Changes of peripheral blood miR-145 level and its effect on PAI-1 in patients with repeated implantation failure
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摘要:
目的 探讨反复种植失败患者取卵前、胚胎移植前血清miR-145水平变化及对纤溶酶原激活物抑制因子-1(PAI-1)的影响。 方法 选取2021年1月—2022年6月湖南省郴州市第一人民医院生殖医学中心胚胎反复种植失败(RIF)患者71例为观察组，妊娠成功者551例为对照组。分析miR-145与PAI-1相关性、miR-145与RIF的独立关系，miR-145对RIF的评估价值。 结果 取卵前、胚胎移植前观察组血清miR-145[(1.09±0.13)ng/mL vs.(0.98±0.14)ng/mL，F=8.419，P=0.004；(1.19±0.16)ng/mL vs.(1.01±0.18)ng/mL，F=58.184，P＜0.001]、PAI-1[(21.36±6.28)ng/mL vs.(15.09±7.16)ng/mL，F=6.463，P=0.017；(25.36±6.18)ng/mL vs.(17.32±6.99)ng/mL，F=78.536，P＜0.001]水平高于对照组；观察组取卵前、胚胎移植前miR-145与PAI-1均呈正相关关系(r=0.725，P＜0.001；r=0.671，P＜0.001)；取卵前、胚胎移植前miR-145均与RIF独立相关(P＜0.05)；取卵前、胚胎移植前miR-145评估RIF的AUC值分别为0.690、0.774。 结论 RIF不孕症患者miR-145呈异常高表达，其可能通过靶向调节PAI-1表达降低子宫内膜容受性，参与RIF的发生过程。 -
关键词:
- 反复种植失败 /
- miR-145 /
- 纤溶酶原激活物抑制因子-1 /
- 体外受精-胚胎移植
Abstract:Objective To investigate the changes of serum miR-145 levels and their impact on plasminogen activator inhibitor 1 (PAI-1) in patients with repeated implantation failure before egg retrieval and embryo transfer. Methods A total of 71 cases of repeated implantation failure (RIF) in the Reproductive Medicine Center of the First People's Hospital of chenzhou were included in the observation group, and 551 cases of successful pregnancy were included in the control group. The correlation between miR-145 and PAI-1, the independent relationship between miR-145 and RIF, and the evaluation value of miR-145 on RIF were analyzed. Results The levels of miR-145 [(1.09±0.13)ng/mL vs. (0.98±0.14) ng/mL, F=8.419, P=0.004; (1.19±0.16) ng/mL vs. (1.01±0.18) ng/mL, F=58.184, P<0.001] and PAI-1 [(21.36±6.28) ng/mL vs. (15.09±7.16) ng/mL, F=6.463, P=0.017; (25.36±6.18) ng/mL vs.(17.32±6.99) ng/mL, F=78.536, P<0.001] in the observation group were higher than those in the control group before egg retrieval and embryo transfer. There was a positive correlation between miR-145 and PAI-1 in the observation group before egg retrieval and embryo transfer (r=0.725, P<0.001; r=0.671, P<0.001). miR-145 was independently correlated with RIF before egg retrieval and embryo transfer (P<0.05). The AUC values of RIF evaluated by miR-145 before egg retrieval and embryo transfer were 0.690 and 0.774, respectively. Conclusion Patients with RIF infertility have abnormally high expression of miR-145, and it may reduce endometrial receptivity by targeting PAI-1 expression, thus participating in the process of RIF. -
图 1 取卵前和胚胎移植前miR-145水平评估RIF的ROC曲线
Figure 1. ROC curves of RIF evaluated by miR 145 levels before egg retrieval and embryo transfer
表 1 2组不孕症患者临床资料比较
Table 1. Comparison of clinical data of two groups of infertility patients
