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Cited by 66Endometriosis Research and TreatmentInflammatory mediators and NSAID effectsProtease and Inhibitor Mechanisms

Hypoxia‐inhibited dual‐specificity phosphatase‐2 expression in endometriotic cells regulates cyclooxygenase‐2 expression

Wu, Meng‐Hsing, Lin, Shih‐Chieh, Hsiao, Kuei‐Yang, Tsai, Shaw‐Jenq·2011·The Journal of Pathology
DOI 10.1002/path.2963
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Abstract

Endometriosis is one of the most common gynaecological diseases that significantly reduces the life qualify of affected women and their families. Aberrant expression of cyclooxygenase‐2 (COX‐2), and thus over‐production of prostaglandin E 2 (PGE 2 ) has been shown to play critical roles in the development of this disease. However, the mechanism responsible for COX‐2 over‐expression remains obscure. Here, we provide evidence for what we believe is a novel mechanism in regulating COX‐2 expression in endometriotic stromal cells. Dual‐specificity phosphatase‐2 (DUSP2), a nuclear phosphatase that inactivates mitogen‐activated protein kinase (MAPK), is markedly down‐regulated in stromal cells of ectopic endometriotic tissues, which results in prolonged activation of extracellular signal‐regulated kinase (ERK) and p38 MAPK and increased COX‐2 expression. Expression of DUSP2 is inhibited by hypoxia inducible factor‐1α (HIF‐1α) at the transcriptional level. Treatment of normal endometrial stromal cells with hypoxia, or chemicals that cause HIF‐1α accumulation, results in DUSP2 down‐regulation, prolonged ERK phosphorylation and COX‐2 over‐expression. In contrast, forced expression of DUSP2 under hypoxia abolishes HIF‐1α‐induced ERK phosphorylation and COX‐2 expression. Furthermore, suppression of DUSP2 by HIF‐1α in eutopic endometrial stromal cells increases sensitivity of cox‐2 gene to interleukin‐1β stimulation, a phenomenon resembling endometriotic stromal cell characteristics. Taken together, these data suggest that DUSP2 is an important molecule in endometrial physiology and that hypoxia‐inhibited DUSP2 expression is a critical factor for the development of endometriosis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Crossref · 10.1002/path.2963

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  • Increased HIF-1α accumulation results in DUSP2 down-regulation, which results in prolonged activation of ERK and p38 MAPK and increased COX-2 expression in endometriotic stromal cells, as well as increased ERβ expression which can also be induced by activated platelets.

    “Increased HIF-1α accumulation results in DUSP2 down-regulation, which results in prolonged activation of ERK and p38 MAPK and increased COX-2 expression in endometriotic stromal cells49, as well as increased ERβ expression66 which can also be induced by activated platelets.”

    From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [49]

  • Activation of HIF-1α and thus hypoxia can lead to increased estrogen production through depressing DUSP2 expression and thus COX-2 overexpression in endometriotic stromal cells, as well as increased ERβ expression.

    “Our results are consistent with the finding that activation of HIF-1α and thus hypoxia can lead to increased estrogen production through depressing DUSP2 expression and thus COX-2 overexpression in endometriotic stromal cells49, as well as increased ERβ expression66.”

    From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [49]

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Authors
Wu, M., Lin, S., Hsiao, K., & Tsai, S.
Affiliations
National Cheng Kung University (TW)
Corresponding author
Tsai, Shaw‐Jenq
ORCID
Venue
The Journal of Pathology
Publisher
Wiley
Published
2011-08-24
Volume
225
Issue
3
Pages
390-400
ISSN
  • 0022-3417 (ISSN-L)
  • 1096-9896
DOI
10.1002/path.2963
OpenAlex
W2140955394
Cited by
65
References
35
Citations by year
2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 14 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 3 · 2012: 4
FWCI
4.26
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Pathology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Council of Taiwan (NSC 97-2627-B-006-003)
  • National Health Research Institute of Taiwan (NHRI-EX9932BI)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
endometriosis, endometriotic stromal cells, DUSP2, cyclooxygenase-2, hypoxia, hypoxia-inducible factor-1α, ERK1/2 phosphorylation, p38 MAPK, prostaglandin E2, IL-1β, MAPK signaling, transcriptional regulation
MeSH terms
Endometriosis, Endometrium, Female, Humans, Phosphorylation, RNA, Messenger, Down-Regulation, Cell Hypoxia, Up-Regulation, Gene Expression Regulation, Enzymologic, Stromal Cells, DNA Methylation, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Cyclooxygenase 2, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-1beta, Dual Specificity Phosphatase 2

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