,4A是对照组小鼠肺内转移灶情况图,4B是实验组小鼠肺内转移灶情况图;
图5是CITED1在肺癌组织及癌旁组织的表达情况图;
图6是CITED1在肺癌组织中的表达情况散点图;
图7是CITED1高低表达与患者的生存期图。
具体实施方式
下文提供了本说明书中使用的一些术语的定义。除非另有说明,本文中使用的所有技术和科学用语通常具有和本发明所属领域的普通技术人员通常理解的意思相同的意思。
本发明提供了检测CITED1表达水平的试剂在制备诊断肺癌/预测肺癌预后的产品中的应用。
在本发明中,CITED1包括野生型、突变型或其片段。该术语涵盖全长,未加工的CITED1,源自细胞中加工的任何形式的CITED1,以及CITED1的天然发生变体(例如剪接变体或等位变体)。该术语涵盖例如人的CITED1以及来自任何其它脊椎动物来源的CITED1,包括哺乳动物,诸如灵长动物和啮齿动物(例如小鼠和大鼠)的CITED1,基因ID:4435。
在本发明中,诊断及其术语的变化型是指基于与个体相关的一个或其以上的征兆、症状、数据或其他信息,来对个体的健康状态或状况的发现、判断或认知。个体的健康状态可被诊断为健康的/正常的(即,不存在疾病或疾患),或者可被诊断为不健康的/异常的(即,存在疾病或疾患或特性的评估)。诊断及其术语的变化型包括与特定疾病或疾患相关地,疾病的早期发现;疾病的特性或分类;疾病的进展、治愈或复发的发现;个体的处置或治疗后,对疾病的反应的发现。
在本发明中,预后是指关于医学发展(例如,长期存活可能性、无疾病存活率等)的预期,包括积极预后或消极预后,所述消极预后包括疾病进展如复发、肺癌生长、转移和耐药死亡率,积极预后包括疾病缓解如无疾病状态,疾病改善如肺癌消退或稳定。
在本发明中,表达水平或表达的水平一般指生物学样品中生物标志物的量。表达一般指信息(例如基因编码和/或表观遗传信息)转化成细胞中存在并运行的结构的过程。因此,如本发明中使用的,表达可以指转录成多核苷酸,翻译成多肽,或甚至多核苷酸和/或多肽修饰(例如多肽的翻译后修饰)。转录的多核苷酸的,翻译的多肽的或多核苷酸和/或多肽修饰(例如多肽的翻译后修饰)的片段也应视为表达的,无论它们是源自通过可变剪接生成的转录物或经过降解的转录物,或者是源自多肽的翻译后加工(例如通过蛋白水解)。表达的基因包括转录成多核苷酸(如mRNA),然后翻译成多肽的基因,还有转录成RNA但不翻译成多肽的基因(例如转运和核糖体RNA)。
所述试剂选自特异性识别CITED1基因的探针、特异性扩增CITED1基因的引物或特异性结合CITED1基因编码的蛋白的结合剂。
在本发明中,探针是指能与另一分子的特定序列或亚序列或其它部分结合的分子。除非另有指出,探针通常指能通过互补碱基配对与另一多核苷酸(往往称为靶多核苷酸)结合的多核苷酸探针。根据杂交条件的严谨性,探针能和与该探针缺乏完全序列互补性的靶多核苷酸结合。探针可作直接或间接的标记,其范围包括引物。杂交方式包括但不限于:溶液相、固相、混合相或原位杂交测定法。
在本发明中,引物指短核酸序列,作为具有短的游离3’末端羟基(游离3’羟基)的核酸序列,它可以与互补模板(template)形成碱基对(basepair)并充当复制模板的起点。
在本发明中,结合剂是指特异性结合靶的天然存在的或非天然存在的分子。特异性结合剂的实例包括但不限于蛋白、肽、核酸、碳水化合物和脂质。
在本发明中,特异性结合CITED1基因编码的蛋白的结合剂例如蛋白质CITED1的受体、结合蛋白质CITED1的凝集素、针对蛋白质CITED1的抗体、针对蛋白质CITED1的肽抗体(peptidebody)、双特异性双重结合剂或双特异性抗体形式。特异性结合剂的具体例子是肽、肽模拟物、aptamer、spiegelmer、darpin、锚蛋白重复蛋白、Kunitz型域、抗体。
所述试剂还包括可检测标记。
在本发明中,可检测标记是指能够产生表明在测定样品中存在靶多核苷酸的可检测信号的组合物。合适的标记包括但不限于放射性同位素、核苷酸发色团、酶、底物、荧光分子、化学发光部分、磁粒、生物发光部分。因此,标记是能够由装置或方法检测的任意组合物,包括但不限于光谱、光化学、生物化学、免疫化学、电、光学、化学检测装置或任何其他合适的装置。在一些实施方案中,标记可无需借助于装置而在视觉上检测。
