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Xie C, Lu C, Lv N, Kong W, Liu Y. Identification and analysis of oxidative stress-related genes in endometriosis. Front Immunol 2025; 16:1515490. [PMID: 40124382 PMCID: PMC11925871 DOI: 10.3389/fimmu.2025.1515490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
Background Early diagnosis and treatment of endometriosis (EM) remain challenging because of the lack of knowledge about EM development. While oxidative stress (OS) has been associated with EM, the link is unclear. We explored OS-related genes (OSRGs) and their role in EM pathogenesis. Material and methods We combined two ectopic endometrium (EC) and eutopic endometrium (EU) datasets (GSE11691 and GSE25628) into a dataset for analysis. Bioinformatic analyses were used to identify differentially expressed genes (DEGs), OS-related genes (OSRGs), enriched pathways, competitive endogenous RNA network, and immune cell infiltration. Finally, real time-quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) were used to validate the expression of key OSRGs in clinical patient samples. Results Bioinformatic analysis identified 459 DEGs between EC and EU samples, including 67 OSRGs. A ceRNA network was established, encompassing 28 DE-OSRGs, 32 miRNAs, and 53 lncRNAs. Four key OSRGs (CYP17A1, NR3C1, ENO2, and NGF) were selected from protein-protein interaction network analysis. The RT-qPCR and WB analysis showed that these genes' abnormal changes in RNA and protein levels were consistent with data in public databases. Weighted gene co-expression network analysis identified three immune-related OSRGs (CYP17A1, NR3C1, and NGF) and 20 lncRNAs that may regulate NR3C1 through 10 miRNAs. Conclusion The key OSRGs may function via multilayered networks in EM. We provide insights into EM and underscore the potential significance of OSRGs and the immune environment for diagnostic and prognosis evaluation.
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Affiliation(s)
| | | | | | | | - Yong Liu
- Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
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2
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Parvin A, Erabi G, Mohammadpour D, Maleki-Kakelar H, Sadeghpour S, Pashaei MR, Taheri-Anganeh M, Ghasemnejad-Berenji H. Infertility: Focus on the therapeutic potential of extracellular vesicles. Reprod Biol 2024; 24:100925. [PMID: 39018753 DOI: 10.1016/j.repbio.2024.100925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/28/2024] [Accepted: 07/05/2024] [Indexed: 07/19/2024]
Abstract
Infertility is a well-known problem that arises from a variety of reproductive diseases. Until now, researchers have tried various methods to restore fertility, including medication specific to the cause, hormone treatments, surgical removals, and assisted reproductive technologies. While these methods do produce results, they do not consistently lead to fertility restoration in every instance. The use of exosome therapy has significant potential in treating infertility in patients. This is because exosomes, microvesicles, and apoptotic bodies, which are different types of vesicles, play a crucial role in transferring bioactive molecules that aid in cell-to-cell communication. Reproductive fluids can transport a variety of molecular cargos, such as miRNAs, mRNAs, proteins, lipids, and DNA molecules. The percentage of these cargos in the fluids can be linked to their physiological and pathological status. EVs are involved in several physiological and pathological processes and offer interesting non-cellular therapeutic possibilities to treat infertility. EVs (extracellular vesicles) transplantation has been shown in many studies to be a key part of regenerating different parts of the reproductive system, including the production of oocytes and the start of sperm production. Nevertheless, the existing evidence necessitates testifying to the effectiveness of injecting EVs in resolving reproductive problems among humans. This review focuses on the current literature about infertility issues in both females and males, specifically examining the potential treatments involving extracellular vesicles (EVs).
