CN110082536A - 一种乳腺癌细胞标志物细胞因子群及其应用 - Google Patents

一种乳腺癌细胞标志物细胞因子群及其应用 Download PDF

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CN110082536A
CN110082536A CN201910307371.7A CN201910307371A CN110082536A CN 110082536 A CN110082536 A CN 110082536A CN 201910307371 A CN201910307371 A CN 201910307371A CN 110082536 A CN110082536 A CN 110082536A
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郑国沛
张志杰
刘浩
罗凯
贺智敏
李洪胜
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Abstract

本发明一种乳腺癌标志物细胞因子群及其应用，涉及生物技术和医药技术领域，所述乳腺癌标志物细胞因子群包括TNFα蛋白、FGF2蛋白、IL‑6蛋白和Wnt4蛋白，所述乳腺癌标志物细胞因子群能够诱导乳腺癌细胞发生上皮‑间质转化，诱导乳腺癌细胞发生转移，诱导乳腺癌细胞发生侵袭，提高成球能力，提高CD44+CD24‑细胞含量。

Description

一种乳腺癌细胞标志物细胞因子群及其应用
技术领域
本发明涉及生物技术和医药技术领域，具体涉及一种乳腺癌标志物细胞因子群及其应用。
背景技术
乳腺癌是女性中发病率最高、危害最严重的恶性肿瘤之一，每年的发病人数和死亡人数相当巨大，其中化疗耐受和转移是导致乳腺癌患者治疗失败和死亡的关键因素。因此，阐明乳腺癌化疗耐受及转移的分子机制，筛选鉴定相关标志物，完善信号调控网络，对于设计开发特异性靶向药物，提高乳腺癌治疗效果具有重要的理论价值和应用前景。上皮间质转化(epithelial-mesenchymal transition，EMT)现象可能架起了肿瘤耐药和转移的内在联系。发生EMT后的肿瘤细胞粘附能力降低、易自原发灶脱落，且易穿过血管壁而远处迁移；同时EMT过程使乳腺癌干细胞得以富集，继而增强细胞的药物抗性、凋亡抗性及转移能力。可见，乳腺癌EMT形成机制的阐述将可望阐述乳腺癌耐药、转移机制以及二者内在联系的规律。肿瘤细胞EMT启动与肿瘤微环境的改变相关，肿瘤细胞、肿瘤间质细胞、免疫细胞在肿瘤微环境变化时能自分泌或/和旁分泌一系列细胞因子来启动EMT进程，不幸的是手术、放化疗等均能引起微环境的改变，可见化疗、放疗在杀灭肿瘤细胞的同时也能诱导肿瘤细胞EMT及耐药和转移。但是现有技术中，并未有能完整解释上述生物学现象及其内在联系的乳腺癌标志物的记载。
发明内容
本发明的目的在于提供一种乳腺癌标志物细胞因子群及其应用，所述乳腺癌标志物细胞因子群包括TNFα蛋白、FGF2蛋白、IL-6蛋白和Wnt4蛋白，所述乳腺癌标志物细胞因子群能够高效诱导乳腺癌细胞发生上皮-间质转化，诱导乳腺癌细胞发生转移，诱导乳腺癌细胞发生侵袭，提高成球能力，提高CD44+CD24-细胞含量。
本发明提供了一种乳腺癌标志物细胞因子群，所述乳腺癌标志物细胞因子群包括TNFα蛋白、FGF2蛋白、IL-6蛋白和Wnt4蛋白。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生上皮-间质转化的试剂中的应用。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生转移的试剂中的应用。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生侵袭的试剂中的应用。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备提高成球能力的试剂中的应用。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备提高CD44+CD24-细胞含量的试剂中的应用。
