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中华妇幼临床医学杂志(电子版) ›› 2023, Vol. 19 ›› Issue (05) : 530 -539. doi: 10.3877/cma.j.issn.1673-5250.2023.05.006

论著

子宫内膜异位症患者在位及异位内膜上皮细胞-间充质转化相关生物标志物的变化
罗丹, 孔为民†(), 陈姝宁, 赵小玲, 谢云凯   
  1. 首都医科大学附属北京妇产医院/北京妇幼保健院妇科　100020
  • 收稿日期:2023-02-17 修回日期:2023-09-02 出版日期:2023-10-01
  • 通信作者: 孔为民

Differences in epithelial mesenchymal transition-related biological markers between in-situ and ectopic endometrial epithelial cells in endometriosis patients

Dan Luo, Weimin Kong†(), Shuning Chen, Xiaoling Zhao, Yunkai Xie   

  1. Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100006, China
  • Received:2023-02-17 Revised:2023-09-02 Published:2023-10-01
  • Corresponding author: Weimin Kong
  • Supported by:
    National Natural Science Foundation of China(81871142)
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引用本文：

罗丹, 孔为民, 陈姝宁, 赵小玲, 谢云凯. 子宫内膜异位症患者在位及异位内膜上皮细胞-间充质转化相关生物标志物的变化[J]. 中华妇幼临床医学杂志(电子版), 2023, 19(05): 530-539.

Dan Luo, Weimin Kong, Shuning Chen, Xiaoling Zhao, Yunkai Xie. Differences in epithelial mesenchymal transition-related biological markers between in-situ and ectopic endometrial epithelial cells in endometriosis patients[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2023, 19(05): 530-539.

目的

探讨子宫内膜异位症(EMS)患者在位及异位内膜上皮细胞-间充质转化(EMT)相关生物标志物的表达特点。

方法

在R语言GEOquery包的基因表达总览(GEO)数据库中，下载EMS相关数据集GSE7305。该数据集来源于10例EMS患者的异位子宫内膜与10例正常子宫内膜受试者的子宫内膜组织，采用生物信息学方法分析该数据集中，EMT相关差异基因表达情况。选择2020年10月1日至2022年3月31日首都医科大学附属北京妇产医院收治的采取全子宫切除术(6例)、经腹腔镜患侧卵巢囊肿剔除术＋宫腔镜检查(8例)、经腹腔镜患侧卵巢囊肿剔除术(13例)治疗的27例EMS患者，以及采取全子宫切除术治疗的14例宫颈上皮内瘤变(CIN)3与宫颈癌ⅠA1期患者为研究对象。根据患者术后活组织病理学诊断结果，将其分别纳入EMS异位内膜组(n＝27，所有EMS患者的异位子宫内膜)，EMS在位内膜组(n＝14，采取全子宫切除术、经腹腔镜患侧卵巢囊肿剔除术＋宫腔镜检查治疗的EMS患者的在位子宫内膜)，以及对照组(n＝14，CIN3与宫颈癌ⅠA1期患者的正常子宫内膜)。再根据获取EMS异位内膜组患者子宫内膜时所处月经周期，将其进一步分为EMS异位内膜增生期亚组(n＝14)与EMS异位内膜分泌期亚组(n＝13)。采用免疫组织化学(IHC)方法检测EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织EMT相关生物标志物，如E-钙黏着蛋白(E-cadherin)、N-钙黏着蛋白(N-cadherin)、波形蛋白(vimentin)及snail家族(snail、slug)与碱性螺旋-环-螺旋家族twist转录因子表达情况，这些生物标志物阳性表达率与组织化学评分(H-score)值比较，采用χ2检验、Fisher确切概率法与Kruskal-Wallis H检验，进一步两两比较采用Bonferroni法校正检验水准。本研究遵行的程序符合首都医科大学附属北京妇产医院伦理委员会规定，并获得该伦理委员会批准(审批文号：2019-KY-002-01)，所有患者均签署临床研究知情同意书。EMS异位内膜组、EMS在位内膜组与对照组患者年龄、人体质量指数(BMI)、月经周期等一般临床资料分别比较，差异均无统计学意义(P>0.05)。