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Affiliation(s)
- Ali Parvin
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Gisou Erabi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Donna Mohammadpour
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Hadi Maleki-Kakelar
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Sonia Sadeghpour
- Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Obstetrics & Gynecology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Reza Pashaei
- Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Hojat Ghasemnejad-Berenji
- Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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3
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Zervou MI, Tarlatzis BC, Grimbizis GF, Spandidos DA, Niewold TB, Goulielmos GN. Association of endometriosis with Sjögren's syndrome: Genetic insights (Review). Int J Mol Med 2024; 53:20. [PMID: 38186322 PMCID: PMC10781419 DOI: 10.3892/ijmm.2024.5344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 12/20/2023] [Indexed: 01/09/2024] Open
Abstract
Patients with a history of endometriosis have an increased risk of developing various autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and celiac disease. There is a potential association between endometriosis and an increased susceptibility for Sjögren's syndrome (SS). SS is a common chronic, inflammatory, systemic, autoimmune, multifactorial disease of complex pathology, with genetic, epigenetic and environmental factors contributing to the development of this condition. It occurs in 0.5‑1% of the population, is characterized by the presence of ocular dryness, lymphocytic infiltrations and contributes to neurological, gastrointestinal, vascular and dermatological manifestations. Endometriosis is an inflammatory, estrogen‑dependent, multifactorial, heterogeneous gynecological disease, affecting ≤10% of reproductive‑age women. It is characterized by the occurrence of endometrial tissue outside the uterine cavity, mainly in the pelvic cavity, and is associated with pelvic pain, dysmenorrhea, deep dyspareunia and either subfertility or infertility. It is still unclear whether SS appears as a secondary response to endometriosis, or it is developed due to any potential shared mechanisms of these conditions. The aim of the present review was to explore further the biological basis only of the co‑occurrence of these disorders but not their association at clinical basis, focusing on the analysis of the partially shared genetic background between endometriosis and SS, and the clarification of the possible similarities in the underlying pathogenetic mechanisms and the relevant molecular pathways.
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Affiliation(s)
- Maria I. Zervou
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71403 Heraklion, Greece
| | - Basil C. Tarlatzis
- First Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Grigoris F. Grimbizis
- Unit for Human Reproduction, First Department of Obstetrics and Gynecology, 'Papageorgiou' General Hospital, Aristotle University Medical School, 56403 Thessaloniki, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71403 Heraklion, Greece
| | - Timothy B. Niewold
- Barbara Volcker Center for Women and Rheumatic Disease, New York, NY 10021, USA
- Hospital for Special Surgery, New York, NY 10021, USA
| | - George N. Goulielmos
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71403 Heraklion, Greece
- Department of Internal Medicine, University Hospital of Heraklion, 71500 Heraklion, Greece
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4
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Shi J, Qi Y, Sun Y, Huang Y. Kallikrein-Related Peptidase 4 Promotes Proliferation, Migration, Invasion, and Pro-Angiogenesis of Endometrial Stromal Cells via Regulation of Brain-Derived Neurotrophic Factor Production in Endometriosis. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:121-134. [PMID: 37918799 DOI: 10.1016/j.ajpath.2023.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 09/08/2023] [Accepted: 10/02/2023] [Indexed: 11/04/2023]
Abstract
Endometriosis is a common benign gynecologic condition. Endometriosis lesions are associated with endometrial cell proliferation, migration, invasion, and neovascularization, while the specific molecular mechanisms are still elusive. Transcriptome sequencing has been used for the identification of diagnostic markers in endometriosis. Here, transcriptome profiling revealed that kallikrein-related peptidase 4 (KLK4) expression was up-regulated in ectopic endometrium (EC) tissues of patients with endometriosis. KLK4 mediates the degradation of extracellular matrix proteins, and its proteolytic activity activates many tumorigenic and metastatic pathways via tumor invasion and migration. Nevertheless, whether KLK4 serves as an important regulatory factor in endometriosis remains unclear. This study confirmed that KLK4 was highly expressed in ectopic endometrial stromal cells (EC-ESCs). KLK4 overexpression promoted proliferation and suppressed apoptosis of EC-ESCs, induced cell migration and invasion, and enhanced angiogenesis in vivo. Mechanistically, KLK4 overexpression mediated the protein cleavage of pro-brain-derived neurotrophic factor in EC-ESCs. Finally, brain-derived neurotrophic factor was a vital downstream substrate of KLK4 maintained the proliferation, metastasis, and pro-angiogenesis abilities and inhibited apoptosis of ESCs through a rescue study. Together, these findings demonstrate the promotive role of KLK4 in endometriosis development. In addition, the study provides a new insight that KLK4 might be a potential therapeutic target and prognostic marker for patients with endometriosis.
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Affiliation(s)
- Jingwen Shi
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yue Qi
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yuanchen Sun
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China
| | - Ying Huang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.
