{"paper_id":"573f4280-8afa-4968-b889-9cbe36af4f71","body_text":"REVIEW\nPharmazie 71 (2016)434\n1. Introduction\nEndometriosis (EMS), characterized by the presence and growth \nof functional endometrial-like tissues outside the uterine cavity, is \na common and benign gynecological disorder with a poorly under-\nstood and somewhat enigmatic etiopathogenesis and pathophysi-\nology (Giudice and Kao 2004). It is a leading cause of disability \nin women of reproductive age, responsible for dysmenorrhea, \npelvic pain and infertility (Farquhar 2000). Endometriosis is \nlikely a polygenic multifactorial disease (Santamaria and Tayler \n2014), which has a genetic predisposition with a sevenfold risk of \nendometriosis in women whose mother or sister has the disease \n(Moen et al. 1993; Simpson and Bischoff 2002). Specific genes are \ndifferentially expressed in eutopic endometrium of endometriosis \npatients as compared to those from normal woman controls (Kao et \nal. 2003; Taylor et al. 2008). The results suggest that gene dysregu-\nlation may play a role in the pathogenesis of endometriosis.\nMicroRNAs (miRNAs) are single-stranded 19-25 nucleotide-long \nRNAs and have an important role in post-transcriptional gene \nsilencing by base pairing with target mRNAs (Ma et al. 2014). miRNA \n“genes” are transcribed in the nucleus, producing primary transcripts \ntermed “pri-miRNAs”. pri-miRNAs undergo substantial processing, \nresulting in the generation of a 70- to 90-nucleotide (nt) stem-loop \nprecursor miRNA (pre-miRNA) in the nucleus. After transportation \ninto the cytoplasm, the pre-miRNAs undergo a second cleavage by \nDicer, generating a double-stranded miRNA duplex containing 2-nt-\nlong 3′ overhangs. Double-stranded miRNAs unwind to form single-\nstrand, mature miRNAs (Bernstein et al. 2001,  2003; Paroo et al. \n2007). Mature miRNAs incorporate into the RNA-induced silencing \ncomplex (RISC) and regulate target gene expression mostly, but not \nalways through translational repression by complementary interac-\ntion with target genes (Bartel 2004; Zamore and Haley 2005). \nmiRNA-induced translational repression is considered to involve two \ndistinct mechanisms: the inhibition of translation initiation and/or \ninhibition of a “postinitiation” step in translation, which also elicits \ncotranslational degradation of the nascent peptide (Jackson and Stan-\ndart 2007; Nilsen 2007; Pillai et al. 2007). Through this mechanism, \nmiRNAs influence the outcome of various cellular activities under \nnormal and disease conditions. To date, it has been estimated that \n2588 unique mature human miRNAs have been identified (http://\nwww.mirbase.org/). Usually a total of 1,309 human miRNAs are \nused in analysis (Cook et al. 2015). MiRNAs are essential for normal \nmammalian development, determining cell identity and fate and \nregulating diverse biological processes including cell proliferation, \nmetabolism, differentiation and apoptosis. Recent research has shown \nthat miRNAs and their target mRNAs are differentially expressed in \nendometriosis and other disorders of the female reproductive system \n(Teague et al. 2010). miRNAs may thus be attractive candidates for \nnovel diagnostic markers and therapeutic interventions in endome-\ntriosis, as recently demonstrated in other miRNA regulated diseases \n(Elmen et al. 2008; Mitchell et al. 2008).Thus, research on the role \nof miRNAs in endometriosis has attracted much attention (Fig. 1). In \nthis paper, we review the recent progress in understanding the roles of \nmiRNAs in endometriosis, and specific miRNAs as biomarkers and \ntherapeutic targets for endometriosis.\nInstitute for Tumor Immunology, Ludong University School of Life Sciences, Shandong, China\nExpression, regulation and function of MicroRNAs in endometriosis\nPing Mu, Juhua Zhou, Xinting Ma, Guichun Zhang, Y anmin Li\nReceived December 27, 2015, accepted February 12, 2016\nJ.