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MicroRNA-Regulated Pathways Associated with Endometriosis

Research Centre for Reproductive Health (E.M.C.O.T., K.H.V., N.P., S.A.R., M.L.H.), School of Paediatrics and Reproductive Health, University of Adelaide, and Adelaide Microarray Centre (M.B.V.), Hanson Institute, Adelaide, South Australia 5005, Australia; Department of Gynaecology (P.W.), Women’s and Children’s Hospital, Adelaide, South Australia 5006, Australia; and Department of Molecular Medicine and Pathology (C.G.P.), University of Auckland, Private Bag 92019, Auckland, New Zealand

Address all correspondence and requests for reprints to: Maria Ohlsson Teague, Ph.D., and Louise Hull, MBChB., Ph.D., Research Centre for Reproductive Health, School of Paediatrics and Reproductive Health, Sixth Floor, Medical School North, University of Adelaide, South Australia 5005, Australia. E-mail: maria.teague{at}adelaide.edu.au (http://www.adelaide.edu.au/rcrh).

ABSTRACT

Endometriosis is a prevalent gynecological disease characterized by growth of endometriotic tissue outside the uterine cavity. MicroRNAs (miRNAs) are naturally occurring posttranscriptional regulatory molecules that potentially play a role in endometriotic lesion development. We assessed miRNA expression by microarray analysis in paired ectopic and eutopic endometrial tissues and identified 14 up-regulated (miR-145, miR-143, miR-99a, miR-99b, miR-126, miR-100, miR-125b, miR-150, miR-125a, miR-223, miR-194, miR-365, miR-29c and miR-1) and eight down-regulated (miR-200a, miR-141, miR-200b, miR-142-3p, miR-424, miR-34c, miR-20a and miR-196b) miRNAs. The differential expression of six miRNAs was confirmed by quantitative RT-PCR. An in silico analysis identified 3851 mRNA transcripts as putative targets of the 22 miRNAs. Of these predicted targets, 673 were also differentially expressed in ectopic vs. eutopic endometrial tissue, as determined by microarray. Functional analysis suggested that the 673 miRNA targets constitute molecular pathways previously associated with endometriosis, including c-Jun, CREB-binding protein, protein kinase B (Akt), and cyclin D1 (CCND1) signaling. These pathways appeared to be regulated both transcriptionally as well as by miRNAs at posttranscriptional level. These data are a rich and novel resource for endometriosis and miRNA research and suggest that the 22 miRNAs and their cognate mRNA target sequences constitute pathways that promote endometriosis. Accordingly, miRNAs are potential therapeutic targets for treating this disease.

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