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5
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Banerjee S, Xu W, Doctor A, Driss A, Nezhat C, Sidell N, Taylor RN, Thompson WE, Chowdhury I. TNFα-induced altered miRNA expression links to NF-κB signaling pathway in endometriosis. RESEARCH SQUARE 2023:rs.3.rs-2870585. [PMID: 37205467 PMCID: PMC10187425 DOI: 10.21203/rs.3.rs-2870585/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Endometriosis is a common gynecological inflammatory disorder characterized by immune system dysregulation, which is involved in lesion initiation and progression. Studies have demonstrated that several cytokines are associated with the evolution of endometriosis, including tumor necrosis factor-α (TNFα). TNFα is a non-glycosylated cytokine protein with potent inflammatory, cytotoxic, and angiogenic potential. In the current study, we examined the ability of TNFα to induce dysregulation of microRNAs (miRNAs) linked to NFkB-signaling pathways, thus contributing to the pathogenesis of endometriosis. Using RT-QPCR, the expression of several miRNAs were quantified in primary cells derived from eutopic endometrium of endometriosis subjects (EESC) and normal endometrial stromal cells (NESC) and also TNFα treated NESCs. The phosphorylation of the pro-inflammatory molecule NF-κB and the candidates of the survival pathways PI3K, AKT and ERK was measured by westernblot analysis. The elevated secretion of TNFα in EESCs downregulates the expression level of several miRNAs significantly (p < 0.05) in EESCs compared to NESC. Also treatment of NESCs with exogenous TNFα significantly reduced the expression of miRNAs in a dose-dependent manner to levels similar to EESCs. In addition, TNFα significantly increased the phosphorylation of the PI3K, AKT, ERK, and NF-κB signaling pathways. Notably, treatment with curcumin (CUR, diferuloylmethane), an anti-inflammatory polyphenol, significantly increased the expression of dysregulated miRNAs in EESC in a dose-dependent manner. Our findings demonstrate that TNFα is upregulated in EESCs, which subsequently dysregulates the expression of miRNAs, contributing to the pathophysiology of endometriotic cells. CUR effectively inhibits the expression of TNFα, subsequently altering miRNA levels and suppresses the phosphorylation of AKT, ERK, and NF-κB.
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Affiliation(s)
| | - Wei Xu
- Morehouse School of Medicine
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6
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Martino S, Tammaro C, Misso G, Falco M, Scrima M, Bocchetti M, Rea I, De Stefano L, Caraglia M. microRNA Detection via Nanostructured Biochips for Early Cancer Diagnostics. Int J Mol Sci 2023; 24:7762. [PMID: 37175469 PMCID: PMC10178165 DOI: 10.3390/ijms24097762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/15/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
MicroRNA (miRNA) are constituted of approximately 22 nucleotides and play an important role in the regulation of many physiological functions and diseases. In the last 10 years, an increasing interest has been recorded in studying the expression profile of miRNAs in cancer. Real time-quantitative polymerase chain reaction (RT-qPCR), microarrays, and small RNA sequencing represent the gold standard techniques used in the last 30 years as detection methods. The advent of nanotechnology has allowed the fabrication of nanostructured biosensors which are widely exploited in the diagnostic field. Nanostructured biosensors offer many advantages: (i) their small size allows the construction of portable, wearable, and low-cost products; (ii) the large surface-volume ratio enables the loading of a great number of biorecognition elements (e.g., probes, receptors); and (iii) direct contact of the recognition element with the analyte increases the sensitivity and specificity inducing low limits of detection (LOD). In this review, the role of nanostructured biosensors in miRNA detection is explored, focusing on electrochemical and optical sensing. In particular, four types of nanomaterials (metallic nanoparticles, graphene oxide, quantum dots, and nanostructured polymers) are reported for both detection strategies with the aim to show their distinct properties and applications.
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Affiliation(s)
- Sara Martino
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (C.T.); (M.F.); (M.B.); (M.C.)
- Unit of Naples, National Research Council, Institute of Applied Sciences and Intelligent Systems, 80138 Naples, Italy;
| | - Chiara Tammaro
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (C.T.); (M.F.); (M.B.); (M.C.)
| | - Gabriella Misso
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (C.T.); (M.F.); (M.B.); (M.C.)
| | - Michela Falco
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (C.T.); (M.F.); (M.B.); (M.C.)