项目 观察组(71例) 对照组(551例) 统计量 P值 年龄(x±s，岁) 32.06±3.18 30.14±2.92 5.161a < 0.001 配偶年龄(x±s，岁) 35.26±6.72 34.19±7.03 1.213a 0.226 不孕年限(x±s，年) 4.31±1.05 3.70±1.13 4.315a < 0.001 体重指数[例(%)] <18.5 17(23.94) 63(11.43) 8.783b 0.003 18.5~<25.0 34(47.89) 303(54.99) 1.278b 0.258 25.0~<30.0 20(28.17) 185(33.58) 0.832b 0.362 吸烟史[例(%)] 6(8.45) 46(8.35) 0.001b 0.977 饮酒史[例(%)] 9(12.68) 59(10.71) 0.250b 0.617 不孕类型[例(%)] 10.242b 0.001 原发性 21(29.58) 274(49.73) 继发性 50(70.42) 277(50.27) 人工流产次数[例(%)] 2.707c 0.007 0次 50(70.42) 459(83.30) 1次 15(21.13) 72(13.07) 2次 6(8.45) 20(3.63) 宫腔镜检查异常[例(%)] 20(28.17) 387(70.24) 49.210b < 0.001 女方染色体核型异常[例(%)] 3(4.23) 15(2.72) 0.112b 0.738 男方染色体核型异常[例(%)] 7(9.86) 51(9.26) 0.027b 0.869 SAS评分(x±s，分) 68.98±6.73 64.86±7.02 4.676a < 0.001 SDS评分(x±s，分) 63.25±5.44 60.05±5.18 4.871a < 0.001 AMH(x±s，ng/mL) 4.02±1.89 5.12±2.01 4.369a < 0.001 FSH(x±s，IU/L) 6.91±1.04 6.40±1.11 3.669a < 0.001 LH(x±s，IU/L) 5.59±2.13 5.71±2.30 0.417a 0.677 雌二醇(x±s，pg/mL) 43.26±18.28 45.61±20.01 0.940a 0.348 孕酮(x±s，ng/mL) 0.42±0.16 0.39±0.15 1.574a 0.116 睾酮(x±s，ng/mL) 0.34±0.13 0.37±0.15 1.609a 0.108 PRL(x±s，ng/mL) 19.67±6.32 18.56±7.04 1.264a 0.207 移植日内膜厚度(x±s，mm) 10.01±2.02 10.79±2.11 2.946a 0.003 移植日宫腔深度(x±s，cm) 8.09±0.57 7.99±0.61 1.310a 0.191 注：a为t值，b为χ2值, c为Z值。 
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表 2 2组不孕症患者取卵前、胚胎移植前血清miR-145、PAI-1水平比较(x±s)
Table 2. Comparison of serum miR-145 and PAI-1 levels between two groups of infertility patients before egg retrieval and embryo transfer (x±s)
组别 例数 miR-145 PAI-1(ng/mL) 取卵前 胚胎移植前 取卵前 胚胎移植前 观察组 71 1.09±0.13 1.19±0.16 21.36±6.28 25.36±6.18 对照组 551 0.98±0.14 1.01±0.18 15.09±7.16 17.32±6.99 F值 8.419 58.184 6.463 78.536 P值 0.004 < 0.001 0.017 < 0.001
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表 3 Logistic回归模型分析miR-145与RIF发生的独立关系
Table 3. Logistic regression model analysis of the independent relationship between miR-145 and RIF
因素 B SE Wald χ2 P值 OR值 95% CI 模型1 取卵前 Q2 0.750 0.319 5.535 0.041 2.118 1.352~3.318 Q3 0.790 0.334 5.594 0.037 2.203 1.427~3.402 Q4 0.880 0.327 7.241 0.025 2.411 1.609~3.612 胚胎移植前 Q2 0.780 0.324 5.793 0.039 2.181 1.393~3.415 Q3 0.870 0.335 6.741 0.030 2.386 1.505~3.784 Q4 0.969 0.332 8.512 0.013 2.634 1.693~4.099 模型2 取卵前 Q2 0.805 0.329 5.984 0.035 2.236 1.428~3.502 Q3 0.897 0.318 7.960 0.021 2.453 1.521~3.955 Q4 1.053 0.336 9.822 0.002 2.866 1.973~4.164 胚胎移植前 Q2 0.917 0.322 8.106 0.018 2.501 1.699~3.682 Q3 1.011 0.338 8.938 0.010 2.747 1.872~4.031 Q4 1.083 0.321 11.388 < 0.001 2.954 2.043~4.272 模型3 取卵前 Q2 0.988 0.319 9.595 0.006 2.686 1.882~3.834 Q3 1.062 0.320 11.016 < 0.001 2.892 2.038~4.105 Q4 1.153 0.324 12.662 < 0.001 3.167 2.220~4.519 胚胎移植前 Q2 1.014 0.327 9.625 0.004 2.758 1.915~3.972 Q3 1.135 0.341 11.069 < 0.001 3.110 2.139~4.521 Q4 1.224 0.332 13.588 < 0.001 3.400 2.407~4.803 注：模型1无调整混杂因素；模型2调整年龄、不孕年限、体重指数、不孕类型、宫腔镜检查异常、SAS评分、SDS评分；模型3调整年龄、不孕年限、体重指数、不孕类型、宫腔镜检查异常、SAS评分、SDS评分、FSH、AMH、移植日内膜厚度。均以Q1为参照。
