Altered expression of microRNA-451 in eutopic endometrium of baboons (Papio anubis) with endometriosis

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Endometriosis induction altered the expression of eight microRNAs, including miR-451, in baboon endometrium, with decreased miR-451 correlating to increased target gene expression and reduced cell proliferation.

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Abstract

STUDY QUESTION: Are microRNAs (miRs) altered in the eutopic endometrium (EuE) of baboons following the induction of endometriosis? SUMMARY ANSWER: Induction of endometriosis causes significant changes in the expression of eight miRs, including miR-451, in the baboon endometrium as early as 3 months following induction of the disease. WHAT IS KNOWN ALREADY: Endometriosis is one of the most common gynecological disorders and causes chronic pelvic pain and infertility in women of reproductive age. Altered expression of miRs has been reported in women and has been suggested to play an important role in the pathophysiology of several gynecological disorders including endometriosis. STUDY DESIGN, SIZE, DURATION: EuE was obtained from the same group of baboons before and 3 months after the induction of endometriosis. The altered expression of miR-451 was validated in the eutopic and ectopic endometrium of additional baboons between 3 and 15 months following disease induction. Timed endometrial biopsies from women with and without endometriosis were also used to validate the expression of miR-451. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total RNA was extracted from EuE samples before and after the induction of endometriosis, and miRNA expression was analyzed using a 8 × 15 K miR microarray. Microarray signal data were preprocessed by AgiMiRna software, and an empirical Bayes model was used to estimate the changes. The present study focused on quantitative RT-PCR validation of the microarray data, specifically on miR-451 and its target genes in both baboons (n = 3) and women [control (n = 7) and endometriosis (n = 19)]. Descriptive and correlative analysis of miR-451 and target gene expression was conducted using in situ hybridization and immunohistochemistry, while functional analysis utilized an in vitro 3' untranslated region (UTR) luciferase assay and overexpression of miR-451 in human endometrial and endometriotic cell lines. MAIN RESULTS AND THE ROLE OF CHANCE: Induction of endometriosis results in the altered expression of miR-451, -141, -29c, -21, -424, -19b, -200a and -181a in the baboon endometrium. In the baboon, induction of endometriosis significantly decreased the expression of miR-451 at 3 months (P < 0.001), which was also associated with increased expression of its target gene YWHAZ (14.3.3ζ). A similar significant (P < 0.0001) decrease in miR-451 expression was observed in women with endometriosis. The 3' UTR luciferase assay confirmed the regulation of YWHAZ expression by miR-451. Furthermore, overexpression of miR-451 in 12Z cells (immortalized human endometriotic epithelial cell line) led to the decreased expression of its target YWHAZ and this was correlated with decreased cell proliferation. LIMITATIONS, REASONS FOR CAUTION: The study focused only on miR-451 and one of its targets, namely YWHAZ. A single miR could target number of genes and a single gene could also be regulated by number of miRs; hence, it is possible that other miRs and their regulated genes may contribute to the pathophysiology of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that the presence of ectopic lesions in baboon causes changes in EuE miR expression as early as 3 months postinduction of the disease, and some of these changes may persist throughout the course of the disease. We propose that the marked down-regulation of miR-451 in both baboons and women with endometriosis increases the expression of multiple target genes. Increased expression of one of the target genes, YWHAZ, increases proliferation, likely contributing to the pathophysiology of the disease.

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Condition tags

endometriosischronic_pelvic_paininfertility

MeSH descriptors

Endometriosis Endometrium Gene Expression Regulation MicroRNAs Adult Animals Cell Proliferation Endometriosis Endometriosis Endometriosis Endometrium Endometrium Female Humans MicroRNAs MicroRNAs Papio anubis

Funding

funders
[{'doi': None, 'name': 'Eunice Kennedy Shriver NICHD/NIH', 'awards': ['U54 HD40093']}, {'doi': None, 'name': 'Specialized Cooperative Centers Program in Reproduction and Infertility Research', 'awards': ['R21 HD 082453']}, {'doi': None, 'name': 'Specialized Cooperative Centers Program in Reproduction and Infertility Research', 'awards': ['R01 HD 067721']}]

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References (83)

SciLite annotations

chemicals 14
formaldehyde digoxigenin sodium diethylcarbamazine citrate nucleotide nitrogen tetrazolium blue chlorocyclohexane thiophanate-methyl water pyruvate polyacrylamide macromolecule sodium sulfate polyurethane polymer
organisms 27
papio papio papio sensu groves noordeloos 2009062 papio papio human papio papio sensu groves papio papio sensu groves human papio papio sensu groves papio papio papio hamadryas doguera noordeloos 2009062 humans rodents old world monkeys hominoidea papio human papio papio sensu groves multicellular animals papio hamadryas doguera naine d'afrique de l'ouest muscisaxicola rufivertex occipitalis renilla primates

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