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. 2011 May;25(5):821-32.
doi: 10.1210/me.2010-0371. Epub 2011 Mar 24.

Functional microRNA involved in endometriosis

Shannon M Hawkins  1 , Chad J Creighton, Derek Y Han, Azam Zariff, Matthew L Anderson, Preethi H Gunaratne, Martin M Matzuk
Affiliations

Functional microRNA involved in endometriosis

Shannon M Hawkins et al. Mol Endocrinol. 2011 May.

Abstract

Endometriosis is a common disease seen by gynecologists. Clinical features involve pelvic pain and unexplained infertility. Although endometriosis is pathologically characterized by endometrial tissue outside the normal uterine location, endometriosis is otherwise not easily explained. Endometriomas, endometriotic cysts of the ovary, typically cause pain and distortion of pelvic anatomy. To begin to understand the pathogenesis of endometriomas, we describe the first transcriptome-microRNAome analysis of endometriomas and eutopic endometrium using next-generation sequencing technology. Using this approach, we generated a total of more than 54 million independent small RNA reads from our 19 clinical samples. At the microRNA level, we found 10 microRNA that were up-regulated (miR-202, 193a-3p, 29c, 708, 509-3-5p, 574-3p, 193a-5p, 485-3p, 100, and 720) and 12 microRNA that were down-regulated (miR-504, 141, 429, 203, 10a, 200b, 873, 200c, 200a, 449b, 375, and 34c-5p) in endometriomas compared with endometrium. Using in silico prediction algorithms, we correlated these microRNA with their corresponding differentially expressed mRNA targets. To validate the functional roles of microRNA, we manipulated levels of miR-29c in an in vitro system of primary cultures of human endometrial stromal fibroblasts. Extracellular matrix genes that were potential targets of miR-29c in silico were significantly down-regulated using this biological in vitro system. In vitro functional studies using luciferase reporter constructs further confirmed that miR-29c directly affects specific extracellular matrix genes that are dysregulated in endometriomas. Thus, miR-29c and other abnormally regulated microRNA appear to play important roles in the pathophysiology of uterine function and dysfunction.

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Figures

Fig. 1.
Fig. 1.
Expression profiling of microRNAs in nonendometriosis control endometrium and endometriomas. A, Heat map representation of transcripts overexpressed (yellow) and underexpressed (blue) in control endometrium vs. endometriomas (P < 0.01, fold change >1.5). Rows, microRNAs; columns, profiled samples. B, RQ QPCR of microRNAs in endometrioma compared with nonendometriosis control endometrium. *, P < 0.05.
Fig. 2.
Fig. 2.
Expression profiling of genes in nonendometriosis control endometrium and endometriomas. A, Heat map representation of transcripts overexpressed (yellow) and underexpressed (blue) in control endometrium vs. endometriomas (P < 0.01, fold change >1.5). Menstrual cycle phase is indicated by S, secretory; I, interval; P, proliferative; or H, prior hysterectomy. Rows, Transcripts; columns, profiled samples. B, Hierarchical clustering of control endometrium and endometriomas. Menstrual cycle phase is indicated.
Fig. 3.
Fig. 3.
QPCR analysis of steroid hormone-responsive genes. RQ of estrogen- and progesterone-responsive genes in nonendometriosis control and endometriomas. *, P < 0.05.
Fig. 4.
Fig. 4.
QPCR analysis of genes targeted by miR-29c. A, RQ of miR-29c target genes in nonendometriosis control endometrium and endometriomas in independent samples. B, RQ of gene expression with transfection of miR-29c mimic compared with control mimic construct and RQ of gene expression with transfection of miR-29c hairpin inhibitor compared with control hairpin inhibitor. *, P < 0.05.
Fig. 5.
Fig. 5.
Biological effects of miR-29c in vitro. A, Luciferase activity repression with miR-29c mimics in HEK293T. RQ of luciferase activity with cotransfection of 3′ UTR constructs and miR-29c mimic compared with control mimic and luciferase activity with cotransfection of 3′ UTR constructs and miR-29c hairpin inhibitor compared with nontargeting hairpin inhibitor control. Empty, luciferase parent vector only; random, random 3′ UTR construct in parent luciferase vector. B and C, RQ of WNT4 (B) and IGFBP1 (C) in HESF overexpressing miR-29c and undergoing in vitro decidualization compared with nondecidualized cells. *, P < 0.05.
Fig. 6.
Fig. 6.
Venn diagram of overlap of differentially expressed microRNA in multiple studies.
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