Ma Hai-Lan, Gong Fei, Tang Yi, Li Xihong, Li Xiaofeng, Yang Xiaoyi, Lu Guangxiu
Institute of Reproductive & Stem Cell Engineering, Central South University, Changsha, Hunan, P.R. China.
Institute of Reproductive & Stem Cell Engineering, Central South University, Changsha, Hunan, P.R. China Reproductive & Genetic Hospital of Citic-Xiangya, Changsha, Hunan, P.R. China.
Biol Reprod. 2015 Jun;92(6):152. doi: 10.1095/biolreprod.115.128603. Epub 2015 Apr 29.
This study assessed first the impact of endometrial Tiam1/Rac1 signals and microRNA-22 (miR-22) on embryo implantation in mice, and then the expression of the above three genes in the endometrium during the embryo implantation window in the natural menstrual cycle in women with repeated implantation failure (RIF) after in vitro fertilization treatment. Four hundred fifty-two Kun-ming female mice and 200 women (70 infertility patients with RIF, 130 women as controls) were entered into this study. Endometrial Tiam1/Rac1 signals and miR-22 expression were studied in clinical and mouse samples and serum estrogen (E2) and progesterone (P) were analyzed in clinical subjects. A pregnant mouse model based on an endometrial miR-22 and Tiam1 mRNA expression trend of patients with RIF was constructed and then the embryo implantation numbers were analyzed, and an ovariectomized mouse model was used to assess correlations of expression of these three genes with E2 and P. The results showed that during the embryo implantation window in the natural menstrual cycle, endometrial miR-22 was significantly higher whereas Tiam1/Rac1 signals were notably lower in patients with RIF than in controls, and the P:E2 ratio was statistically lower in the RIF group. Tiam1/Rac1 signal down-regulation and miR-22 up-regulation contributed to the inhibition of embryo implantation in mice. We also found a suppressive effect of miR-22 up-regulation on Tiam1/Rac1 signal expression, and reciprocal regulation of E2 and P for these three genes' expression in mice. In conclusion, miR-22 up-regulation and Tiam1/Rac1 signal down-regulation inhibited embryo implantation in mice; this mechanism may be partially due to the suppressive effect of miR-22 on Tiam1 expression, and is regulated to some extent by serum E2 and P. Our findings provide evidence that endometrial Tiam1/Rac1 signal down-regulation along with miR-22 up-regulation during embryo implantation window in the natural menstrual cycle may be one of the reasons for the failure of embryo implantation in patients with RIF.
本研究首先评估了子宫内膜Tiam1/Rac1信号和微小RNA-22（miR-22）对小鼠胚胎着床的影响，然后检测了体外受精治疗后反复种植失败（RIF）女性自然月经周期中胚胎着床窗期间上述三个基因在子宫内膜中的表达。452只昆明雌性小鼠和200名女性（70例RIF不孕患者，130名女性作为对照）纳入本研究。对临床和小鼠样本中的子宫内膜Tiam1/Rac1信号和miR-22表达进行研究，并对临床受试者的血清雌激素（E2）和孕激素（P）进行分析。基于RIF患者子宫内膜miR-22和Tiam1 mRNA表达趋势构建妊娠小鼠模型，然后分析胚胎着床数，并使用去卵巢小鼠模型评估这三个基因的表达与E2和P的相关性。结果显示，在自然月经周期的胚胎着床窗期间，RIF患者子宫内膜miR-22显著高于对照组，而Tiam1/Rac1信号显著低于对照组，且RIF组的P:E2比值在统计学上更低。Tiam1/Rac1信号下调和miR-22上调导致小鼠胚胎着床受到抑制。我们还发现miR-22上调对Tiam1/Rac1信号表达有抑制作用，以及E2和P对小鼠这三个基因表达的相互调节作用。总之，miR-22上调和Tiam1/Rac1信号下调抑制小鼠胚胎着床；这种机制可能部分归因于miR-22对Tiam1表达的抑制作用，并在一定程度上受血清E2和P的调节。我们的研究结果表明，自然月经周期胚胎着床窗期间子宫内膜Tiam1/Rac1信号下调以及miR-22上调可能是RIF患者胚胎着床失败的原因之一。
