CN112899363B - FoxM1在诊断和治疗宫腔粘连疾病中的应用 - Google Patents

FoxM1在诊断和治疗宫腔粘连疾病中的应用 Download PDF

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CN112899363B
CN112899363B CN202110341445.6A CN202110341445A CN112899363B CN 112899363 B CN112899363 B CN 112899363B CN 202110341445 A CN202110341445 A CN 202110341445A CN 112899363 B CN112899363 B CN 112899363B
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adhesion
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胡娅莉
赵光锋
周振华
李若天
戴建武
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Institute of Genetics and Developmental Biology of CAS
Nanjing Drum Tower Hospital
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Nanjing Drum Tower Hospital
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Abstract

本发明公开了FoxM1在制备诊断和治疗宫腔粘连疾病的试剂中的应用。FoxM1作为检测靶点在制备宫腔粘连诊断试剂中的应用。FoxM1在制备治疗子宫纤维化引起的疾病的药物中的应用。本发明通过实验发现宫腔粘连患者子宫内膜组织中FoxM1表达显著减少，尤其以上皮细胞减少最为显著，且FoxM1的表达水平与宫腔粘连患者子宫内膜厚度有一定正相关性。做ROC图表明，FoxM1对宫腔粘连具有较好的诊断价值。体外结果显示，在TGFβ1诱导的上皮细胞纤维化中，FoxM1的表达水平也显著下降。因此，FoxM1在宫腔粘连检测和治疗方面可能发挥重要作用，可用于宫腔粘连的临床诊断及治疗。