-H. Zhou, PhD, Institute for Tumor Immunology, Ludong University School of Life Sciences, 186 Hongqi Middle \nRoad, Yantai, Shandong 264025, PR China\nJuhua.zhou@gmail.com\nPharmazie 71: 434–438 (2016) doi: 10.1691/ph.2016.5904\nEndometriosis (EMS), characterized by the presence and growth of functional en do met rial-like tissues outside the \nuterine cavity, is a common and benign gyneco logical disorder with a poorly understood and somewhat enigmatic \netiopathogenesis and pathophysiology. MicroRNAs (miRNAs) are single-stranded 19-25 nucleotide-long RNAs \nand have an important role in post-transcriptional gene silencing by base pairing with target mRNAs. Recent \nresearch has shown that miRNAs and their target mRNAs are differentially expressed in endometriosis and other \ndisorders of the female reproductive system. In this paper, we review the recent progress in understanding the \nroles of miRNAs in endometriosis, and specific miRNAs as biomarkers and therapeutic targets for endometriosis.\nFig. 1:  Estimated number of publications about studies on miRNAs in endometriosis \nyearly from 2006 to 2014. Based on the retrieved papers from the PUBMED \ndatabase after searching related references by means of miRNA, endometrio-\nsis key words, the number of publications about the studies on miRNAs in \nendometriosis were calculated.\n2. Expression of microRNAs in endometriosis\nIn recent years, there has been a significant focus on understanding \nthe pathogenesis of endometriosis and the role of miRNAs in the \npathogenesis of the disease. It has been considered that the aber-\nrantly expressed miRNAs in endometriosis may be responsible \nfor and may stimulate the development of endometriosis (Burney \net al. 2009). Previous studies have profiled miRNA expression in \n\nREVIEW\nPharmazie 71 (2016) 435\nendometriotic implants and in the eutopic endometrium of women \nwith or without endometriosis (Burney 2009; Hawkins et al. 2011; \nOhlsson Teague et al. 2009; Pan et al. 2008). Pan et al. (2007) \nidentified 48 aberrantly expressed miRNAs in endometriosis, which \naffected a variety of target genes involved in the development of \nendometriosis, such as estrogen receptor a (ERa), ERb, progesterone \nreceptor and transforming growth factor- β. Toloubeydokhti et al. \n(2008) demonstrated an aberrant miRNA expression pattern in endo-\nmetriotic tissues. They observed repressed expression of miR-23b \nand miR-542-3p and increased expression of miR-17-5p in paired \nendometriotic tissues when compared with normal endometrium. \nFiligheddu et al. (2010) investigated the differential expression of \nmiRNAs in endometriosis by direct comparison between paired \nectopic and eutopic endometrium samples. About 50 microRNAs \nwere identified to be differentially expressed and the differential \nexpression of five microRNAs (including miR-200a, miR-200b, \nmiR-200c, -miR-182 and miR-202) was validated by real-time \nRT-PCR in other 13 patients. Indeed, these reports demonstrated that \nthere were significant differential expressions of specific miRNAs in \neutopic versus ectopic tissue. miR-200a, miR-200b, miR-200c and \nmiR-182 levels in ectopic endometrium were reduced up to 95%, \nwhile miR-202 expression in ectopic endometrium was increased up \nto 60 folds as compared to that in eutopic endometrium.