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

Meng-Hsing Wu, Meng‐Hsing Wu, Shih‐Chieh Lin, Shih-Chieh Lin, Kuei-Yang Hsiao, Kuei‐Yang Hsiao, Shaw‐Jenq Tsai, Shaw-Jenq Tsai
The Journal of Pathology · 2011 · vol. 225(3) , pp. 390–400 · doi:10.1002/path.2963 · PMID:21984126 · W2140955394
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Hypoxia-inducible factor-1α down-regulates DUSP2 expression in endometriotic stromal cells, leading to prolonged MAPK activation and increased COX-2 expression, contributing to endometriosis development.

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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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Cyclooxygenase 2 Dual Specificity Phosphatase 2 Endometriosis Cell Hypoxia Cell Hypoxia Cyclooxygenase 2 Cyclooxygenase 2 Cyclooxygenase 2 DNA Methylation Down-Regulation Down-Regulation Dual Specificity Phosphatase 2 Dual Specificity Phosphatase 2 Dual Specificity Phosphatase 2 Dual Specificity Phosphatase 2 Endometriosis Endometriosis Endometrium Endometrium Endometrium

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