Description

FoxM1在诊断和治疗宫腔粘连疾病中的应用
技术领域
本发明属于生物医药技术领域，具体涉及一种Forkhead家族转录因子FoxM1在诊断和治疗宫腔粘连中的应用。
背景技术
宫腔粘连(intrauterine adhesion,IUA)是多种因素引起的子宫内膜基底层受损，内膜功能性修复障碍，进而子宫内壁粘连造成宫腔部分或完全闭塞。临床表现为月经异常(月经量减少或闭经)、不孕或反复流产，是子宫性不孕最常见的原因之一。IUA的发病机制不明确，流产和感染及医源性损伤是常见的诱因。近年来，随着宫腔镜操作及无痛人流术的增加，在我国IUA的发生率呈上升趋势。在组织学上，IUA患者内膜表现为厚度减少，功能层缺乏，基底层结构发生变化，内膜组织中腺体稀疏，腔上皮失去完整性，上皮细胞体积变小，胞浆减少，间质细胞被纤维组织替代，分泌大量的细胞外基质。此外，IUA子宫内膜组织中细胞增殖分化能力减弱，血管生成障碍，表明IUA是子宫内膜功能细胞再生障碍的纤维化疾病。目前主要治疗方法仍是宫腔镜下粘连分离辅以性激素建立人工周期疗法，其对轻中度的IUA可有一定疗效，但对重度IUA患者术后复发率达50％以上，造成妊娠率及活产率的显著下降，因此迫切的需要寻找一种新的针对重度IUA的检测及治疗方法。
叉头盒M1转录因子(Forkhead Box M1,FoxM1)调控细胞许多重要的生理功能，包括DNA损伤修复、调控细胞有丝分裂和细胞增殖，是负责启动细胞增殖的必需基因。有文献报道，在肺、肾、肝脏等多种器官纤维化中，FoxM1表达显著上调，并且与疾病的严重程度相关，而抑制FoxM1表达可有效治疗纤维化。那么，FoxM1与宫腔粘连是否存在关联，是否影响子宫内膜纤维化，迄今未见报道。我们的研究发现，通过对重度IUA患者子宫内膜组织中FoxM1表达水平检测，能够为其诊断、治疗、严重程度评估提供可靠的依据。
发明内容
本发明的目的是提供一种FoxM1在诊断宫腔粘连中的应用。
本发明的另一目的是提供FoxM1及其类似物在治疗宫腔粘连中的应用。
本发明的目的通过以下技术方案实现：
FoxM1在诊断宫腔粘连中的应用，所述的检测FoxM1表达水平的试剂为FoxM1基因的特异性引物序列(如PCR引物或qPCR引物)或者检测FoxM1蛋白的抗体。
FoxM1在制备治疗宫腔粘连及因子宫纤维化引起的疾病的药物中的应用。
本发明中所述的宫腔粘连是指由于子宫内膜基底层损伤，功能层再生修复障碍，形成以内膜纤维化为特征的子宫壁间粘连。
本发明中所述的子宫内膜纤维化引起的疾病指宫腔粘连或子宫内膜疤痕化以及由此导致的子宫性不孕、反复流产及胎盘植入等。
本发明的有益效果为：
本发明通过实验发现，在重度宫腔粘连患者子宫内膜中，FoxM1表达显著下降，尤其以上皮细胞减少最为显著，体外结果也证实，FoxM1在TGFβ1诱导的上皮细胞纤维化中显著下降，并且FoxM1的表达水平与子宫内膜的厚度存在一定的正相关性。ROC图表明，FoxM1对宫腔粘连具有诊断价值。此外，在上皮细胞中干扰FoxM1表达后，上皮细胞发生上皮-间质转化和纤维化。因此，FoxM1在宫腔粘连的诊断及治疗方面可能发挥重要作用，为宫腔粘连的诊断、治疗和病情评估提供一个可靠的依据。
附图说明
图1、A：qPCR检测子宫内膜组织中FoxM1的mRNA水平；B：免疫组化分析子宫内膜组织中FoxM1的表达量；
图2、A：qPCR检测TGFβ1诱导子宫内膜上皮细胞纤维后FoxM1的mRNA水平；B：WB检测TGFβ1诱导子宫内膜上皮细胞纤维后FoxM1的蛋白水平
图3、A：重度IUA患者子宫内膜组织中FoxM1的表达水平与增殖晚期内膜厚度的相关性分析；B：子宫内膜组织中FoxM1表达水平的ROC曲线。
图4、A：子宫内膜上皮细胞转染FoxM1小干扰片段48h后上皮-间质转化和纤维化相关指标表达变化。
具体实施方式
实施例1 FoxM1在正常及重度宫腔粘连患者子宫内膜组织中的表达
1、材料，试剂，设备
1.1人子宫内膜组织来源
收集24例正常子宫内膜组织以及24例重度宫腔粘连患者子宫内膜组织，获取子宫内膜组织时，根据激素水平确保内膜组织获取阶段全部统一为增殖晚期阶段。所有参与者签署知情同意书，并经过南京鼓楼医院伦理委员会批准。
1.2主要试剂
TRNzol(天根)、氯仿、异丙醇、无水乙醇、DEPC水、无酶水、反转录试剂(雅酶)、SYBRGreen(雅酶)、二甲苯、95％、80％及75％乙醇、3％双氧水、柠檬酸修复液、FoxM1抗体(abcam)、DAB显色液、苏木素、氨水、中性树脂。
FoxM1引物序列：Forward primer 5’-3’：ATACGTGGATTGAGGACCACT(SEQ IDNO.1)；
Reverse primer 5’-3’：TCCAATGTCAAGTAGCGGTTG(SEQ ID NO.2)
1.3主要仪器
Nano Drop、金属浴、qPCR仪(Roche)、PCR仪(ABI)、烘箱、显微镜(Leica)。
1.4主要方法
1.4.1组织RNA提取及实时荧光定量PCR
采用TRNzol法提取总RNA。内膜组织中加入1ml TRNzol溶液，充分匀浆，加入200μL氯仿，充分振荡，静置10min；在4℃12000rpm离心15min，吸取上清，加入等体积异丙醇，充分混匀，静置15min，4℃12000rpm离心15min；弃去上清，加入1ml 75％乙醇，充分振荡，4℃7500g离心5min，弃去上清，重复乙醇清洗一次，室温干燥20min，加入20μL无酶水56℃金属浴溶解，测浓度及纯度。取1ug RNA反转录后得到cDNA，用适量体积的RNase-free水稀释后，SYBR Green方法进行荧光定量PCR检测，目标基因的表达量，采用18S作为内参，相对表达水平用2-ΔCT值表示。
