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Publications (2)12.99 Total impact

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    ABSTRACT: Context: Endometriosis is one of the most common gynecological diseases in women with a prevalence rate of approximately 10%. Chronic pelvic inflammation has been observed in patients with endometriosis and is associated with disease severity. However, how pelvic inflammation promotes endometriosis progression remains unknown. Objective: To investigate the regulatory network of pro-inflammatory cytokines in endometriosis progression. Design, settings, and patients: Immunostaining of human endometrial (n=21) and endometriotic (n=36) sections, quantitative RT-PCR, Western blotting, chromatin immunoprecipitation (ChIP), and luciferase reporter assays in primary culture human endometrial stromal cells were performed. Autologous transplantation of uterine endometrium from control (COUP-TFII flox/flox) and uterus-specific COUP-TFII knockout mice was performed. Results: Expression of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) was significantly reduced in endometriotic stroma. Reduction of COUP-TFII in endometriotic stromal cells was mediated by proinflammatory cytokines including interleukin-1β, tumor necrosis factor-α, and transforming growth factor-β1 via a common effector, microRNA-302a (miR-302a). Treatment with these proinflammatory cytokines increased the expression of miR-302a, which targets the 3'UTR of COUP-TFII to cause its downregulation. Intriguingly, downregulation of COUP-TFII in endometrial stromal cells resulted in de-repression of cyclooxygenase-2 (COX-2). Further investigation demonstrated that COUP-TFII directly binds to COX-2 promoter to inhibit its transcription. Forced expression of COUP-TFII inhibited interleukin-1β-induced COX-2 upregulation while knockdown of COUP-TFII augmented this effect. Conclusion: Since overexpression of COX-2 has been demonstrated to be a master regulator in endometriosis progression, our data demonstrate the critical function of pro-inflammatory cytokines and COUP-TFII regulatory gene network in the progression of endometriosis.
    The Journal of clinical endocrinology and metabolism 01/2014; · 6.50 Impact Factor
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    ABSTRACT: Aberrant activation of MAPK has been implicated to play important roles in pathological processes of endometriosis. However, how MAPK are constitutively activated in endometriotic tissues remains largely unknown. microRNA are small noncoding RNA that regulate the stability or translational efficiency of target mRNA by interacting with the 3' untranslated region. Thus, miRNA are thought to be modulators of the transcriptional response, fine-tuning gene expression. The aim of this study was to evaluate the functional roles of microRNA-20a (miR20a) in MAPK activation and the pathogenesis of endometriosis. miR20a expression was analyzed in nonpaired (endometrium = 17; endometriosis = 37) and paired (n = 12) endometriotic tissues by quantitative RT-PCR. Overexpression of miR20a in eutopic endometrial stromal cells or inhibition of miR20a in ectopic endometriotic stromal cells was used to evaluate its impact on ERK phosphorylation and subsequently angiogenesis- and proliferation-related gene expression. Levels of miR20a were up-regulated in endometriotic stromal cells. Elevation of miR20a was up-regulated by hypoxia inducible factor-1α. The up-regulation of miR20a causes the down-regulation of dual-specificity phosphatase-2, which leads to prolonged ERK phosphorylation and an increase in the expression of several angiogenic genes. Furthermore, the up-regulation of miR20a enhances the prostaglandin E(2)-induced expression of fibroblast growth factor-9, a potent mitogen that stimulates both endothelial and endometrial cell proliferation. Our findings provide the novel mechanism that not only functionally links together hypoxic stress, miR20a expression, aberrant ERK phosphorylation, and angiogenesis but also demonstrates that miR20a is an important modulator in the development of endometriosis.
    The Journal of clinical endocrinology and metabolism 05/2012; 97(8):E1515-23. · 6.50 Impact Factor