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy;
| | - Marianna Scrima
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy;
| | - Marco Bocchetti
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (C.T.); (M.F.); (M.B.); (M.C.)
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy;
| | - Ilaria Rea
- Unit of Naples, National Research Council, Institute of Applied Sciences and Intelligent Systems, 80138 Naples, Italy;
| | - Luca De Stefano
- Unit of Naples, National Research Council, Institute of Applied Sciences and Intelligent Systems, 80138 Naples, Italy;
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (C.T.); (M.F.); (M.B.); (M.C.)
- Laboratory of Molecular and Precision Oncology, Biogem Scarl, Institute of Genetic Research, 83031 Ariano Irpino, Italy;
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7
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Antonio LGL, Meola J, Rosa-e-Silva ACJDS, Nogueira AA, Candido dos Reis FJ, Poli-Neto OB, Rosa-e-Silva JC. Altered Differential Expression of Genes and microRNAs Related to Adhesion and Apoptosis Pathways in Patients with Different Phenotypes of Endometriosis. Int J Mol Sci 2023; 24:ijms24054434. [PMID: 36901866 PMCID: PMC10002379 DOI: 10.3390/ijms24054434] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 03/12/2023] Open
Abstract
We aim to investigate the expression of genes (MAPK1 and CAPN2) and microRNAs (miR-30a-5p, miR-7-5p, miR-143-3p, and miR-93-5p) involved in adhesion and apoptosis pathways in superficial peritoneal endometriosis (SE), deep infiltrating endometriosis (DE), and ovarian endometrioma (OE), and to evaluate whether these lesions share the same pathophysiological mechanisms. We used samples of SE (n = 10), DE (n = 10), and OE (n = 10), and endometrial biopsies of these respective patients affected with endometriosis under treatment at a tertiary University Hospital. Endometrial biopsies collected in the tubal ligation procedure from women without endometriosis comprised the control group (n = 10). Quantitative real-time polymerase chain reaction was performed. The expression of MAPK1 (p < 0.0001), miR-93-5p (p = 0.0168), and miR-7-5p (p = 0.0006) was significantly lower in the SE group than in the DE and OE groups. The expression of miR-30a (p = 0.0018) and miR-93 (p = 0.0052) was significantly upregulated in the eutopic endometrium of women with endometriosis compared to the controls. MiR-143 (p = 0.0225) expression also showed a statistical difference between the eutopic endometrium of women with endometriosis and the control group. In summary, SE showed lower pro-survival gene expression and miRNAs involved in this pathway, indicating that this phenotype has a different pathophysiological mechanism compared to DE and OE.
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Neuhausser WM, Faure-Kumar E, Mahurkar-Joshi S, Iliopoulos D, Sakkas D. Identification of miR-34-3p as a candidate follicular phase serum marker for endometriosis: a pilot study. F&S SCIENCE 2022; 3:269-278. [PMID: 35977804 DOI: 10.1016/j.xfss.2022.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/13/2022] [Accepted: 02/14/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To identify early follicular phase microribonucleic acids (miRNAs) that are altered in serum of women with endometriosis. DESIGN Case-control study. SETTING Large university-affiliated in vitro fertilization center. PATIENT(S) Women with (n = 21) and without (n = 24) endometriosis. INTERVENTION(S) Serum samples were obtained from laparoscopy-confirmed patients with endometriosis. MAIN OUTCOME MEASURE(S) The differential expression of serum miRNAs relative to controls was measured using the NanoString nCounter technology and validated by quantitative real-time polymerase chain reaction in an independent cohort of 27 patients with endometriosis and controls (n = 24). Microribonucleic acid target signaling pathways and genes were analyzed bioinformatically. A chemically modified stable miR-34-3p oligonucleotide was used to examine the effect on proliferation of VK2E6/E7 endometrial cells in vitro. RESULT(S) Eighteen miRNAs were significantly up-regulated, and 1 miRNA (hsa-miR-34c-3p) was significantly down-regulated in the follicular phase of patients with endometriosis. The analysis of target signaling pathways using TargetScan predicted regulation of the mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B, Hippo, adenosine monophosphate-activated protein kinase, transforming growth factor beta, and endometrial cancer pathways, which have been implicated in the pathogenesis of endometriosis, by these miRNAs. The analysis of sequence complementarity identified prostaglandin E2 receptor 4, interleukin 6 signal transducer, and polo-like kinase 4 genes as possible direct targets of hsa-miR-34-3p. DSDI-1, a chemically modified stable miR-34-3p oligonucleotide, reduced cell proliferation in VK2E6/E7 endometrial cells in vitro. CONCLUSION(S) The follicular phase miRNA levels are altered in serum of women with endometriosis and may be useful as reproducible detection biomarkers for early diagnosis of endometriosis. hsa-miR-34-3p is significantly down-regulated in endometriosis, targets endometriosis genes, and reduces endometrial cell proliferation in vitro. These results support hsa-miR-34-3p as a potential therapeutic target in endometriosis.