本发明提供了一种乳腺癌标志物细胞因子群及其应用，所述乳腺癌标志物细胞因子群包括TNFα蛋白、FGF2蛋白、IL-6蛋白和Wnt4蛋白，所述乳腺癌标志物细胞因子群能够高效诱导乳腺癌细胞发生上皮-间质转化，诱导乳腺癌细胞发生转移，诱导乳腺癌细胞发生侵袭，提高成球能力，提高 CD44+CD24-细胞含量。
附图说明
图1为EMT表型的耐药细胞培养上清中TNFα、FGF2、IL-6和Wnt4 蛋白水平；
图2为FGF2、IL-6和Wnt4协同诱导乳腺癌细胞发生EMT变结果；
图3为抑制细胞因子群诱导的下游信号逆转耐药细胞的EMT表型的结果；
图4为TNFα、FGF2、IL-6和Wnt4细胞因子群在转移组乳腺癌患者血清中升高及其下游信号在转移组肿瘤组中活化的结果。
具体实施方式
本发明提供了一种乳腺癌标志物细胞因子群，所述乳腺癌标志物细胞因子群包括TNFα蛋白、FGF2蛋白、IL-6蛋白和Wnt4蛋白。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生上皮-间质转化的试剂中的应用。在本发明中，所述乳腺癌标志物细胞因子群能够诱导乳腺癌细胞发生上皮-间质转化。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生转移的试剂中的应用。在本发明中，所述乳腺癌标志物细胞因子群能够诱导乳腺癌细胞发生转移。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生侵袭的试剂中的应用。在本发明中，所述乳腺癌标志物细胞因子群能够诱导乳腺癌细胞发生侵袭。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备提高成球能力的试剂中的应用。在本发明中，所述乳腺癌标志物细胞因子群能够提高成球能力。
本发明还提供了上述技术方案所述的乳腺癌标志物细胞因子群在制备提高CD44+CD24-细胞含量的试剂中的应用。在本发明中，所述乳腺癌标志物细胞因子群能够提高CD44+CD24-细胞含量。
在本发明中，所述乳腺癌细胞优选为Luminal型乳腺癌细胞。
下面结合具体实施例对本发明所述的一种乳腺癌标志物细胞因子群及其应用做进一步详细的介绍，本发明的技术方案包括但不限于以下实施例。
实施例1
一、Luminal型乳腺癌细胞发生上皮-间质转化(EMT)表型的耐药细胞培养上清中TNFα、FGF2、IL-6和Wnt4蛋白水平明显上调
通过药物5-Fu低浓度递增结合大剂量反复诱导方式体外诱导Luminal 型乳腺癌T47D和MCF-7细胞建立稳定耐药细胞模型：T47D/5-Fu和 MCF-7/5-Fu，在显微镜下观察发现相比于亲本细胞T47D和MCF-7，耐药细胞呈现典型的EMT表型(图1A)，首次发现用耐药细胞的培养上清孵育亲本细胞，能诱导亲本细胞获得稳定的EMT表型(图1A)和耐药性(图1B)。为了鉴定参与耐药细胞培养上清诱导亲本细胞发生EMT变和耐药性的机制，通过细胞因子芯片分析耐药细胞T47D/5-Fu和亲本细胞T47D培养上清中的差异表达细胞因子(图1C和D)，经ELISA验证发现耐药细胞培养上清中TNFα、FGF2、IL-6和Wnt4的蛋白水平上调(图1E)。
二、FGF2、IL-6和Wnt4协同诱导乳腺癌细胞发生EMT变