\nIt has been reported that 10 miRNAs were upregulated (miR-202, \n193a-3p, 29c, 708, 509-3-5p, 574-3p, 193a-5p, 485-3p, 100 and \n720) and 12 miRNAs were downregulated (miR-504, 141, 429, \n203, 10a, 200b, 873, 200c, 200a, 449b, 375 and 34c-5p) in ovarian \nendometriotic cysts when compared with endometrium (Hawkins \n2011). Similarly, Ohlsson et al. (2009) investigated miRNA expres-\nsion profiles in paired ectopic and eutopic endometrial tissues and \nidentified 14 upregulated (miR-145, miR-143, miR-99a, miR-99b, \nmiR-126, miR-100, miR-125b, miR-150, miR-125a, miR-223, \nmiR-194, miR-365, miR-29c and miR-1) and 8 downregulated \n(miR-200a, miR-141, miR-200b, miR-142-3p, miR-424, miR-34c, \nmiR-20a and miR-196b) miRNAs.     \nInterestingly, the perturbed gene expression in eutopic secretory \nendometrium of affected patients coincides with differential expres-\nsion of several miRNA species (Burney 2009). Eutopic secretory \nendometrium from women with endometriosis is characterized by a \nmiRNA expression profile that differs from that of healthy eutopic \nsecretory endometrium. In particular, members of the miR-9 and \nmiR-34 families (i.e. miR-9, miR-34b and miR-34c-5p) are down-\nregulated in the endometrium from women with endometriosis \ncompared with healthy individuals. The predicted targets of the \nmiR-9 and miR-34 families include the cell-cycle regulator genes \ncyclin E1, cyclin E2, CDK4, CDK6 and CDC25A and the anti-apop-\ntotic gene, BCL-2, which are also differently expressed in endome-\ntrium from women with and without endometriosis (Hawkins 2011). \nSpecifically, several miRNA families including miR-9, miR-34, \nlet-7, miR-15, miR16, and miR-125 were found to be downregulated \nin eutopic secretory endometrium from women with endometriosis. \nOther miRNAs such as miR-199a and miR-122 are upregulated in \nendometriotic patients compared to non-endometriotic women (Pan \net al. 2008; Pan 2008). Total RNA extracted from serum and quanti-\ntative reverse-transcription polymerase chain reaction to determine \nlevels of miRNA let-7a-f and miR-135a,b. The levels of circulating \nlet-7b and miR-135a were statistically significantly decreased in \nwomen with endometriosis compared with controls, and let-7d and \n7f showed a trend toward downregulation. When the patients were \nanalyzed according to phase of the menstrual cycle, the expression \nof let-7b, 7c, 7d, and 7e was statistically significantly lower in the \nwomen with endometriosis during the proliferative phase. These \nresults indicated that the combination of serum let-7b, 7d, and \n7f levels during the proliferative phase may serve as a diagnostic \nmarker for endometriosis (Cho et al. 2015).\nTaken together, these findings suggest that endometriotic tissues \nhave aberrant miRNA expression patterns and these aberrantly \nexpressed miRNAs may be responsible for the pathogenesis \nof endometriosis. Upregulated and downregulated miRNAs in \ndifferent samples from the patients with endometriosis were shown \nin Table 1 and Table 2, respectively. \nTable 1:  Upregulated miRNAs expressed in different samples from \nendometriosis patients\nmiRNA Sample Reference\nmiR-145\nmiR-143\nmiR-99a \nmiR-99b \nmiR-126 \nmiR-100 \nmiR-125b \nmiR-150 \nmiR-125a \nmiR-223 \nmiR-194 \nmiR-365 \nmiR-29c \nmiR-1\nmiR-17-5p\nmiR-202\nmiR-193a-3p\nmiR-29c\nmiR-708\nmiR-509-3-5p\nmiR-574-3p\nmiR-193a-5p\nmiR-485-3p\nmiR -720\nEctopic endometrial tissues\nEndometriotic tissues\nOvarian endometriotic cysts\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Filigheddu 2010)\n(Filigheddu 2010)\n(Filigheddu 2010)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011) \nTable 2:  Downregulated miRNAs expressed in different samples from \nendometriosis patients\nmiRNA Sample Reference\nmiR-200a\nmiR-141 \nmiR-200b \nmiR-142-3p \nmiR-424 \nmiR-34c \nmiR-20a \nmiR-196b\nmiR-23b\nmiR-542-3p\nmiR -504\nmiR -141\nmiR- 429\nmiR -203\nmiR -10a\nmiR -873\nmiR -200c\nmiR -449b\nmiR -375\nmiR -34c-5p\nEctopic endometrial tissues\nEndometriotic tissues\nOvarian endometriotic cysts\n(Filigheddu 2010)\n(Hawkins 2011)\n(Filigheddu 2010)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Toloubeydokhti 