title: Altered expression of microRNA-451 in eutopic endometrium of baboons (Papio anubis) with endometriosis.
abstract: OBJECTIVE
  Are microRNAs (miRs) altered in the eutopic endometrium (EuE) of baboons following the induction of endometriosis?
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Joshi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Su
authors.affiliation: GenEpria Consulting Inc., Columbia, MD 21046, USA.
authors.forename: G V R
authors.initials: GV
authors.lastname: Chandramouli
authors.affiliation: Department of Cell and Molecular Biology, Grand Valley State University, Grand Rapids, MI 49503, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Khoo
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Obstetrics and Gynecology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Young
authors.affiliation: Greenville Hospital System, University of South Carolina School of Medicine, Greenville, SC 29605, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Lessey
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA asgi@hc.msu.edu.
authors.forename: A T
authors.initials: AT
authors.lastname: Fazleabas
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D048530:Papio anubis
chemical_list: D035683:MicroRNAs
keywords: YWHAZ; endometriosis; endometrium; microRNA-451; proliferation