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Affiliation(s)
- Werner Maria Neuhausser
- Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | - Emmanuelle Faure-Kumar
- UCLA Center for Systems Biomedicine, David Geffen School of Medicine, Los Angeles, California
| | - Swapna Mahurkar-Joshi
- UCLA Center for Systems Biomedicine, David Geffen School of Medicine, Los Angeles, California
| | - Dimitrios Iliopoulos
- UCLA Center for Systems Biomedicine, David Geffen School of Medicine, Los Angeles, California
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The expression pattern of endometrial receptivity genes is desynchronized between endometrium and matched endometriomas. Reprod Biomed Online 2022; 45:713-720. [DOI: 10.1016/j.rbmo.2022.05.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 05/16/2022] [Accepted: 05/31/2022] [Indexed: 11/21/2022]
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Zafari N, Bahramy A, Majidi Zolbin M, Emadi Allahyari S, Farazi E, Hassannejad Z, Yekaninejad MS. microRNAs as novel diagnostic biomarkers in endometriosis patients: a systematic review and meta-analysis. Expert Rev Mol Diagn 2022; 22:479-495. [PMID: 34304687 DOI: 10.1080/14737159.2021.1960508] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 07/20/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To investigate whether miRNAs have a remarkable pooled diagnostic accuracy, sensitivity, and specificity as noninvasive biomarkers to distinguish endometriosis patients from non-endometriosis women. METHODS A comprehensive literature search of PubMed, Embase, and ProQuest was performed through February 21, 2021 to find relevant studies. Two reviewers independently screened each article, and discrepancies were resolved by consensus. Deeks' funnel plot asymmetry test was performed to assess the publication bias of included studies. The STATA software and RevMan 5.4 were used for data analysis and quality assessment, respectively. RESULTS The overall quality of the studies was moderate to high. In total 87 datasets were assessed miRNAs' performance which results in sensitivity: 0.82, specificity: 0.79, DOR: 18, NPV: 0.80, PPV: 0.78, PLR: 3.97, and NLR: 022. We conducted subgroup analyses, which showed panels of miRNAs (DOR: 54) and serum (DOR: 43) as a target tissue was more reliable to utilize as biomarkers. Deeks' funnel plot showed that there is no publication bias (P-value = 0.25). CONCLUSIONS Panels of miRNAs differentiate endometriosis patients from non-endometriosis women with high sensitivity and specificity; therefore, it has the potential to use as a noninvasive biomarker.
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Affiliation(s)
- Narges Zafari
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Afshin Bahramy
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Masoumeh Majidi Zolbin
- Pediatric Urology and Regenerative Medicine Research Center, Section of Tissue Engineering and Stem Cells Therapy, Children's Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran (IRI)
| | - Sima Emadi Allahyari
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Farazi
- Department of Medicine, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Zahra Hassannejad
- Pediatric Urology and Regenerative Medicine Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mir Saeed Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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11
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de Oliveira RZ, de Oliveira Buono F, Cressoni ACL, Penariol LBC, Padovan CC, Tozetti PA, Poli-Neto OB, Ferriani RA, Orellana MD, Rosa-E-Silva JC, Meola J. Overexpression of miR-200b-3p in Menstrual Blood-Derived Mesenchymal Stem Cells from Endometriosis Women. