Expression, regulation and function of MicroRNAs in endometriosis

indicated that the combination of serum let-7b, 7d, and 7f levels during the proliferative phase may serve as a diagnostic marker for endometriosis (Cho et al. 2015). Taken together, these findings suggest that endometriotic tissues have aberrant miRNA expression patterns and these aberrantly expressed miRNAs may be responsible for the pathogenesis of endometriosis. Upregulated and downregulated miRNAs in different samples from the patients with endometriosis were shown in Table 1 and Table 2, respectively. Table 1: Upregulated miRNAs expressed in different samples from endometriosis patients miRNA Sample Reference 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 miR-1 miR-17-5p miR-202 miR-193a-3p miR-29c miR-708 miR-509-3-5p miR-574-3p miR-193a-5p miR-485-3p miR -720 Ectopic endometrial tissues Endometriotic tissues Ovarian endometriotic cysts (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Filigheddu 2010) (Filigheddu 2010) (Filigheddu 2010) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) Table 2: Downregulated miRNAs expressed in different samples from endometriosis patients miRNA Sample Reference miR-200a miR-141 miR-200b miR-142-3p miR-424 miR-34c miR-20a miR-196b miR-23b miR-542-3p miR -504 miR -141 miR- 429 miR -203 miR -10a miR -873 miR -200c miR -449b miR -375 miR -34c-5p Ectopic endometrial tissues Endometriotic tissues Ovarian endometriotic cysts (Filigheddu 2010) (Hawkins 2011) (Filigheddu 2010) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Toloubeydokhti 2008) (Toloubeydokhti 2008) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) (Filigheddu 2010) (Hawkins 2011) (Hawkins 2011) (Hawkins 2011) 3. Regulation and function of microRNAs in endome- triosis The presence of distinct miRNA profiles between endometriotic and nonendometriotic tissues indirectly indicates that miRNA may have a function in the pathophysiology of endometriosis. Several pathological processes such as inflammation, local estrogen biosyn- thesis, progesterone resistance, cell invasion, extracellular matrix remodelation, angiogenesis, and epigenetic regulation are crucial in the pathophysiology of endometriosis, miRNAs seem to have an essential role in regulating these processes (Santamaria and Taylor 2014). In particular, miRNAs target the expression of genes involved in cell-cycle progression, differentiation, apoptosis, inflammatory and immune response, and angiogenesis (Carleton et al. 2007; Harfe et al. 2005; Jovanovic et al. 2006; Kuehbacher et al. 2008; Li et al. 2007; Linsley et al. 2007). These cellular processes are integrated in parts of the endometrial regeneration throughout the menstrual cycle and a vast number of gene products whose expression may be the target of miRNA regulatory functions (Pan 2008) (Fig. 2). REVIEW Pharmazie 71 (2016)436 3.1. Regulation and function of microRNAs in infl am- mation of endometriosis The onset of menstruation is associated with the expression of a network of highly active substances with inflammatory and immune- related activities (Chegini et al. 2002; Jabbour et al. 2006). Abdom- inal local microenvironment inflammation plays an important role in breeding and planting of ectopic endometrial cells. MicroRNA involved in regulation of inflammatory cells to raise and the release of inflammatory cytokines, may play an important role in the forma- tion of the local microenvironment of ectopic lesions. Anyhow, MicroRNA may participate in raising the inflammatory cells, and the formation of the inflammatory microenvironment, be benefi- cial to the occurrence and development of endometriosis. NF- κB pathway is a critical path of the inflammatory cytokine release of ectopic lesions. The study of Chen et al. showed that miR-199a negatively regulates the NF – κB pathway to inhibit the expression of protein kinase B whereas the expression of miR-199a is reduced in endometriosis which may be related to the abnormal activation of NF – κB in ectopic endometrial cells (Dai and Di 2011). A recent study revealed that stromal cells from endometriosis lesions have higher miR20a levels. MiR200a expression results in decreased expression of dual-specificity phosphatase-2 that subsequently results in prolonged extracellular-signal-regulated kinases activation through hypoxia-inducible factor. Moreover, fibroblast growth factor-9 is induced by prostaglandin E2 through extracellular-signal-regulated kinases activation in endometriotic stromal cells contributing to inflammation in the pathogenesis of endometriosis (Lin et al. 2012; Santamaria and Taylor 2014). 3.2. Regulation and function of microRNAs in cell sur- vival and cell invasion of endometriosis Adhesion and invasion are the key steps in the formation of endometriosis which has similar transfer and erosion character- istics than a malignant tumor. Degradation and reshaping of extra cellular matrix (ECM) are essential conditions of the adhesion and invasion of ectopic endometrial cells, miRNA participates in regulating the degradation and reshaping of ECM and may have an important regulatory role in adhesion and invasion of ectopic endo- metrial cells. Matrix metalloproteinase (MMP) 9 is an important protein kinase which is closely related to the degradation of ECM and the formation of endometriosis. The expression of MMP-9 in the eutopic and ectopic endometrium of endometriosis patients increased to promote the degradation of the ECM and increase the aggressivity of endometrial