1.4.2子宫内膜组织免疫组化
1.石蜡切片80℃烘箱60min，二甲苯处理3次，每次5min，100％乙醇5min，95％乙醇5min，80％乙醇5min，75％乙醇5min，流水冲洗适当时间，3％H2O215min(去除内源性过氧化物酶)，流水冲洗适当时间；柠檬酸热修复，一抗37℃孵育2h，PBST冲洗3遍，每次5min，二抗孵育8min，PBST冲洗3遍，每次5min。显微镜下DAB显色，苏木素染核，氨水返蓝，中性树脂封片后显微镜观察并拍照。
2、实验结果
重度宫腔粘连患者子宫内膜组织中，FoxM1的mRNA和蛋白表达显著下降，并且以上皮细胞中的表达下降最为显著(图1)。
实施例2 TGFβ1诱导子宫内膜上皮细胞纤维化中FoxM1表达变化
1、材料，试剂，设备
1.1主要试剂
I型胶原酶(Sigma)、透明质酸酶(Sigma)、DNAase(Roche)、PBS、上皮细胞培养基(Gibco)、FBS血清(Gibco)、抗生素、TGFβ1(PeproTech)、FoxM1抗体(abcam)、电泳液、转膜液、脱脂牛奶(bio-rad)、TBST
1.2主要仪器
滤网、离心机、细胞培养箱、摇床、PVDF硝酸纤维素膜、双垂直电泳槽、凝胶成像分析系统
1.3主要方法
1.3.1人原代子宫内膜上皮细胞分离培养
新鲜内膜组织用含抗生素的PBS清洗至无肉眼可见血块，于60mm培养皿中剪碎组织至无肉眼可见块状，加入配置好的组织消化液，充分吹打混匀，37℃培养箱消化3min；镜下观察组织消化情况；充分吹打消化后的组织，加DMEM/F12完培终止消化，将组织悬液滴加到40μm孔径的滤网中滤出间质细胞。筛子里剩余的组织加入DMEM/F12培基，吹打混匀后将悬液滴加到100μm孔径的滤网中，获得上皮细胞，根据组织多少，重复消化3-5遍，将上皮细胞铺在Matrigel包被的24孔板中，24h后细胞换液，细胞长至合适密度时予以TGFβ1(10ng/ml)处理48h后提取蛋白。
1.3.2 WB
弃去培基，用预冷的PBS清洗洗3-4遍，加适量细胞裂解液(含蛋白酶抑制剂)，冰上裂解30min，刮下细胞4℃12000rpm离心15min取上清，BCA法测蛋白浓度，加loadingbuffer，99℃金属水浴锅加热10-15min。30μg上样量，转膜后5％牛奶封闭1h；一抗4℃孵育过夜，TBST洗5min，洗3遍，二抗室温孵育1h，TBST洗5min，洗3遍；曝光。
2、结果
TGFβ1处理48h后，FoxM1的表达显著下降(图2)。
实施例3FoxM1对宫腔粘连的诊断价值
1、统计学处理
用Graphpad prism软件进行统计学分析，符合正态分布的数据，线性相关采用pearson相关分析，P<0.05认为差异有统计学意义。
2、结果
重度IUA患者内膜组织中FoxM1的表达水平与子宫内膜厚度存在相关性，r＝0.5756,P＝0.0079；FoxM1诊断宫腔粘连的ROC曲线图可以看出FoxM1对宫腔粘连诊断具有诊断价值：AUC为0.8351，面积标准误为0.06288，面积的95％CI为0.7130-0.9572(图3)。
实施例4上皮细胞低表达FoxM1后上皮-间质转化和纤维化相关指标变化
1、材料，试剂，设备
1.1主要试剂
I型胶原酶(Sigma)、透明质酸酶(Sigma)、DNAase(Roche)、PBS、上皮细胞培养基(Gibco)、FBS血清(Gibco)、抗生素、FoxM1抗体(abcam)、电泳液、转膜液、脱脂牛奶(bio-rad)、TBST、opti-MEM(Gibco)、Lipofectamine 3000(Invitrogen)、FoxM1小干扰片段：5’-CUCUUCUCCCUCAGAUAUATT-3’
1.2主要仪器
同实施例2。
1.3主要方法
同实施例2。
2、结果
上皮细胞转染FoxM1小干扰片段48h后，FoxM1、上皮标志E-cad显著下降，间质标志N-cad以及肌成纤维细胞标志α-SMA表达显著增加，表明低表达FoxM1后，上皮细胞发生上皮-间质转化和纤维化(图4)。
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<110> 南京鼓楼医院
中国科学院遗传与发育生物学研究所
<120> FoxM1 在诊断和治疗宫腔粘连疾病中的应用
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<170> SIPOSequenceListing 1.0
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<212> DNA
<213> 人工序列(Artificial Sequence)
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atacgtggat tgaggaccac t 21
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<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
tccaatgtca agtagcggtt g 21

Claims (2)

1.检测FoxM1的表达量的试剂在制备重度宫腔粘连诊断试剂中的应用。
2.根据权利要求1所述的应用，其特征在于所述的检测FoxM1的表达量的试剂为FoxM1基因的特异性核苷酸序列或者FoxM1蛋白抗体。
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