其中,放射性同位素包括但不限于3H、14C、35S、125I、131I。
酶包括但不限于辣根过氧化物酶、β-半乳糖苷酶、荧光素酶、碱性磷酸酶、乙酰胆碱酶。
荧光分子包括但不限于FITC、罗丹明、镧系磷光体(lanthanide phosphors)。
所述产品包括芯片、试剂盒、试纸或核酸膜条。
在本发明中,试剂盒是指在用于对核苷酸进行测序和/或分离核苷酸序列和/或基于来自样品或细胞的表达核苷酸序列的存在、不存在和/或量来诊断患有疾病或感染的受试者的系统的情况下提供的一组组件。
所述试剂盒包括基因检测试剂盒、蛋白检测试剂盒,所述基因检测试剂盒包括用于检测CITED1基因转录水平的试剂或芯片,所述蛋白检测试剂盒包括用于检测CITED1蛋白表达水平的试剂或芯片。
本发明的试剂盒还包括以下组的一种或多种物质:容器、阳性对照物、阴性对照物、缓冲剂、防腐剂、蛋白质稳定剂。
试剂盒中还可附有试剂盒的使用说明书,其中记载了如何采用试剂盒进行检测,和如何利用检测结果对肿瘤发展进行判断、对治疗方案进行选择。
试剂盒的组分可以以水介质的形式或以冻干的形式来包装。试剂盒中适当的容器通常至少包括一种小瓶、试管、长颈瓶、宝特瓶、针筒或其它容器,其中可放置一种组分,并且优选地,可进行适当地等分。在试剂盒中存在多于一种的组分时,试剂盒中通常也将包含第二、第三或其它附加的容器,其中分离地放置附加的组分。然而,不同组合的组分可被包含在一个小瓶中。本发明的试剂盒通常也包括一种用于容纳反应物的容器,密封以用于商业销售。这种容器可包括注模或吹模的塑料容器,其中可保留所需的小瓶。
本发明中所述的芯片、试剂盒、试纸或核酸膜条可用于检测包括CITED1基因或蛋白在内的多个基因或蛋白及其表达产物(例如,肺癌相关的多个基因或蛋白)的表达水平。将肺癌的多个标志物同时进行检测,可大大提高肺癌诊断或预后预测的准确率。
本发明提供了CITED1的抑制剂在制备治疗肺癌的药物组合物中的应用。
在本发明中,抑制剂是指任何可减少CITED1蛋白的活性、降低CITED1基因或蛋白的稳定性、下调CITED1蛋白的表达、减少CITED1蛋白有效作用时间或抑制CITED1基因的转录和翻译的物质,这些物质均可用于本发明,作为对于下调CITED1有用的物质,从而可用于预防或治疗肺癌。
在本发明中,抑制剂包括核酸抑制剂、蛋白抑制剂。其中核酸抑制剂选自:以CITED1或其转录本为靶序列、且能够抑制CITED1基因表达或基因转录的干扰分子,包括但不限于shRNA、siRNA、核酶、反义寡核苷酸,或能表达或形成所述shRNA、siRNA、核酶、反义寡核苷酸的构建物。蛋白抑制剂选自与CITED1蛋白特异性结合的物质,如能够抑制CITED1蛋白活性的抗体或配体。
在本发明的实施方案中,所述抑制剂选自核酸抑制剂。
在本发明中,siRNA可包括部分纯化的RNA、基本上纯的RNA、合成的RNA或重组产生的RNA以及通过添加、缺失、替换和/或改变一个或多个核苷酸而不同于天然RNA的改变的RNA。所述改变可包括添加非核苷酸物质,例如添加到siRNA的末端或siRNA的一个或多个内部核苷酸;使siRNA抵抗核酸酶消化的修饰(例如,使用2'-取代的核糖核苷酸或者对糖磷酸骨架进行修饰);或用脱氧核糖核苷酸替换siRNA中的一个或多个核苷酸。
shRNA是能够形成发夹结构的非编码小RNA分子,shRNA能够通过RNA干扰途径来抑制基因的表达。
反义寡核苷酸(反义核酸序列)可包括与编码蛋白质的有义核酸互补(例如与双链cDNA分子编码链互补或与CITED1 mRNA互补)的核苷酸序列。反义寡核苷酸和递送方法是本领域众所周知的(Goodchild,Curr.Opin.Mol.Ther.,6(2):120-128(2004);Clawson等,Gene Ther.,11(17):1331-1341(2004)),其通过引用以其整体结合到本发明中。反义寡核苷酸可与靶序列的完整编码链互补,或仅与其部分互补。在另一个实施方案中,反义寡核苷酸对CITED1 mRNA中的核苷酸序列的编码链的非编码区而言是反义的。反义寡核苷酸的长度例如可以是约7、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80个或更多个核苷酸。
