Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells.
BACKGROUND
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.


OBJECTIVE
The aim of this study was to evaluate the functional roles of microRNA-20a (miR20a) in MAPK activation and the pathogenesis of endometriosis.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Shih-Chieh
SC
Lin
Chih-Chuan
CC
Wang
Meng-Hsing
MH
Wu
Shang-Hsun
SH
Yang
Yo-Hua
YH
Li
Shaw-Jenq
SJ
Tsai
D015687:Cell Hypoxia; D015232:Dinoprostone / Q000494:pharmacology; D054641:Dual Specificity Phosphatase 2 / Q000235:genetics; D004715:Endometriosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology*; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D017154:Stromal Cells / Q000378:metabolism
C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D048049:Extracellular Signal-Regulated MAP Kinases; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; D015232:Dinoprostone