MANF Promotes Unexplained Recurrent Miscarriages by Interacting with NPM1 and Downregulating Trophoblast Cell Migration and Invasion.
Int J Biol Sci
; 20(1): 296-311, 2024.
Article
em En
| MEDLINE
| ID: mdl-38164189
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Aborto Habitual
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Proteína Supressora de Tumor p53
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Pregnancy
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article