Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Biol Reprod. 2018 Jun 1;98(6):821-833. doi: 10.1093/biolre/ioy038.
Preeclampsia (PE) is a pregnancy-related disorder that occurs after 20 weeks of gestation and affects 3-5% of all human pregnancies worldwide. However, the pathogenesis of PE still remains poorly understood. A deficiency in decidualization is considered a contributing factor to the development of PE. The DNA damage inducible transcript 4 (DDIT4) gene encodes a protein whose main function is inhibiting mammalian target of rapamycin (mTOR) under stress, and several studies have demonstrated that its expression promotes tumor cell apoptosis. Our previous RNA-Seq results showed that DDIT4 is significantly decreased in the decidua of PE women. Here, we aimed to define the role of DDIT4 in human decidualization and its relationship with PE. The results indicated that DDIT4 was markedly decreased in the decidua of severe PE compared with those from uncomplicated pregnancies. The expression of DDIT4 in human endometrial stromal cell (hESC) line and primary hESCs was up-regulated during decidualization. Knockdown DDIT4 in hESCs and primary hESCs caused a significant reduction in the transcription of decidualization markers, insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL). In addition, silencing DDIT4 caused up-regulated p-mTOR and p-p70s6k and reduced apoptosis, whereas rapamycin, an inhibitor of mTOR, reversed the result of apoptosis. Moreover, the expression of cleaved-caspase 3 in severe PE was significantly lower than that of uncomplicated pregnancies, which was unfavorable for trophoblast invasion. Our data suggest that DDIT4 is critical for normal decidualization and the apoptosis of decidual cells. DDIT4 deficiency is likely involved in the development of PE.
子痫前期 (PE) 是一种妊娠相关疾病，发生在妊娠 20 周后，影响全球所有妊娠的 3-5%。然而，PE 的发病机制仍知之甚少。蜕膜化不足被认为是导致 PE 发展的一个因素。DNA 损伤诱导转录物 4 (DDIT4) 基因编码一种蛋白，其主要功能是在应激下抑制哺乳动物雷帕霉素靶蛋白 (mTOR)，几项研究表明其表达促进肿瘤细胞凋亡。我们之前的 RNA-Seq 结果表明，DDIT4 在 PE 妇女的蜕膜中显著降低。在这里，我们旨在确定 DDIT4 在人蜕膜化中的作用及其与 PE 的关系。结果表明，与正常妊娠相比，重度 PE 患者的蜕膜中 DDIT4 明显减少。DDIT4 在人子宫内膜基质细胞 (hESC) 系和原代 hESCs 中的表达在蜕膜化过程中上调。在 hESCs 和原代 hESCs 中敲低 DDIT4 会导致蜕膜化标志物胰岛素样生长因子结合蛋白 1 (IGFBP1) 和催乳素 (PRL) 的转录显著减少。此外，沉默 DDIT4 会导致 mTOR 和 p70s6k 的磷酸化增加和凋亡减少，而 mTOR 的抑制剂 rapamycin 则逆转了凋亡的结果。此外，严重 PE 中的 cleaved-caspase 3 表达明显低于正常妊娠，这不利于滋养细胞浸润。我们的数据表明，DDIT4 对正常蜕膜化和蜕膜细胞的凋亡至关重要。DDIT4 缺乏可能参与了 PE 的发生。