2008)\n(Toloubeydokhti 2008)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n(Filigheddu 2010)\n(Hawkins 2011)\n(Hawkins 2011)\n(Hawkins 2011)\n3. Regulation and function of microRNAs in endome-\ntriosis\nThe presence of distinct miRNA profiles between endometriotic \nand nonendometriotic tissues indirectly indicates that miRNA may \nhave a function in the pathophysiology of endometriosis. Several \npathological processes such as inflammation, local estrogen biosyn-\nthesis, progesterone resistance, cell invasion, extracellular matrix \nremodelation, angiogenesis, and epigenetic regulation are crucial \nin the pathophysiology of endometriosis, miRNAs seem to have an \nessential role in regulating these processes (Santamaria and Taylor \n2014). In particular, miRNAs target the expression of genes involved \nin cell-cycle progression, differentiation, apoptosis, inflammatory and \nimmune response, and angiogenesis (Carleton et al. 2007; Harfe et al. \n2005; Jovanovic et al. 2006; Kuehbacher et al. 2008; Li et al. 2007; \nLinsley et al. 2007). These cellular processes are integrated in parts \nof the endometrial regeneration throughout the menstrual cycle and a \nvast number of gene products whose expression may be the target of \nmiRNA regulatory functions (Pan 2008) (Fig. 2).\n\nREVIEW\nPharmazie 71 (2016)436\n3.1. Regulation and function of microRNAs in infl am-\nmation of endometriosis\nThe onset of menstruation is associated with the expression of a \nnetwork of highly active substances with inflammatory and immune-\nrelated activities (Chegini et al. 2002; Jabbour et al. 2006). Abdom-\ninal local microenvironment inflammation plays an important role \nin breeding and planting of ectopic endometrial cells. MicroRNA \ninvolved in regulation of inflammatory cells to raise and the release \nof inflammatory cytokines, may play an important role in the forma-\ntion of the local microenvironment of ectopic lesions. Anyhow, \nMicroRNA may participate in raising the inflammatory cells, and \nthe formation of the inflammatory microenvironment, be benefi-\ncial to the occurrence and development of endometriosis. NF- κB \npathway is a critical path of the inflammatory cytokine release of \nectopic lesions. The study of Chen et al. showed that miR-199a \nnegatively regulates the NF – κB pathway to inhibit the expression \nof protein kinase B whereas the expression of miR-199a is reduced \nin endometriosis which may be related to the abnormal activation of \nNF – κB in ectopic endometrial cells (Dai and Di 2011).\nA recent study revealed that stromal cells from endometriosis \nlesions have higher  miR20a levels. MiR200a expression results \nin decreased expression of dual-specificity phosphatase-2 that \nsubsequently results in prolonged extracellular-signal-regulated \nkinases activation through hypoxia-inducible factor. Moreover, \nfibroblast growth factor-9 is induced by prostaglandin E2 through \nextracellular-signal-regulated kinases activation in endometriotic \nstromal cells contributing to inflammation in the pathogenesis of \nendometriosis (Lin et al. 2012; Santamaria and Taylor 2014).\n3.2. Regulation and function of microRNAs in cell sur-\nvival and cell invasion of endometriosis\nAdhesion and invasion are the key steps in the formation of \nendometriosis which has  similar transfer and erosion character-\nistics than a malignant tumor. Degradation and reshaping of extra \ncellular matrix (ECM) are essential conditions of the adhesion \nand invasion of ectopic endometrial cells, miRNA participates in \nregulating the degradation and reshaping of ECM and may have an \nimportant regulatory role in adhesion and invasion of ectopic endo-\nmetrial cells. Matrix metalloproteinase (MMP) 9 is an important \nprotein kinase which is closely