用含不同浓度的TNFα(0、2、5、10ng/ml)和FGF2(0、5、10、15ng/ml) 重组蛋白的培养液分别培养T47D和MCF-7细胞12小时后，抽提细胞总蛋白，经western blot检测发现二者处理均能明显上调细胞p-Akt和p-IκBα蛋白水平，而对p-ERK蛋白水平无影响，提示TNFα和FGF2可共同活化 Akt-NF-κB信号(故在后续中将采用FGF2重组蛋白进行相关机制研究)，用含不同浓度IL-6(0、5、10、20ng/ml)重组蛋白的培养液分别培养T47D和 MCF-7细胞，能活化STAT3信号，即p-STAT3蛋白水平升高；用含不同浓度Wnt4(0、10、20、40ng/ml)重组蛋白的培养液分别培养T47D和MCF-7 细胞，发现能活化Wnt-β-catenin信号，虽然各重组蛋白能活化相应信号通路，但单独处理并不能有效的诱导处理细胞发生EMT变，然而，用FGF2 (10ng/ml)、IL-6(10ng/ml)和Wnt4(20ng/ml)重组蛋白同时处理T47D 和MCF-7细胞1周，三者能协同诱导亲本细胞获得稳定的EMT表型，且撤消FGF2、IL-6和Wnt4重组蛋白后，细胞仍能维持EMT表型(图2A)，Western blot检测发现EMT变细胞中上皮标志物E-cadherin和Claudin4表达下调，间质标志物Vimentin、Twist1、ZEB1和ZEB2表达上调(图2B)；用Transwell 实验检测发现EMT变细胞的侵袭能力增加(图2C)；用成球实验和流式细胞分析发现EMT变细胞的乳腺癌干细胞特性增强即成球能力增加(图2D) 和CD44+CD24-细胞比例增加(图2E)。
三、抑制细胞因子群诱导的下游信号逆转耐药细胞的EMT表型
用BAY11(20uM)抑制耐药细胞中TNFα和FGF2活化的NF-κB信号，用S3I(120uM)抑制IL-6活化的STAT3信号，用sFRP1(50uM)抑制 Wnt4活化Wnt-β-catenin信号，同时抑制上述三条信号通路能协同逆转耐药细胞的EMT表型(图3A和B)、侵袭能力(图3C)及乳腺癌干细胞特性即成球能力增加(图3D)和CD44+CD24-细胞比例增加(图3E)。
四、TNFα、FGF2、IL-6和Wnt4细胞因子群在转移组乳腺癌患者血清中升高，转移组乳腺癌组织中EMT标志物表达上调
收集23例无转移的乳腺癌患者血清和32例有远处转移的乳腺癌患者血清，经ELISA实验检测得出，转移组患者血清中TNFα、FGF2、IL-6和Wnt4 的蛋白水平高于无转移组(图4A)。同时收集上述无转移组和有远处转移组乳腺癌患者的肿瘤组织，用免疫组化方法检测发现转移组乳腺癌组织中 TNFα、FGF2、IL-6和Wnt4下游信号活性高于无转移组乳腺癌组织，即转移组组织中IκBα蛋白水平低于无转移组，而p65、β-catenin及pSTAT3核移位高于无转移线(图4B)；同时转移组乳腺癌组织中上皮标志物即E-cadherin 表达低于无转移组，而EMT标志物即Vimentin、Twist1、ZEB1及ZEB2表达高于无转移组(图4B)。
由以上实施例可以得出，本发明提供的乳腺癌标志物细胞因子群能够高效诱导乳腺癌细胞发生上皮-间质转化，诱导乳腺癌细胞发生转移，诱导乳腺癌细胞发生侵袭，提高成球能力，提高CD44+CD24-细胞含量。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (6)

1.一种乳腺癌标志物细胞因子群，其特征在于，所述乳腺癌标志物细胞因子群包括TNFα蛋白、FGF2蛋白、IL-6蛋白和Wnt4蛋白。
2.权利要求1所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生上皮-间质转化的试剂中的应用。
3.权利要求1所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生转移的试剂中的应用。
4.权利要求1所述的乳腺癌标志物细胞因子群在制备诱导乳腺癌细胞发生侵袭的试剂中的应用。
5.权利要求1所述的乳腺癌标志物细胞因子群在制备提高成球能力的试剂中的应用。
6.权利要求1所述的乳腺癌标志物细胞因子群在制备提高CD44+CD24-细胞含量的试剂中的应用。
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