结果

①GSE7305数据集中，与正常子宫内膜组织相比，EMS患者异位内膜组织SNAI2基因表达上调，而SNAI1、TWIST2、CDH1基因表达下调。②EMS异位内膜组、EMS在位内膜组与对照组患者E-cadherin阳性表达率分别为0、35.7%(5/14)、42.9%(6/14)，E-cadherin的H-score值分别为0.9分(0.3分，2.5分)，5.7分(1.3分，11.6分)，7.2分(1.0分，24.5分)，vimentin阳性表达率分别为70.4%(19/27)、14.3%(2/14)、21.4%(3/14)，vimentin的H-score值分别为107.9分(86.7分，122.8分)，42.8分(29.4分，75.4分)，51.8分(37.8分，100.2分)，这3组患者E-cadherin、vimentin阳性表达率与H-score值分别总体比较，差异均有统计学意义(E-cadherin：P<0.001，H＝20.14、P<0.001；vimentin：χ2＝15.56、P<0.001，H＝17.31、P＝0.004)。进一步两两比较结果显示，EMS异位内膜组患者E-cadherin阳性表达率、H-score值，均显著低于EMS在位内膜组与对照组患者，而vimentin阳性表达率、H-score值，均显著高于EMS在位内膜组与对照组患者，并且差异均有统计学意义(P<0.05)，而EMS在位内膜组与对照组患者E-cadherin、vimentin阳性表达率与H-score值分别比较，差异均无统计学意义(P>0.05)。这3组患者N-cadherin、slug、snail、twist阳性表达率与H-score值分别比较，差异均无统计学意义(P>0.05)。③EMS异位内膜增生期亚组EMS患者异位内膜组织twist的H-score值，显著高于EMS异位内膜分泌期亚组EMS患者异位内膜组织，并且差异有统计学意义(H＝5.42、P＝0.020)。

结论

EMS患者E-cadherin表达下降，可能促进EMS的发生、发展。vimentin、N-cadherin、slug、snail与twist在EMS发病机制中的作用迄今尚未完全阐明，尚需进一步研究、证实。

关键词: 子宫内膜异位症, 上皮细胞-间充质转化, 生物标志物, 差异基因, 子宫内膜异位症在位与异位子宫内膜, 妇女
Objective

To investigate the expression characteristics of epithelial mesenchymal transition (EMT)-related biological markers in in-situ and ectopic endometrium of endometriosis (EMS) patients.

Methods

The EMS-related dataset GSE7305 was downloaded from the Gene Expression Omnibus (GEO) database via the GEOquery package in R language. The dataset was derived from ectopic endometrial tissues of 10 EMS patients and in-situ endometrial tissues of 10 subjects with normal endometrial tissues. EMT-related differential gene expression in this dataset was analyzed by bioinformatics method. A total of 27 EMS patients who received total hysterectomy (6 cases) or laparoscopic oophorocystectomy of affected side and hysteroscopy (8 cases) or laparoscopic oophorocystectomy of affected side (13 cases) and 14 patients with cervical intraepithelial neoplasia (CIN)3 and cervical carcinoma stage ⅠA1 who underwent total hysterectomy in Beijing Obstetrics and Gynecology Hospital, Capital Medical University from October 1, 2020 to March 31, 2022 were selected as study subjects. The patients were included in EMS ectopic endometrium group (n=27, ectopic endometrium in all EMS patients), EMS in-situ endometrium group (n=14, in-situ endometrium in EMS patients who received total hysterectomy or laparoscopic oophorocystectomy of affected side and hysteroscopy), and control group (n=14, normal endometrium in patients with CIN3 and cervical carcinoma stage ⅠA1), according to the diagnostic results of postoperative biopsy histopathology. The patients in EMS ectopic endometrium group were further divided into EMS ectopic endometrium proliferative subgroup (n=14) and EMS ectopic endometrium secretory subgroup (n=13) according to the menstrual cycle of patients in EMS ectopic endometrium group during which the endometrium was obtained. Immunohistochemistry (IHC) was used to detect the expression of EMT-related markers, such as E-cadherin, N-cadherin, vimentin, snail family (snail, slug) and twist transcription factors in endometrial tissues of patients in EMS ectopic endometrium group, EMS in-situ endometrium group, and control group. Their positive expression rates and histochemistry score (H-score) of these biological markers were compared by chi-square test, Fisher′s exact probability test and Kruskal-Wallis H test. Further pairwise comparisons were conducted by Bonferroni method to adjust the test level. The procedures followed in this study were in accordance with the regulations of the Ethics Committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University and were approved by this Ethics Committee (Approval No. 2019-KY-002-01). All patients signed an informed consent form for the clinical study. There was no statistically significant difference in general clinical data among EMS ectopic endometrium group, EMS in-situ endometrium group, and control group, such as age, body mass index (BMI), and menstrual cycle (P>0.05).