核酶是可经工程改造而以特异性序列依赖性方式酶促切割和钝化其它RNA靶标的一类RNA。核酶及其递送方法是本领域众所周知的(Hendry等,BMC Chem.Biol.,4(1):1(2004);Grassi等,Curr.Pharm.Biotechnol.,5(4):369-386(2004);Bagheri等,Curr.Mol.Med.,4(5):489-506(2004);Kashani-Sabet M.,Expert Opin.Biol.Ther.,4(11):1749-1755(2004),其各自通过引用以其整体结合到本发明中。通过切割靶RNA,核酶抑制翻译,因而阻止靶基因的表达。可采用本领域已知方法,在实验室中化学合成核酶并对其进行结构修饰以增加其稳定性和催化活性。或者,可通过本领域已知的基因递送机制,将核酶基因引入细胞中。
在本发明的具体实施方案中,核酸抑制剂选自shRNA。
在本发明中,治疗可指治疗性处理或预防性措施,其中目标是预防或减慢(减轻)非期望的生理状况、障碍或疾病,或获得有益的或所需的临床结果。在本发明中,治疗既可以指代治疗也可以指代预防。有益的或所需的临床结果包括但不限于缓解症状;减轻病症、障碍或疾病的程度;稳定(即,不恶化)病症、障碍或疾病的状态;延迟病症、障碍或疾病的发生或减缓其进展;改善病症、障碍或疾病状态;以及缓解(无论是部分的还是完全的)(无论是可检测的还是不可检测的)或改进或改善病症、障碍或疾病。治疗可包括引起临床上明显的反应,而无过度的副作用。治疗还包括相比未接受治疗时的预期存活期延长的存活期。
本发明提供了一种用于治疗肺癌的药物组合物,所述药物组合物包括CITED1的抑制剂。
本发明所述药物组合物可口服给药、非胃肠道给药、通过吸入喷雾给药、局部给药、直肠给药、鼻给药、颊给药、阴道给药或通过植入的贮药装置给药。
本发明的药物还可与其他治疗肺癌的药物联用,其他治疗性化合物可以与主要的活性成分(例如,CITED1的抑制剂)同时给药,甚至在同一组合物中同时给药。还可以以单独的组合物或与主要的活性成分不同的剂量形式单独给予其它治疗性化合物。主要成分(如CITED1的抑制剂)的部分剂量可以与其它治疗性化合物同时给药,而其它剂量可以单独给药。
发明的药物组合物还包括药学上可接受的载体。
药学上可接受的载体包括但不限于稀释剂、粘合剂、表面活性剂、致湿剂、吸附载体、润滑剂、填充剂、崩解剂。
其中,稀释剂如乳糖、氯化钠、葡萄糖、尿素、淀粉、水等;粘合剂如淀粉、预胶化淀粉、糊精、麦芽糖糊精、蔗糖、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素、乙基纤维素、聚乙烯醇、聚乙二醇、聚乙烯比咯烷酮、海藻酸及海藻酸盐、黄原胶、羟丙基纤维素和羟丙基甲基纤维素等;表面活性剂如聚氧化乙烯山梨聚糖脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘油酯、十六烷醇等;致湿剂如甘油、淀粉等;吸附载体如淀粉、乳糖、斑脱土、硅胶、高岭土和皂粘土等;润滑剂如硬脂酸锌、单硬脂酸甘油酯、聚乙二醇、滑石粉、硬脂酸钙和镁、聚乙二醇、硼酸粉末、氢化植物油、硬脂富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸镁、十二烷基硫酸镁等;填充剂如甘露醇(粒状或粉状)、木糖醇、山梨醇、麦芽糖、赤藓糖、微晶纤维素、聚合糖、偶合糖、葡萄糖、乳糖、蔗糖、糊精、淀粉、海藻酸钠、海带多糖粉末、琼脂粉末、碳酸钙和碳酸氢钠等;崩解剂如交联乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基甲基、交联羧甲基纤维素钠、大豆多糖。
在本发明中,药物组合物还酌情包括合适的防腐剂,所述防腐剂包括但不限于苯扎氯铵、氯丁醇、尼泊金(paraben)和硫柳汞。