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表 4 取卵前和胚胎移植前miR-145水平对RIF的评估价值
Table 4. Assessment value of miR-145 levels on RIF before egg retrieval and embryo transfer
指标 AUC 95% CI Z值 P值 Cut-off值 Youden指数 灵敏度(%) 特异度(%) 取卵前miR-145 0.690 0.652~0.727 5.843 < 0.001 >1.02 0.319 71.83 60.07 胚胎移植前miR-145 0.774 0.739~0.806 9.776 < 0.001 >1.06 0.428 78.87 63.88
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[1] SAXTORPH M H, HALLAGER T, PERSSON G, et al. Assessing endometrial receptivity after recurrent implantation failure: a prospective controlled cohort study[J]. Reprod Biomed Online, 2020, 41(6): 998-1006. doi: 10.1016/j.rbmo.2020.08.015 [2] SHAULOV T, SIERRA S, SYLVESTRE C. Recurrent implantation failure in IVF: a canadian fertility and andrology society clinical practice guideline[J]. Reprod Biomed Online, 2020, 41(5): 819-833. doi: 10.1016/j.rbmo.2020.08.007 [3] FODINA V, DUDOROVA A, ERENPREISS J. Evaluation of embryo aneuploidy (PGT-A) and endometrial receptivity (ERA) testing in patients with recurrent implantation failure in ICSI cycles[J]. Gynecol Endocrinol, 2021, 37(sup1): 17-20. doi: 10.1080/09513590.2021.2006466 [4] DIENER C, KELLER A, MEESE E. Emerging concepts of miRNA therapeutics: from cells to clinic[J]. Trends Genet, 2022, 38(6): 613-626. doi: 10.1016/j.tig.2022.02.006 [5] 陶中娥, 张晔. 子宫内膜异位症合并不孕患者血清miR-145表达及与临床病理类型及妊娠结局关系[J]. 中国计划生育学杂志, 2021, 29(6): 1266-1269. https://www.cnki.com.cn/Article/CJFDTOTAL-JHSY202106045.htmTAO Z E, ZHANG Y. Expression of serum miR-145 level of infertility women with endometriosis, and its association with clinicopathological type and pregnancy outcomes[J]. Chinese Journal of Family Planning, 2021, 29(6): 1266-1269. https://www.cnki.com.cn/Article/CJFDTOTAL-JHSY202106045.htm [6] LIU X M, ZHAO H S, LI W S, et al. Up-regulation of miR-145 may contribute to repeated implantation failure after IVF-embryo transfer by targeting PAI-1[J]. Reprod Biomed Online, 2020, 40(5): 627-636. doi: 10.1016/j.rbmo.2020.01.018 [7] 刘美霞, 刘群会, 朱祖欣, 等. 急性脑梗死患者血清lncRNA SNHG14和miR-145-5p水平变化及其与疾病发生风险的关系[J]. 卒中与神经疾病, 2020, 27(1): 47-51, 55. doi: 10.3969/j.issn.1007-0478.2020.01.010LIU M X, LIU Q H, ZHU Z X, et al. Serum levels of LncRNA SNHG14 and MiR-145-5p in patients with acute cerebral infarction and their relationships with risk of disease[J]. Stroke and Nervous Diseases, 2020, 27(1): 47-51, 55. doi: 10.3969/j.issn.1007-0478.2020.01.010 [8] 陈曼, 夏汝斌, 林虹, 等. 反复种植失败的子宫内膜异位症患者冻融胚胎移植结局的影响因素[J]. 实用医学杂志, 2022, 38(9): 1070-1075. doi: 10.3969/j.issn.1006-5725.2022.09.006CHEN M, XIA R B, LIN H, et al. An analysis on factors influencing the outcome of frozen-thawed embryo transfer in endometriosis patients with repeated implantation failure[J]. The Journal of Practical Medicine, 2022, 38(9): 1070-1075. doi: 10.3969/j.issn.1006-5725.2022.09.006 [9] 李杨, 刘芦屏, 展照双. 