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LIM homeobox 1 (LHX1) induces endoplasmic reticulum stress and promotes preterm birth.
- Source :
-
Heliyon [Heliyon] 2024 Jun 18; Vol. 10 (13), pp. e32457. Date of Electronic Publication: 2024 Jun 18 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Background: Premature birth (PTB) is a major cause of neonatal mortality and has enduring consequences. LIM Homeobox 1 (LHX1) is vital in embryonic organogenesis, while Inositol-Requiring Enzyme 1 (IRE-1) regulates endoplasmic reticulum stress (ERS). This study explores whether IRE-1 impacts PTB via LHX1 modulation.<br />Methods: We analyzed LHX1 expression in placental samples from PTB patients and examined its impact on the viability, migration, invasion, and apoptosis of the human placental trophoblast cell line HTR8/Svneo, particularly when treated with the ERS inducer tunicamycin (TM). We also assessed the levels of ERS-related genes and autophagy activation in response to LHX1 deficiency. To gain mechanistic insights, we evaluated the ERS-mediated activation of the IRE-1/XBP1/CHOP signaling pathway in LHX1-silenced HTR8/Svneo cells. Additionally, we examined the transcriptional activation of IRE-1 and the binding of LHX1 to the IRE-1 promoter in HTR8/Svneo cells. We overexpressed IRE-1 in LHX1-silenced HTR8/Svneo cells to assess its effects on cell viability, migration, invasion, apoptosis, and autophagy. Finally, we induced LHX1 knockdown in mice through intraperitoneal injections of tunicamycin (TM) and Sh-LHX1 over a 24-h period to evaluate PTB symptoms.<br />Results: We observed LHX1 overexpression in placental tissue from PTB cases and TM-induced HTR8/Svneo cells. LHX1 depletion enhanced cell viability, migration, and invasion while reducing autophagy and apoptosis. This reduction in LHX1 led to decreased levels of IRE-1, XBP1, CHOP, and other ERS-related genes, indicating LHX1's role in ERS induction and the activation of the IRE-1/XBP1/CHOP pathway. Mechanistically, LHX1 was found to bind to the IRE-1 promoter, inducing its transcriptional activation. Notably, overexpressing IRE-1 counteracted the impact of LHX1 depletion on trophoblast cell behavior, suggesting that LHX1 modulates IRE-1. In line with our in vitro studies, LHX1 knockdown ameliorated PTB symptoms in TM-treated mice.<br />Conclusion: LHX1 contributes to the progression of PTB by regulating the IRE-1-XBP1-CHOP pathway.<br />Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (© 2024 The Author(s).)
Details
- Language :
- English
- ISSN :
- 2405-8440
- Volume :
- 10
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Heliyon
- Publication Type :
- Academic Journal
- Accession number :
- 39027525
- Full Text :
- https://doi.org/10.1016/j.heliyon.2024.e32457