Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.
Int J Biol Sci. 2024 Jan 1;20(1):296-311. doi: 10.7150/ijbs.85378. eCollection 2024.
Dysplasia and invasive defects in early trophoblasts contribute to unexplained recurrent miscarriages (URMs). Mesencephalic astrocyte-derived neurotrophic factor (MANF) inhibits migration and invasion in some cancer cells, but its role in pregnancy-related diseases remains unresolved. Here, we found that MANF levels in the peripheral blood and aborted tissue of URM women were higher than in normal controls, irrespective of pregnancy or miscarriage. We confirm the interaction between MANF and nucleophosmin 1 (NPM1) in trophoblasts of URM patients, which increases the ubiquitination degradation of NPM1, leading to upregulation of the p53 signaling pathway and inhibition of cell proliferation, migration, and invasion ability. Using a URM mouse model, we found that MANF downregulation resulted in reduced fetal resorption; however, concomitant NPM1 downregulation led to increased abortion rates. These data indicate that MANF triggers miscarriage via NPM1 downregulation and p53 activation. Thus, MANF downregulation or disruption of the MANF-NPM1 interaction could be targets for URM therapeutics.
早期滋养层中的发育不良和侵袭性缺陷导致不明原因的反复性流产（URM）。中脑神经胶质细胞衍生的神经营养因子（MANF）抑制某些癌细胞的迁移和侵袭，但它在妊娠相关疾病中的作用仍未得到解决。在这里，我们发现无论是否怀孕或流产，URM 女性的外周血和流产组织中的 MANF 水平均高于正常对照组。我们证实了 MANF 与 URM 患者滋养层中的核仁磷酸蛋白 1（NPM1）之间的相互作用，这增加了 NPM1 的泛素化降解，导致 p53 信号通路的上调和细胞增殖、迁移和侵袭能力的抑制。使用 URM 小鼠模型，我们发现 MANF 的下调导致胎儿吸收减少；然而，同时下调 NPM1 会导致流产率增加。这些数据表明，MANF 通过下调 NPM1 和激活 p53 引发流产。因此，下调 MANF 或破坏 MANF-NPM1 相互作用可能成为 URM 治疗的靶点。