在本发明中,药物组合物还包括补充的免疫增强物质,所述补充的免疫增强物质例如佐剂,所述佐剂包括但不限于CpG寡核苷酸、细胞因子、趋化因子、皂苷、GM-CSF和/或RNA。
通常以均一剂型提供所述药物组合物,并可通过已知的方式制备。本发明的药物组合物可采用例如胶囊、片剂、锭剂、溶液剂、混悬剂、糖浆剂、酏剂的形式,或是乳剂的形式。
本发明提供了CITED1在构建诊断肺癌/预测肺癌预后的系统中的应用。
所述系统包括:
获取单元:用于获取样本中CITED1的表达水平;
处理单元:根据CITED1的表达情况,获得肺癌的诊断/预后预测结果。
与正常样本相比,若所述CITED1的表达水平呈现显著性上调,则诊断为肺癌;
CITED1的表达水平高的表示肺癌的预后不良。
下面结合具体实施例进一步阐述此发明。应理解的是,在此描述的特定实施方式通过举例的方式来表示,并不作为对本发明的限制。在不偏离本发明范围的情况下,本发明的主要特征可以用于各种实施方式。
实施例
1实验材料
肺癌细胞株、裸鼠、CITED1试剂
NSCLC患者样本及对照样本选自2016-2017年就诊于大连大学附属中山医院肿瘤科收集的样本。
2实验方法及结果
2.1CITED1在NSCLC的表达及促肺癌转移功能
选取7株NSCLC细胞株,包括肺腺癌5株(A549、H1299、PC9、SPCA1、H1975)、肺鳞癌2株(H226、H1703),同时以目前研究公认的正常人肺支气管上皮细胞BEAS-2B作为对照,利用WB和RT-qPCR技术分析,比较CITED1在各NSCLC细胞株及正常人支气管上皮细胞BEAS-2B的表达水平差异。结果发现,CITED1蛋白水平在NSCLC细胞株的表达由高至低分别为:A549、H1703、H1299、SPCA1、H226、PC9及H1975,这与不同肺癌细胞株的转移能力呈正相关,CITED1蛋白表达量均明显高于对照组正常人支气管上皮细胞BEAS-2B(图1A,1B)。类似地,RT-qPCR结果提示在mRNA水平,CITED1表达在各NSCLC细胞株明显高于正常人支气管上皮细胞,其表达水平趋势大致与蛋白相同(图1C)。
基于上述研究结果,筛选出CITED1高表达细胞株A549,利用RNA干扰下调CITED1表达水平,通过划痕实验、Transwell实验观察不同CITED1表达水平对肺癌细胞转移能力的影响。设计CITED1小干扰RNA片段,利用RNA干扰技术,成功构建了CITED1表达水平下调的A549细胞株(sh1#,sh2#,sh3#),其序列如表1所示。并通过WB实验证实了该蛋白的下调表达,选择敲减效率最高的sh1#片段用于后续研究(图2A,2B)。并利用划痕实验、Transwell实验观察下调CITED1表达水平对肺癌迁移的影响,结果如下:
1)划痕实验:以CITED1表达水平下调的A549细胞为实验组,空转质粒组及未转染组为对照组。利用划痕实验,分别观察各组细胞0h、24h、48h的迁移距离,并计算对应的迁移率,实验三次取平均值,结果发现,实验组(shRNA)的24小时迁移率25.48%,明显低于阴性对照组(NC)的35.89%及未转染组(Control)的37.62%(p=0.024);实验组细胞48小时迁移率41%,明显低于阴性对照组的66.59%及未转染组的66.71%(p=0.008)(图2C,2D)。
2)Transwell实验:实验组及两对照组同前。将Transwell小室放入24孔板中,下室加入含30%FBS的培养液800μl,向Transwell上层小室中加入分别各组细胞,均为3×103个/孔的细胞悬液,体积为200μl。将24孔板置于细胞培养箱中培养24h或48h。在倒置显微镜下对迁移至微孔膜下层的细胞计数,每个样本选取5个视野计数细胞个数,取平均值,结果发现,24h细胞迁移个数实验组平均每个视野22.40个,明显少于阴性对照转染组32.60个及未转染组32.00(p=0.001);48h细胞迁移个数实验组28.20个,明显少于阴性对照转染组49.20个及未转染组45.40(p=0.000,图2E,2F)。
表1shRNA序列
2.2利用体内动物实验明确CITED1促肺癌转移功能研究