Results

①In GSE7305 dataset, compared with normal endometrial tissues, ectopic endometrial tissues of EMS patients showed up-regulated expression of SNAI2 gene and down-regulated expression of SNAI1, TWIST2, and CDH1 genes. ②The positive expression rates of E-cadherin in EMS ectopic endometrium group, EMS in-situ endometrium group, and control group were 0, 35.7% (5/14), 42.9% (6/14), respectively, and the H-score values of E-cadherin of these three groups were 0.9 points (0.3 points, 2.5 points), 5.7 points (1.3 points, 11.6 points), 7.2 points (1.0 points, 24.5 points), respectively, the positive expression rates of vimentin of these three groups were 70.4% (19/27), 14.3% (2/14), and 21.4% (3/14), respectively, and the H-score values of vimentin of these three groups were 107.9 points (86.7 points, 122.8 points), 42.8 points (29.4 points, 75.4 points), and 51.8 points (37.8 points, 100.2 points), respectively. The overall comparison of E-cadherin, vimentin positive expression rate and H-score values among three groups of patients showed statistical significance (E-cadherin: P<0.001, H=20.14, P<0.001; vimentin: χ2=15.56, P<0.001, H=17.31, P=0.004). Further pairwise comparisons showed that the E-cadherin positive expression rate and H-score value in EMS ectopic endometrium group were significantly lower than those in the EMS in-situ endometrium group and control group, whereas the vimentin positive expression rate and H-score value were significantly higher than those in EMS in-situ endometrium group and control group, and all the differences were statistically significant (P<0.05). There was no statistically significant difference in the positive expression rates and H-score values of E-cadherin and vimentin between EMS in-situ endometrium group and control group (P>0.05). There was no statistically significant difference in the positive expression rates and H-score values of N-cadherin, slug, snail, and twist among three groups (P>0.05). ③The H-score value of twist in ectopic endothelial tissues of EMS patients in EMS ectopic endometrium proliferative subgroup was significantly higher than that of ectopic endothelial tissues of EMS patients in EMS ectopic endometrium secretory subgroup, and the difference was statistically significant (H=5.42, P=0.020).

Conclusions

Decreased expression of E-cadherin in EMS patients may promote the occurrence and development of EMS. The roles of vimentin, N-cadherin, slug, snail and twist in the pathogenesis of EMS have not been fully clarified so far, and still need to be further studied.

