| Summary: | 碩士 === 國立成功大學 === 生理學研究所 === 100 === Endometriosis affects about 10-15% women of reproductive age, resulting in chronic pelvic inflammation, abdominal pain, and infertility. Endometriosis was first described in 1860. However, the etiology and pathogenesis remain unclear. Prostaglandin E2 (PGE2) is the master regulator that promotes endometriosis formation and causes severe pathological symptoms. We have previously demonstrated that high PGE2 is produced by upregulation of cyclooxygenase-2 (COX-2) in endometriotic stromal cells through activation of mitogen-activated protein kinase (MAPK) pathway. Dual specificity phosphatases (DUSPs) are downstream phosphatases of MAPKs, which act to terminate the activity of MAPKs. Here we showed that expression of DUSP4 in endometriotic tissue was lower than that in normal tissue. Reduced expression of DUSP4 was correlated with aberrant phosphorylation of ERK in endometriotic stromal cells and overexpression of COX-2. To further investigate the effect of DUSP4 on COX-2 expression, we cloned full-length human DUSP4 cDNA and overexpressed it in cells. Results demonstrated that overexpression of DUSP4 reduced the levels of phosphorylated ERK, and ultimately resulted in reduced COX-2 expression. Finally, we showed that reduced expression of DUSP4 in endometriotic cells was mediated by hypoxia-induced transcriptional suppression. Taken together, we provide compelling evidence to demonstrate that hypoxia inhibits DUSP4 expression leading to aberrant activation of ERK, which results in overexpression of COX-2. Our data indicate that hypoxia-inhibited DUSP4 expression is a critical factor for the development of endometriosis.
|
|---|