cells. MMP-9 is the target gene of NF – κB whereas the activation of NF – κB is negatively regulated by miRNA-199a which is down-expressed in endometriosis. So miRNA-199a may indirectly regulate the synthesis and release of MMP-9 through the NF – κB pathway (Dai and Di 2011). There is increasing evidence that incomplete transition of the endo- metrium from proliferative to secretory phase enhances the survival capacity and implantation of the refluxed endometrium. Certain miRNAs such as miR-183 that are downregulated in endometriosis seem to be involved in this process through regulation of cell growth, cell differentiation, cell invasion, cell adhesion, and apoptosis. Local inflammation and tissue remodeling are crucial during endometrial role development. The downregulation of miR-17-5p induces lower expression of transforming growth factor-b and interleukin-8 and higher expression of hypoxia inducible transcription factor-1a and vascular endothelial growth factor (VEGF)-A enhancing cell survival and cell proliferation in endometriosis (Flores et al. 2007; Santamaria and Taylor 2014; Shi et al. 2014; V olinia et al. 2006; Yu et al. 2010). Dai and Di (2011) found miR-199a can inhibit the adhesion, migra- tion and invasion of the human eutopic endometrial stromal cells (ESC), Ikappa B kinase beta (IKKβ) is the target gene of miR-199a in ESC, which means one of the mechanisms of the inhibition effect is probably that miR-199a inhibits the activation of nuclear factor-kappa B (NF-κB) signaling pathway by targeting IKKβ gene. 3.3. Regulation and function of microRNAs in angiogen- esis of endometriosis Vascularization degree around the endometriosis lesions is the important factor of affecting the growth and invasion of ectopic endometrium. Ectopic lesions stimulate the proliferation and migration of vascular endothelial cells by release of a variety of angiogenic factors to form new capillaries. MiRNA participates in the regulation of various angiogenesis factors, and may play an important role in the formation of blood vessels in endometriosis. Fig. 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 invasion, inflammation, cellular proliferation, apoptosis, angiogenesis, progesterone resistance and extracellular matrix remodelling. REVIEW Pharmazie 71 (2016) 437 Studies showed that miR-126 participates in regulating angiogen- esis during development as well as the vascular remodeling. This shows that miR-126 plays a crucial role during angiogenesis while it is up-expressed in endometriosis which means it may be involved in the blood vessel formation in endometriosis (Dai and Di 2011). Meanwhile, VEGF-A and the angiogenesis inhibitor thrombos- pondin-1 (TSP-1) play an important role in the pathogenesis of endometriosis. Women with endometriosis showed a significant increase in TSP-1 protein levels and a decrease in VEGF-A expression in ovarian endometriomas compared to the eutopic endometrium in a recent study. While miR-125a, miR-222, and miR-17-5p showed a significant inverse correlation with VEGF-A and TSP-1 protein levels, suggesting that the expression of TSP-1 and VEGF-A may be regulated by these miRNAs (Santamaria and Taylor 2014). Additionally, some miRNAs have demonstrated anti- angiogenic properties (miRNA-15b, -16, -221, and -222), whereas others are proangiogenic (miRNA-17-92 cluster) (Santamaria and Taylor 2014; Urbich et al. 2008; Wu et al. 2009). In an another recent study (Braza-Boils et al. 2014), endometrial tissue showed significantly lower levels of miR-202-3p, miR-424-5p, miR-449b-3p and miR-556-3p, and higher levels of VEGF-A and uPA than healthy (control) endometrium. However, tissue affected by ovarian endometrioma showed significantly lower expression of miR-449b-3p than endometrium from both controls and patients, and higher levels of PAI-1 and the angiogenic inhibitor TSP-1. A significant inverse correlation between miR-424-5p and VEGF-A protein levels was observed in patient endometrium, and an inverse correlation between miR-449b-3p and TSP-1 protein levels was observed in ovarian endometrioma. Peritoneal implants had signifi- cantly higher levels of VEGF-A than ovarian endometrioma. These

suggest that differences in miRNA levels could modulate the expression of VEGF-A and TSP-1, which may play an important role in the pathogenesis of endometriosis. The higher angiogenic and proteolytic activities observed in eutopic endometrium from patients might facilitate the implantation of endometrial cells at ectopic sites. 3.4. Regulation and function of microRNAs in prolifera- tion and apoptosis of endometriosis Proliferation and apoptosis are the basic processes of sustaining the growth and stability of ectopic endometrial cells and are regulated by multiple genes whose expression may be regulated by miRNA. Insulin receptor substrate1 (IRSI) is a gene related to cell growth which is closely associated with insulin biological regulation and can promote cell proliferation. IRSI is the target gene of miR-126 and miR-145. A study showed that both of these miRNA are up-expressed in endo- metriosis suggesting that they play an important role in suppressing ectopic endometrial cell growth. In addition, transforming growth factor (TGF) B is also regulated by miRNA. miR-21 and miR-141 respectively inhibit the transcription of TGFβ-1 and TGFβ-2 whereas the expression of miR-21 and miR-141 decreases in endome- triosis. Thus it can be seen that miR-21 and miR-141 are involved in promoting the transcription of TGFβ and