ArticleFree radical research2022
Hypoxia induces proliferation via NOX4-Mediated oxidative stress and TGF-β3 signaling in uterine leiomyoma cells.
Article in Free radical research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- The relationship between fat-soluble vitamins and uterine fibroids: a systematic review.BMC women's health · 2025Pooled it
- The estrogen-progestogen-oxidative stress network in uterine fibroids: mechanistic insights and therapeutic opportunities.Redox report : communications in free radical research · 2026Review
- HIF-1α Signaling in Uterine Fibroids: A Central Integrator of Hypoxic, Hormonal, and Fibrotic Pathways.Oxygen (Basel, Switzerland) · 2026Article
- Uterine Vulnerability to Environmental PMInternational journal of molecular sciences · 2026Article
- The role of oxidative stress in sleep deprivation-induced reproductive dysfunction: A rationale for anti-oxidant intervention.Iranian journal of basic medical sciences · 2026Review
- Modeling Uterine Fibroids Using Bioengineered Hydrogels.ACS biomaterials science & engineering · 2025Article
- Correlation of sleep-disordered breathing with anemia and microcytosis in premenopausal females: the Nagahama study.Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine · 2025Article
- Hypoxia in uterine fibroids: role in pathobiology and therapeutic opportunities.Oxygen (Basel, Switzerland) · 2024Article
- CD4iScience · 2023Article
- Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma.Redox biology · 2023Article
- Article
- The Role of TGF-β3 in Radiation Response.International journal of molecular sciences · 2023Review
- Oxidative Stress and Antioxidants in Uterine Fibroids: Pathophysiology and Clinical Implications.Antioxidants (Basel, Switzerland) · 2023Review
- Hypoxia-induced ROS aggravate tumor progression through HIF-1α-SERPINE1 signaling in glioblastoma.Journal of Zhejiang University. Science. B · 2023Article
- PLP1 may serve as a potential diagnostic biomarker of uterine fibroids.Frontiers in genetics · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Uterine leiomyomas, the most common tumors of the female reproductive system, are known to have a hypoxic microenvironment. However, the role of such environment in leiomyoma pathobiology remains unknown. The objective was to determine the effects of hypoxia on leiomyoma cells, and the mechanisms. We found that hypoxia induces proliferation and inhibits apoptosis in human leiomyoma cells. This pro-proliferative effect was accompanied by an increase in reactive oxygen species (ROS) generation and the expression of NADPH oxidase 4 (NOX4). The specific NOX4 inhibitor GLX351322 abrogated this hypoxia-induced ROS generation, cellular proliferation, and apoptosis inhibition. To further investigate the mechanism of NOX4-mediated proliferation, we treated leiomyoma cells grown in normoxia with media from leiomyoma cells cultured under hypoxia. This resulted in increased ROS generation and NOX4 expression, suggesting the hypoxia-induced effects are mediated by an autocrine mechanism. We worked to identify the nature of this autocrine factor. We found that the expression of TGF-β3 and its downstream signaling target pSmad3, are increased in hypoxic leiomyoma cells. To examine the hypothesis that TGF-β3 is, at least, a part of this autocrine mechanism, we treated hypoxic leiomyoma cells with the HIF-1α inhibitor KC7F2 which we discovered to ameliorate the hypoxia-induced TGF-β3 expression. Furthermore, pharmacologic inhibition with the TGF-β/Smad inhibitor SB431542 reduced hypoxia-induced NOX4 expression and ROS generation and attenuated cell proliferation. Thus, we have identified a novel mechanism by which hypoxia induces proliferation in leiomyoma cells. This finding adds to our understanding of leiomyoma pathobiology and can help in identifying new therapeutic targets.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.