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

J Pathol. 2011 Nov;225(3):390-400. doi: 10.1002/path.2963. Epub 2011 Aug 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia / physiology
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • DNA Methylation
  • Down-Regulation / physiology
  • Dual Specificity Phosphatase 2 / antagonists & inhibitors
  • Dual Specificity Phosphatase 2 / biosynthesis
  • Dual Specificity Phosphatase 2 / genetics
  • Dual Specificity Phosphatase 2 / physiology*
  • Endometriosis / enzymology*
  • Endometriosis / pathology
  • Endometrium / drug effects
  • Endometrium / enzymology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Interleukin-1beta / pharmacology
  • Phosphorylation
  • RNA, Messenger / genetics
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Up-Regulation / physiology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-1beta
  • RNA, Messenger
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • DUSP2 protein, human
  • Dual Specificity Phosphatase 2