participate in regulating the ectopic endometrium cell growth (Dai and Di 2011). Bcl-2 is an important apoptosis suppressor gene. It is high expressed in ectopic endometrial cells and negatively correlated with the incidence of apoptosis. Xia et al. showed that bcl-2 is the target gene of miR-15b/16 while miR-15b/16 is down-expressed in endometriosis which means miR-15b/16 may be related with the increase of antiapoptotic proteins in ectopic endometrial cells (Dai and Di 2011). Several miRNAs are aberrantly expressed in endometriotic cyst stromal cells (ECSCs), including miR-196b whose expression is repressed in endometriotic stromal cells. The anti-apoptotic and excessive proliferative properties of endometriotic cells are considered to be involved in the development and progression of endometriosis. Abe et al. (2013) identified eight downregulated miRNAs (including miR-196b) and four upregulated miRNAs in ECSCs by miRNA microarray analysis. Compulsory expression of miR-196b directed the inhibition of proliferation and the induction of apoptosis in ECSCs. MiR-196b was found to suppress c-myc and Bcl-2 mRNA expression in ECSCs, and there was a signifi- cant correlation between miR-196b and HOXA10 expression in ECSCs and NESCs. The miR-196b gene was hypermethylated in ECSCs when compared with NESCs, and the treatment with a DNA demethylating agent restored the expression of miR-196b in ECSCs. These findings suggest that aberrant miRNA expression plays an important role in the pathogenesis of endometriosis as a part of epigenetic mechanisms, that expression of miR-196b in ECSCs is repressed by DNA hypermethylation of the miR-196b gene and this repression may be involved in the development of proliferative and anti-apoptotic characteristics of endometriosis (Abe et al. 2013). 4. microRNAs as endometriosis diagnostic markers Endometriosis is generally diagnosed by visualization of the endometriotic lesions and the current gold standard technique for diagnosis of endometriosis is surgical assessment by laparoscopy. For this reason, diagnosis and intervention in this disease are often delayed. This delay is further compounded by the absence of symp- toms in some patients and lack of sensitive biomarkers for detecting early stage disease (Guo 2009; Santamaria and Taylor 2014). There- fore, newer and less invasive diagnostic and therapeutic tools for disease diagnosis and therapy in the early stages are required.

have demonstrated that miR-17-5p, miR-20a, and miR22 were downregulated in women with endometriosis compared to non-endometriotic women (Jia et al. 2013). Several miRNAs have been assessed not only as potential diagnostic markers, but also as markers associated with the distinct clinical features of the disease (Resnick et al. 2009). Among six dysregulated miRNAs analyzed in this study, miR-199a and miR-122 were upregulated in patient serum and could be used to differentiate between severe and mild endometriosis. Further analysis also indicated that the relative concentration of miR-122 might be correlated with that of miR-199a. Among them, miR-199a and miR-542-3p were found to be particularly useful, when combined reaching a sensitivity and a specificity in diagnosing endometriosis of up to 96.61% and 79.66%, respectively (Yu et al. 2012). In addition, miR-199a is correlated with pelvic adhesion and lesion distribution as well as with hormone-mediated signaling pathways, demonstrating that it may play an important role in the progression of the disease (Hull and Nisenblat 2013). Women with endometriosis have characteristic differences in eutopic endometrial transcript and protein profiles when compared with women without endometriosis. Several researchers have tried to develop a semi-invasive test for endometriosis by analyzing eutopic endometrial biopsies obtained at an outpatient clinic visit. It seems reasonable to postulate that the eutopic endometrial miRNA profile can be used to distinguish eutopic endometrium from women with and without endometriosis in a simple, reliable way with good sensitivity and specificity (Teague 2010). A recent study identified three distinct miRNA signatures with reliable differential expression between healthy individuals, patients with endometriosis, and patients with endometriosis-associated ovarian cancer (EAOC). When profiled against the control serous ovarian cancer (SOC) category, the results revealed different miRNAs, suggesting that the identified signatures are reflective of disease- specific pathogenic mechanisms. This study reports that distinct plasma miRNA expression patterns may serve as highly specific and sensitive diagnostic biomarkers to discriminate between healthy, endometriosis, and endometriosis-associated ovarian cancer (EAOC) cases (Suryawanshi et al. 2013). A strong correlation was demonstrated between the miRNA profiles of serum and cancer tissue in patients with ovarian cancer (Resnick 2009; Taylor 2008), suggesting that miRNAs may be secreted from tissues into the bloodstream. If endometriosis associated miRNAs can be identified in serum, a non-invasive blood test could be devel- oped to diagnose this chronic condition (Teague 2010). Therefore, studies on the expression, regulation and function of miRNAs in patients with endometriosis will provide the unique insights for the development of specific miRNAs as diagnostic markers and thera- peutic targets for endometriosis in the future. REVIEW Pharmazie 71 (2016)438

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