related to the degradation of ECM \nand the formation of endometriosis. The expression of MMP-9 in \nthe eutopic and ectopic endometrium of endometriosis patients \nincreased to promote the degradation of the ECM and increase \nthe aggressivity of endometrial cells. MMP-9 is the target gene of \nNF – κB whereas the activation of NF – κB is negatively regulated \nby miRNA-199a which is down-expressed in endometriosis. So \nmiRNA-199a may indirectly regulate the synthesis and release of \nMMP-9 through the NF – κB pathway (Dai and Di 2011). \nThere is increasing evidence that incomplete transition of the endo-\nmetrium from proliferative to secretory phase enhances the survival \ncapacity and implantation of the refluxed endometrium. Certain \nmiRNAs such as miR-183 that are downregulated in endometriosis \nseem to be involved in this process through regulation of cell growth, \ncell differentiation, cell invasion, cell adhesion, and apoptosis. Local \ninflammation and tissue remodeling are crucial during endometrial \nrole development. The downregulation of miR-17-5p induces lower \nexpression of transforming growth factor-b and interleukin-8 and \nhigher expression of hypoxia inducible transcription factor-1a and \nvascular endothelial growth factor (VEGF)-A enhancing cell survival \nand cell proliferation in endometriosis (Flores et al. 2007; Santamaria \nand Taylor 2014; Shi et al. 2014; V olinia et al. 2006; Yu et al. 2010). \nDai and Di (2011) found miR-199a can inhibit the adhesion, migra-\ntion and invasion of the human eutopic endometrial stromal cells \n(ESC), Ikappa B kinase beta (IKKβ) is the target gene of miR-199a in \nESC, which means one of the mechanisms of the inhibition effect is \nprobably that miR-199a inhibits the activation of nuclear factor-kappa \nB (NF-κB) signaling pathway by targeting IKKβ gene.\n3.3. Regulation and function of microRNAs in angiogen-\nesis of endometriosis\nVascularization degree around the endometriosis lesions is the \nimportant factor of affecting the growth and invasion of ectopic \nendometrium. Ectopic lesions stimulate the proliferation and \nmigration of vascular endothelial cells by release of a variety of \nangiogenic factors to form new capillaries. MiRNA participates \nin the regulation of various angiogenesis factors, and may play an \nimportant role in the formation of blood vessels in endometriosis. \nFig. 2:  miRNA regulatory functions in the processes of endometriosis. miRNA expression may play a role in these processes, regulating transcripts involved in cell adhesion and \ninvasion, inflammation, cellular proliferation, apoptosis, angiogenesis, progesterone resistance and extracellular matrix remodelling.\n\nREVIEW\nPharmazie 71 (2016) 437\nStudies showed that miR-126 participates in regulating angiogen-\nesis during development as well as the vascular remodeling. This \nshows that miR-126 plays a crucial role during angiogenesis while \nit is up-expressed in endometriosis which means it may be involved \nin the blood vessel formation in endometriosis (Dai and Di 2011).\nMeanwhile, VEGF-A and the angiogenesis inhibitor thrombos-\npondin-1 (TSP-1) play an important role in the pathogenesis of \nendometriosis. Women with endometriosis showed a significant \nincrease in TSP-1 protein levels and a decrease in VEGF-A \nexpression in ovarian endometriomas compared to the eutopic \nendometrium in a recent study. While miR-125a, miR-222, and \nmiR-17-5p showed a significant inverse correlation with VEGF-A \nand TSP-1 protein levels, suggesting that the expression of TSP-1 \nand VEGF-A may be regulated by these miRNAs (Santamaria and \nTaylor 2014). Additionally, some miRNAs have demonstrated anti-\nangiogenic properties (miRNA-15b, -16, -221, and -222), whereas \nothers are proangiogenic (miRNA-17-92 cluster) (Santamaria and \nTaylor 2014; Urbich et al. 2008; Wu et al. 2009).