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LIM homeobox 1 (LHX1) induces endoplasmic reticulum stress and promotes preterm birth
Liyin Qiu1, Zhaozhen Liu2, Shouzhen Chen1
1Department of Obstetrics, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, China.
Insights
LIM Homeobox 1 (LHX1) promotes premature birth (PTB) by activating the IRE-1/XBP1/CHOP pathway. Reducing LHX1 levels ameliorated PTB symptoms in mouse models, suggesting a therapeutic target.
Area of Science:
- Reproductive Biology
- Cellular Biology
- Molecular Biology
Background:
- Premature birth (PTB) is a leading cause of neonatal mortality with long-term health implications.
- LIM Homeobox 1 (LHX1) is crucial for embryonic development, and Inositol-Requiring Enzyme 1 (IRE-1) regulates endoplasmic reticulum stress (ERS).
- The relationship between IRE-1 and PTB through LHX1 modulation requires investigation.
Purpose of the Study:
- To investigate the role of IRE-1 in premature birth (PTB) via LHX1 modulation.
- To analyze LHX1 expression in PTB placental tissues and its effects on trophoblast cell functions.
- To elucidate the molecular mechanisms linking LHX1, ERS, and PTB.
Main Methods:
- LHX1 expression was analyzed in placental samples from PTB patients and human trophoblast cells (HTR8/Svneo).
- Cell viability, migration, invasion, and apoptosis were assessed following LHX1 manipulation and endoplasmic reticulum stress induction (tunicamycin).
- Mechanisms involving the IRE-1/XBP1/CHOP pathway, LHX1 binding to the IRE-1 promoter, and in vivo PTB models were evaluated.
Main Results:
- LHX1 was overexpressed in PTB placental tissue and in cells under endoplasmic reticulum stress.
- LHX1 depletion enhanced trophoblast cell viability, migration, and invasion while reducing apoptosis and autophagy.
- LHX1 activates the IRE-1/XBP1/CHOP pathway, and its knockdown ameliorated PTB symptoms in mice.
Conclusions:
- LHX1 plays a significant role in the pathogenesis of premature birth.
- LHX1 contributes to PTB progression by regulating the IRE-1-XBP1-CHOP signaling pathway.
- Targeting LHX1 may offer a novel therapeutic strategy for preventing PTB.
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.
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.
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.
Conclusion:
LHX1 contributes to the progression of PTB by regulating the IRE-1-XBP1-CHOP pathway.
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