立体思维在体外受精-胚胎移植反复失败辨治中的应用[J]. 世界中医药, 2022, 17(21): 3112-3115. doi: 10.3969/j.issn.1673-7202.2022.21.023LI Y, LIU L P, ZHAN Z S. Application of Systematic Thinking in the Treatment of Repeated Failure in In-vitro Fertilization-embryo Transfer[J]. World Chinese Medicine, 2022, 17(21): 3112-3115. doi: 10.3969/j.issn.1673-7202.2022.21.023 [10] SHEIKHANSARI G, POURMOGHADAM Z, DANAⅡ S, et al. Etiology and management of recurrent implantation failure: a focus on intra-uterine PBMC-therapy for RIF[J]. J Reprod Immunol, 2020, 139(1): 103121. DOI: 10.1016/j.jri.2020.103121. [11] BEN RAFAEL Z. Repeated implantation failure (RIF): an iatrogenic meaningless definition that generates unnecessary and costly use of add-on procedures[J]. Hum Reprod, 2020, 35(7): 1479-1483. doi: 10.1093/humrep/deaa134 [12] 范洋阳, 袁宁霞, 朱丽红, 等. 血清血管细胞黏附分子-1、纤溶酶原激活物抑制物-1、血管生成素样蛋白8与妊娠期糖尿病患者妊娠结局的关系研究[J]. 现代生物医学进展, 2022, 22(9): 1724-1728. https://www.cnki.com.cn/Article/CJFDTOTAL-SWCX202209025.htmFAN Y Y, YUAN N X, ZHU L H, et al. Relationship study between serum vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, angiopoietin like protein 8 and pregnancy outcome in patients with gestational diabetes mellitus[J]. Progress in Modern Biomedicine, 2022, 22(9): 1724-1728. https://www.cnki.com.cn/Article/CJFDTOTAL-SWCX202209025.htm [13] 叶鸣, 方佳, 赵磊, 等. 皖南地区MTHFR和PAI-1基因多态性分布及与不良妊娠相关性研究[J]. 中国药业, 2022, 31(9): 65-68. https://www.cnki.com.cn/Article/CJFDTOTAL-YYGZ202209015.htmYE M, FANG J, ZHAO L, et al. Distribution of MTHFR and PAI-1 gene polymorphisms and their correlation with adverse pregnancy in Southern Anhui[J]. China Pharmaceuticals, 2022, 31(9): 65-68. https://www.cnki.com.cn/Article/CJFDTOTAL-YYGZ202209015.htm [14] KIM J O, AHN E H, SAKONG J H, et al. Correction to: association of miR-27aA>G, miR-423C>a, miR-449bA>G, and miR-604A>G polymorphisms with risk of recurrent implantation failure[J]. Reprod Sci, 2020, 27(4): 1086. doi: 10.1007/s43032-020-00179-6 [15] VON GROTHUSEN C, FRISENDAHL C, MODHUKUR V, et al. Uterine fluid microRNAs are dysregulated in women with recurrent implantation failure[J]. Hum Reprod, 2022, 37(4): 734-746. doi: 10.1093/humrep/deac019 [16] 王晨晔, 丁彩飞, 张伟, 等. 毓麟珠方加减对反复移植失败患者非移植周期子宫内膜容受性的影响[J]. 浙江中西医结合杂志, 2020, 30(9): 716-720, 781. doi: 10.3969/j.issn.1005-4561.2020.09.006WANG C Y, DING C F, ZHANG W, et al. Effect of Modified Yulinzhu Prescription on Endometrial Receptivity in Patients with Repeated Transplantation Failure in Non-transplantation Cycle[J]. Zhejiang Journal of Integrated Traditional Chinese and Western Medicine, 2020, 30(9): 716-720, 781. doi: 10.3969/j.issn.1005-4561.2020.09.006 [17] 高爽, 徐鹏, 王蓓蒂, 等. microRNA-145在子宫内膜异位症中的研究进展[J]. 