\nIn an another recent study (Braza-Boils et al. 2014), endometrial \ntissue showed significantly lower levels of miR-202-3p, miR-424-5p, \nmiR-449b-3p and miR-556-3p, and higher levels of VEGF-A and \nuPA than healthy (control) endometrium. However, tissue affected \nby ovarian endometrioma showed significantly lower expression of \nmiR-449b-3p than endometrium from both controls and patients, \nand higher levels of PAI-1 and the angiogenic inhibitor TSP-1. A \nsignificant inverse correlation between miR-424-5p and VEGF-A \nprotein levels was observed in patient endometrium, and an inverse \ncorrelation between miR-449b-3p and TSP-1 protein levels was \nobserved in ovarian endometrioma. Peritoneal implants had signifi-\ncantly higher levels of VEGF-A than ovarian endometrioma. These \nresults suggest that differences in miRNA levels could modulate the \nexpression of VEGF-A and TSP-1, which may play an important \nrole in the pathogenesis of endometriosis. The higher angiogenic and \nproteolytic activities observed in eutopic endometrium from patients \nmight facilitate the implantation of endometrial cells at ectopic sites.\n3.4. Regulation and function of microRNAs in prolifera-\ntion and apoptosis of endometriosis\nProliferation and apoptosis are the basic processes of sustaining the \ngrowth and stability of ectopic endometrial cells and are regulated by \nmultiple genes whose expression may be regulated by miRNA. Insulin \nreceptor substrate1 (IRSI) is a gene related to cell growth which is \nclosely associated with insulin biological regulation  and can promote \ncell proliferation. IRSI is the target gene of miR-126 and miR-145. \nA study showed that both of these miRNA are up-expressed in endo-\nmetriosis suggesting that they play an important role in suppressing \nectopic endometrial cell growth. In addition, transforming growth \nfactor (TGF) B is also regulated by miRNA. miR-21 and miR-141 \nrespectively inhibit the transcription of TGFβ-1 and TGFβ-2 whereas \nthe expression of miR-21 and miR-141 decreases in endome-\ntriosis. Thus it can be seen that miR-21 and miR-141 are involved in \npromoting the transcription of TGFβ and participate in regulating the \nectopic endometrium cell growth (Dai and Di 2011). \nBcl-2 is an important apoptosis suppressor gene. It is high \nexpressed in ectopic endometrial cells and negatively correlated \nwith the incidence of apoptosis. Xia et al. showed that bcl-2 is the \ntarget gene of miR-15b/16 while miR-15b/16 is down-expressed \nin endometriosis which means miR-15b/16 may be related with \nthe increase of antiapoptotic proteins in ectopic endometrial cells \n(Dai and Di 2011). \nSeveral miRNAs are aberrantly expressed in endometriotic cyst \nstromal cells (ECSCs), including miR-196b whose expression \nis repressed in endometriotic stromal cells. The anti-apoptotic \nand excessive proliferative properties of endometriotic cells are \nconsidered to be involved in the development and progression of \nendometriosis. Abe et al. (2013) identified eight downregulated \nmiRNAs (including miR-196b) and four upregulated miRNAs in \nECSCs by miRNA microarray analysis. Compulsory expression of \nmiR-196b directed the inhibition of proliferation and the induction \nof apoptosis in ECSCs. MiR-196b was found to suppress c-myc \nand Bcl-2 mRNA expression in ECSCs, and there was a signifi-\ncant correlation between miR-196b and HOXA10 expression in \nECSCs and NESCs. The miR-196b gene was hypermethylated \nin ECSCs when compared with NESCs, and the treatment with a \nDNA demethylating agent restored the expression of miR-196b in \nECSCs. These findings suggest that aberrant miRNA expression \nplays an important role in the pathogenesis of endometriosis as \na part of epigenetic mechanisms, that expression of miR-196b in \nECSCs is repressed by DNA hypermethylation of the miR-196b \ngene and this repression may be involved in the development of \nproliferative and anti-apoptotic characteristics of endometriosis \n(Abe et al. 2013).