1. Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China.
2. Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China.
3. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, China.
4. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No. 81 Meishan Road, Hefei 230032, Anhui, China.
5. Anhui Province Key Laboratory of Reproductive Health and Genetics, No. 81 Meishan Road, Hefei 230032, Anhui, China.
6. Anhui Provincial Engineering Research Center of Biopreservation and Artificial Organs, No. 81 Meishan Road, Hefei 230032, Anhui, China.
7. Anhui Provincial Institute of Translational Medicine, No. 81 Meishan Road, Hefei 230032, Anhui, China.
8. School of Basic Medical Sciences, Anhui Medical University, Hefei 230022, Anhui, China.
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.
Keywords: unexplained recurrent miscarriage, trophoblast cells, MANF, NPM1, p53