为进一步明确CITED1的促肺癌转移功能,利用体内动物模型进行验证。首先,构建稳定下调CITED1的A549细胞株,设计三种稳定下调CITED1表达的慢病毒(KD1、KD2、KD3),利用WB及qPCR验证其效率,选取下调CITED1表达率为82.9%的KD3组用于实验(图3)。然后,选取雌性裸鼠共16只,随机分成实验组及对照组,每组各8只。以鼠尾静脉注射的方式构建肺癌转移模型,选取A549肺腺癌细胞株为研究对象,将稳定下调CITED1表达的A549细胞注入小鼠体内作为实验组,对照组则为注入空转的质粒组。将两组小鼠于同一环境下进行饲养。每天观察小鼠状态及成瘤情况,并观察如下指标:
1)观察两组小鼠体重变化
分别在注入细胞第2天、注入后1周、2周、3周、4周及第5周测量两组小鼠体重,结果发现对照组小鼠的平均体重分别为(17.54g、18.08g、18.65g、19.11g、19.51g、20.04g),实验组则分别为(17.48g、18.16g、18.86g、19.93g、19.84g、20.29g),p=0.8911999,无统计差异,即注入不同CITED1水平的A549细胞对小鼠体重无明显影响。
2)观察两组小鼠活体成像情况
实验结束前对两组小鼠进行活体成像,观察不同组别小鼠成瘤情况。结果发现对照组小鼠形成肺内转移灶的数目分别为27、8、11、31、15、33、36、17,共178个,平均为22.25个/只,实验组则分别为3、3、1、2、1、2、1、3,共16个,平均为2个/只。T检验结果p值为0.00107(p<0.05),差异有统计学意义。
3)小鼠肺癌转移灶观察及病理验证
为了验证动物活体成像中,荧光表达处确实为肺癌组织,将动物的肺癌病灶取出。解剖裸鼠取出肺组织,结果发现实验组敲减CITED1表达后,肺内转移灶明显少于对照组(图4)。
2.3CITED1与NSCLC预后相关性分析
1)CITED1在NSCLC组织中的表达水平
通过免疫组化实验,对150例NSCLC患者癌组织及癌旁组织的CITED1表达进行分析比较,结果发现CITED1在癌组织的平均表达量明显高于癌旁组织,其中以图5中的3例患者为例,A1为例1肺癌组织中细胞核、细胞质CITED1表达呈强阳性;A2为例1对应的癌旁肺癌组织CITED1表达呈阴性;B1为例2肺癌组织中细胞质CITED1表达呈阳性;B2为例2对应的癌旁肺癌组织CITED1表达呈阴性;C1为例3肺癌组织中细胞质CITED1表达呈阳性;C2为例3对应的癌旁肺癌组织CITED1表达呈阴性。采用Kruskal-Wallis test检验分析,CITED1在癌组织表达显著高于癌旁组织,差异有统计学意义(p<0.001)(表2,图5,图6),
表2不同组织CITED1表达水平
2)CITED1表达于临床病理特征相关性分析
依据CITED1表达蛋白表达水平将150例NSCLC患者分为高表达组和低表达组,其中低表达组34例,高表达组为116例,CITED1在NSCLC表达水平分别与N分期(χ2=5.733,P<0.05))及TNM分期(χ2=4.628,P<0.05)有显著差异,而与年龄、性别、肿瘤分级、T分期、M分期、肿瘤大小无显著关联(P>0.05)(表3)。
表3CITED1表达水平与NSCLC患者临床病理相关性
3)CITED1在NSCLC表达水平与预后总生存期相关性分析
上述患者中80例患者进一步进行CITED1表达水平与患者预后总生存期的相关性分析,采用Kaplan-Meier生存分析法和log-rank统计检验进行生存期单因素分析,P<0.05具有统计学意义。在这80例患者中,14例患者CITED1为低表达,在长期随访过程中,11例患者存活,总生存率达78.6%;66例患者为CITED1高表达,共33例存活,总生存率为33.30%,P值为0.0059,差异有统计学意义(表4,图7)。CITED1在肺癌组织中高表达预后不良,且差异显著。
表4不同CITED1表达患者总生存率分析
