STEAP3基因在冻胚移植妊娠后子痫前期发病中的作用及机制研究

我们团队通过多中心随机对照临床研究证实，与鲜胚移植比较，冻胚移植可提高活产率，同时增加母体并发症子痫前期的风险，但机制不明。我们前期通过转录组测序以及扩大样本qRT-PCR验证实验，发现胎盘组织中前列腺六次跨膜上皮抗原3（STEAP3）基因的表达水平在鲜胚正常对照组、冻胚正常对照组、冻胚子痫前期组呈现逐渐增加的趋势。STEAP3是p53抑癌基因信号通路的下游蛋白，可诱导肿瘤细胞凋亡；同时又是细胞内铁还原酶，对铁平衡有重要作用。因此推测，冷冻可能导致胚胎细胞DNA损伤增加，激活p53信号通路，该通路相关蛋白STEAP3表达增加，进而使得绒毛外滋养细胞（EVTs）功能下降，介导了子痫前期的发生。在本项目中，我们通过小鼠体外受精模型明确冷冻对胚胎STEAP3表达的影响，并通过人体胎盘组织标本检测、体外STEAP3过表达细胞系实验、以及STEAP3过表达鼠胚模型进一步解析其在子痫前期发病中的机制。

Our multicenter randomized controlled trials confirmed that frozen embryo transfer (FET) increased the rate of live birth, but also raise the risk of preeclampsia compared with fresh embryo transfer (ET). However, the underlying mechanism is unclear. By performing RNA-seq and validating the results in a expanded sample, we found the expression level of six transmembrane epithelial antigen of prostate 3 (STEAP3) gene in placental tissue stepwisely increased among control of ET, control of FET, and preeclampsia after FET. STEAP3 is down-stream protein of the p53 cancer suppressor pathway and could induce cancer cell apoptosis. On the other hand, STEAP3 is the intracellular iron reductase and important for iron homeostasis. We hypothesize that freezing may cause DNA damage to embryo cells and activate p53 pathway, consequently, increase the expression of STEAP3, which then impairs the function of extravillous trophoblast cell and lead to the occurrence of preeclampsia. In this study, we will access the effect of freezing on embryo STEAP3 expression and investigate the mechanism underlying STEAP3 gene and preeclampsia with human placental tissue measurements, in vitro cell-line experiments, and gene over-expressing mice embryos.