\n4. microRNAs as endometriosis diagnostic markers \nEndometriosis is generally diagnosed by visualization of the \nendometriotic lesions  and the current gold standard technique for \ndiagnosis of endometriosis is surgical assessment by laparoscopy. \nFor this reason, diagnosis and intervention in this disease are often \ndelayed. This delay is further compounded by the absence of symp-\ntoms in some patients and lack of sensitive biomarkers for detecting \nearly stage disease (Guo 2009; Santamaria and Taylor 2014). There-\nfore, newer and less invasive diagnostic and therapeutic tools for \ndisease diagnosis and therapy in the early stages are required. \nResults have demonstrated that miR-17-5p, miR-20a, and miR22 \nwere downregulated in women with endometriosis compared to \nnon-endometriotic women (Jia et al. 2013). Several miRNAs have \nbeen assessed not only as potential diagnostic markers, but also \nas markers associated with the distinct clinical features of the \ndisease (Resnick et al. 2009). Among six dysregulated miRNAs \nanalyzed in this study, miR-199a and miR-122 were upregulated \nin patient serum and could be used to differentiate between severe \nand mild endometriosis. Further analysis also indicated that the \nrelative concentration of miR-122 might be correlated with that of \nmiR-199a. Among them, miR-199a and miR-542-3p were found \nto be particularly useful, when combined reaching a sensitivity \nand a specificity in diagnosing endometriosis of up to 96.61% and \n79.66%, respectively (Yu et al. 2012). In addition, miR-199a is \ncorrelated with pelvic adhesion and lesion distribution as well as \nwith hormone-mediated signaling pathways, demonstrating that it \nmay play an important role in the progression of the disease (Hull \nand Nisenblat 2013). \nWomen with endometriosis have characteristic differences in \neutopic endometrial transcript and protein profiles when compared \nwith women without endometriosis. Several researchers have tried \nto develop a semi-invasive test for endometriosis by analyzing \neutopic endometrial biopsies obtained at an outpatient clinic visit. \nIt seems reasonable to postulate that the eutopic endometrial \nmiRNA profile can be used to distinguish eutopic endometrium \nfrom women with and without endometriosis in a simple, reliable \nway with good sensitivity and specificity (Teague 2010). A recent \nstudy identified three distinct miRNA signatures with reliable \ndifferential expression between healthy individuals, patients with \nendometriosis, and patients with endometriosis-associated ovarian \ncancer (EAOC). When profiled against the control serous ovarian \ncancer (SOC) category, the results revealed different miRNAs, \nsuggesting that the identified signatures are reflective of disease-\nspecific pathogenic mechanisms. This study reports that distinct \nplasma miRNA expression patterns may serve as highly specific \nand sensitive diagnostic biomarkers to discriminate between \nhealthy, endometriosis, and endometriosis-associated ovarian \ncancer (EAOC) cases (Suryawanshi et al. 2013).\nA strong correlation was demonstrated between the miRNA profiles \nof serum and cancer tissue in patients with ovarian cancer (Resnick \n2009; Taylor 2008), suggesting that miRNAs may be secreted from \ntissues into the bloodstream. If endometriosis associated miRNAs \ncan be identified in serum, a non-invasive blood test could be devel-\noped to diagnose this chronic condition (Teague 2010). 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