Key words: Endometriosis, Epithelial-mesenchymal transition, Biomarker, Differential gene, In-situ and ectopic endometrium in endometriosis, Women
图1 EMS患者中EMT相关差异基因(SNAI1、SNAI2、VIM、CDH1、CDH2、TWIST2基因)表达(图1A：GSE7305数据集差异基因与genecard数据库中EMT相关基因取交集的韦恩图；图1B：GSE7305数据集中6个EMT生物标志物相关基因表达热图；图1C：GSE7305数据集中6个EMT生物标志物相关基因表达箱型图)注：EMS为子宫内膜异位症，EMT为上皮间充质转化
表1 EMS异位内膜组、EMS在位内膜组与对照组受试者一般临床资料比较(±s)
组别 例数 年龄(岁) BMI(kg/m2) 月经周期(d)
EMS异位内膜组 27 37.8±6.4 22.2±2.5 29.4±3.3
EMS在位内膜组 14 41.5±6.3 23.9±3.5 28.7±3.6
对照组 14 35.8±6.1 22.9±3.4 29.2±5.3
F值   3.00 1.47 0.15
P值   0.059 0.240 0.857
图2 EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织EMT生物标志物IHC染色结果(图2A～2C：分别为EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织E-cadherin表达情况；图2D～2F：分别为EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织vimentin表达情况；图2G～2I：分别为EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织N-cadherin表达情况；图2J～2L：分别为EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织twist表达情况；图2M～2O：分别为EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织slug表达情况；图2P～2R：分别为EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织snail表达情况) (IHC-SP法染色，高倍)注：EMS为子宫内膜异位症，EMT为上皮间充质转化，IHC为免疫组织化学，SP为链霉菌抗生物素蛋白-过氧化物酶连结
表2 EMS异位内膜组、EMS在位内膜组与对照组患者子宫内膜组织EMT生物标志物阳性表达率与H-score值比较
组别 例数 阳性表达率[例数(%)]
E-cadherin vimentin N-cadherin twist slug snail
EMS异位内膜组 27 0(0) 19(70.4) 4(14.8) 14(51.9) 6(22.2) 4(14.8)
EMS在位内膜组 14 5(35.7) 2(14.3) 4(28.6) 4(28.6) 5(35.7) 1(7.1)
对照组 14 6(42.9) 3(21.4) 3(21.4) 9(64.3) 7(50.0) 6(42.9)
统计量   — χ2＝15.56 — — — —
P值   <0.001 <0.001 0.562 0.183 0.180 0.062
组别 例数 H-score值[分，M(Q1，Q3)]
E-cadherin vimentin N-cadherin twist slug snail
EMS异位内膜组 27 0.9(0.3，2.5) 107.9(86.7，122.8) 1.3(0.3，3.8) 1.9(0.8，47.5) 0.8(0.2，5.4) 0.6(0.3，1.7)
EMS在位内膜组 14 5.7(1.3，11.6) 42.8(29.4，75.4) 0.3(0.1，6.7) 1.0(0.3，17.4) 0.5(0.2，26.4) 0.2(0.1，0.7)
对照组 14 7.2(1.0，24.5) 51.8(37.8，100.2) 1.2(0.3，4.4) 19.8(0.8，54.3) 6.4(0.7，47.0) 1.4(0.2，35.4)
统计量   H＝20.14 H＝17.31 H＝1.37 H＝3.28 H＝3.48 H＝4.81
P值   <0.001 0.004 0.505 0.194 0.176 0.090
表3 EMS异位内膜增生期亚组与EMS异位内膜分泌期亚组EMS患者正常在位内膜组织中EMT相关生物标志物H-score值比较[分，M(Q1，Q3)]
组别 例数 E-cadherin N-cadherin vimentin twist slug snail
EMS异位内膜增生期亚组 14 6.3(1.0，22.2) 1.4(0.3，4.4) 46.8(25.8，56.1) 29.0(7.2，54.3) 3.0(0.5，37.2) 0.5(0.2，13.5)
EMS异位内膜分泌期亚组 13 5.9(1.3，10.3) 0.2(0.1，6.7) 44.5(28.8，75.5) 22.8(6.6，56.1) 0.8(0.2，34.8) 0.2(0.1，3.2)
H值   0.04 2.43 0.02 0.11 0.87 0.70
P值   0.848 0.119 0.886 0.737 0.350 0.401
表4 EMS异位内膜增生期亚组与EMS异位内膜分泌期亚组EMS患者异位内膜组织中EMT相关生物标志物H-score值比较[分，M(Q1，Q3)]
组别 例数 E-cadherin N-cadherin vimentin twist slug snail
EMS异位内膜增生期亚组 14 1.0(0.3，3.3) 1.4(0.6，5.0) 73.6(43.2，111.1) 6.8(1.2，77.1) 1.3(0.3，28.7) 0.9(0.3，1.8)
EMS异位内膜分泌期亚组 13 0.8(0.3，2.3) 0.9(0.2，2.9) 49.7(33.2，77.5) 0.8(0.4，7.5) 0.5(0.2，2.3) 0.5(0.2，3.1)
H值   0.08 1.85 1.73 5.42 1.85 0.53
P值   0.771 0.174 0.133 0.020 0.174 0.467
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