Functional Role of Dual Specificity Phosphatase-2 in Angiogenic Process of Endometriosis

摘要

Endometriosis is one of the most common gynecological disorders defined as the presence of endometrial glands and stroma outside of the uterine cavity The pathogenic mechanism of endometriosis is complicated and is largely unknown It has been well-accepted that endometriotic lesions originated from refluxed endometrial tissues which have to gain the ability of neovasculization to survive under the hypoxic environment of ectopic sites Our previous study has shown that dual specificity phosphatase-2 (DUSP2) a mitogen activated protein kinase (MAPK)-specific nuclear phosphatase is downregulated in endometriotic tissues in a hypoxia inducible factor-dependent manner and contributes to the pathological process of endometriosis Although hypoxia plays important roles in angiogenesis whether DUSP2 is involved in angiogenesis during the development of endometriosis remains unknown This study was designed to investigate the biological functions of hypoxia-mediated DUSP2 downregulation on angiogenesis during the development of endometriosis Whole genome screening data revealed that DUSP2 regulated a subset of angiogenic genes we chose interleukin-8 (IL-8) for subsequent characterization since it is a potent angiogenic factor Quantitative RT-PCR results demonstrated that the levels of IL-8 were elevated in ectopic endometriotic stromal cells which was inversely correlated with levels of DUSP2 Results also showed the induction of IL-8 could be recapitulated by hypoxia treatment or DUSP2 knockdown in eutopic endometrial stromal cells Promoter activity assay results showed that hypoxia-mediated DUSP2 downregulation enhanced IL-8 expression through a transcriptional regulation by CCAAT/enhancer binding protein ? (C/EBP?) Hypoxia-induced binding of C/EBP? to IL-8 promoter was evidenced by chromatin immunoprecipitation-PCR assay Treatment with conditioned medium collected from endometrial stromal cells cultured under hypoxia or with DUSP2 knockdown promoted network formation of human umbilical vein endothelial cells which can be blocked by administration of IL-8 receptor inhibitor Finally results from in vivo angiogenic mouse model demonstrated the number of autoimplant-induced endometriotic-like lesions and the microvasculature within the lesions were significantly reduced by blocking the signaling of IL-8 Taken together results from this study demonstrate that loss-of-DUSP2 in endometriotic stromal cells causes IL-8 upregulation which results in increased angiogenic capacity and promotes the growth of endometriotic lesions This study provides solid evidence to demonstrate that hypoxia-regulated DUSP2 downregulation promotes expression of angiogenic factor IL-8 during the development of endometriosis and suggests it may serve as a potential therapeutic target

獎項日期	2014 8月 21
原文	English
監督員	Shaw-Jenq Tsai (Supervisor)