中华全科医学, 2021, 19(11): 1921-1924. doi: 10.16766/j.cnki.issn.1674-4152.002201GAO S, XU P, WANG B D, et al. Research progress of microRNA-145 in endometriosis[J]. Chinese Journal of General Practice, 2021, 19(11): 1921-1924. doi: 10.16766/j.cnki.issn.1674-4152.002201 [18] 陈双华, 李荣, 周玉生. miR-145通过靶向ABCE1发挥抗乳腺癌作用[J]. 中南药学, 2022, 20(5): 1017-1022. https://www.cnki.com.cn/Article/CJFDTOTAL-ZNYX202205009.htmCHEN S H, LI R, ZHOU Y S. miR-145 exerts anti-breast cancer effects by targeting ABCE1[J]. Central South Pharmacy, 2022, 20(5): 1017-1022. https://www.cnki.com.cn/Article/CJFDTOTAL-ZNYX202205009.htm [19] 杨斌, 汪嫣嫣, 甘家兵. miR-145介导TGF-β/Smad信号通路对乳腺癌患者治疗及预后的影响[J]. 实用癌症杂志, 2020, 35(12): 1950-1954. doi: 10.3969/j.issn.1001-5930.2020.12.009YANG B, WANG Y Y, GAN J B. Effect of Mir-145-mediated TGF-β/Smad signaling pathway on the treatment and prognosis of breast cancer patients[J]. Journal of Applied Cancer, 2020, 35(12): 1950-1954. doi: 10.3969/j.issn.1001-5930.2020.12.009 [20] 余兰, 藏汉青, 伟乃莲. miR-145、ABCD2评分联合动脉超声对TIA患者进展为脑梗死的风险评估价值分析[J]. 河北医科大学学报, 2021, 42(10): 1139-1143. https://www.cnki.com.cn/Article/CJFDTOTAL-HBYX202110006.htmYU L, ZANG H Q, WEI N L. Analysis of the risk assessment value of miR-145, ABCD2 score combined with arterial ultrasound for the progression of cerebral infarction after TIA attack[J]. Journal of Hebei Medical University, 2021, 42(10): 1139-1143. https://www.cnki.com.cn/Article/CJFDTOTAL-HBYX202110006.htm [21] SIROHI V K, GUPTA K, KAPOOR R, et al. MicroRNA-145 targets Smad1 in endometrial stromal cells and regulates decidualization in rat[J]. J Mol Med (Berl), 2019, 97(4): 509-522. [22] SHEKIBI M, HENG S, WANG Y, et al. Progesterone suppresses podocalyxin partly by up-regulating miR-145 and miR-199 in human endometrial epithelial cells to enhance receptivity in in vitro models[J]. Mol Hum Reprod, 2022, 28(11): gaac034. DOI: 10.1093/molehr/gaac034. [23] TENG F, ZHANG J X, CHEN Y, et al. LncRNA NKX2-1-AS1 promotes tumor progression and angiogenesis via upregulation of SERPINE1 expression and activation of the VEGFR-2 signaling pathway in gastric cancer[J]. Mol Oncol, 2021, 15(4): 1234-1255. [24] CHEN Y, YANG C W, LI Y J, et al. MiR145-5p inhibits proliferation of PMVECs via PAI-1 in experimental hepatopulmonary syndrome rat pulmonary microvascular hyperplasia[J]. Biol Open, 2019, 8(11): bio044800. DOI: 10.1242/bio.044800. [25] 郭玲, 杨芳, 郭安良, 等. 体外受精-胚胎移植后反复种植失败的相关因素分析[J]. 现代妇产科进展, 2022, 31(6): 435-439, 442. https://www.cnki.com.cn/Article/CJFDTOTAL-XDFC202206007.htmGUO L, YANG F, GUO A L, et al. Analysis of factors related to repeated implantation failure after in vitro fertilization-embryo transfer[J]. Progress in Obstetrics and Gynecology, 2022, 31(6): 435-439, 442. https://www.cnki.com.cn/Article/CJFDTOTAL-XDFC202206007.htm -
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