最后,进行COX多因素回归分析,明确与肺癌患者预后生存相关性最强的因素,P值<0.05具有统计学意义。首先,将CITED1表达情况、年龄、性别、肿瘤大小、分级、TNM分期等因素纳入单因素分析,结果发现CITED1表达水平、TNM分期、T分期与患者生存相关。再将这三个因素纳入COX多因素回归分析,结果发现CITED1表达与肺癌患者预后显著相关(P=0.032),可作为影响肺癌患者预后等独立因素(表5)。
表5单因素及多因素分析与肺癌患者预后相关性
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (12)
1.检测CITED1表达水平的试剂在制备诊断肺癌/预测肺癌预后的产品中的应用,所述肺癌选自非小细胞肺癌。
2.根据权利要求1所述的应用,其特征在于,所述试剂选自特异性识别CITED1基因的探针、特异性扩增CITED1基因的引物或特异性结合CITED1基因编码的蛋白的结合剂。
3.根据权利要求2所述的应用,其特征在于,所述试剂还包括可检测标记。
4.根据权利要求3所述的应用,其特征在于,所述可检测标记包括放射性同位素、核苷酸发色团、酶、底物、荧光分子、化学发光部分、磁粒、生物发光部分。
5.根据权利要求1所述的应用,其特征在于,所述产品包括芯片、试剂盒、试纸或核酸膜条。
6.根据权利要求5所述的应用,其特征在于,所述芯片包括基因芯片、蛋白芯片,所述基因芯片包括用于检测CITED1基因转录水平的针对CITED1基因的寡核苷酸探针,所述蛋白芯片包括CITED1蛋白的特异性结合剂。
7.根据权利要求5所述的应用,其特征在于,所述试剂盒包括基因检测试剂盒、蛋白检测试剂盒,所述基因检测试剂盒包括用于检测CITED1基因转录水平的试剂,所述蛋白检测试剂盒包括用于检测CITED1蛋白表达水平的试剂。
8.根据权利要求7所述的应用,其特征在于,所述试剂盒还包括缓冲剂、防腐剂或蛋白质稳定剂。
9.根据权利要求7所述的应用,其特征在于,所述试剂盒还包括说明书。
10.根据权利要求7所述的应用,其特征在于,所述试剂盒还包括通过RT-PCR法、生物芯片检测法、DNA印迹法、原位杂交法、免疫印迹法检测CITED1基因或蛋白表达水平的试剂。
11.CITED1在构建诊断肺癌/预测肺癌预后的模型中的应用,所述肺癌选自非小细胞肺癌。
12.CITED1在构建诊断肺癌/预测肺癌预后的系统/装置中的应用,所述肺癌选自非小细胞肺癌。
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Downregulation of Cited1 suppresses cell proliferation by inducing G2/M arrest of the cell cycle in non-small-cell lung cancer cell lines;Jiantao Jiang等;Int J Clin Exp Pathol;第9卷(第11期);摘要 * |
Epithelial-mesenchymal transition markers screened in a cell-based model and validated in lung adenocarcinoma;Jing Song等;BMC cancer;第19卷;摘要、第7页第2段、图5,表S1 * |
Jiantao Jiang等.Downregulation of Cited1 suppresses cell proliferation by inducing G2/M arrest of the cell cycle in non-small-cell lung cancer cell lines.Int J Clin Exp Pathol.2016,第9卷(第11期),摘要. * |
Jing Song等.Epithelial-mesenchymal transition markers screened in a cell-based model and validated in lung adenocarcinoma.BMC cancer.2019,第19卷摘要、第7页第2段、图5,表S1. * |
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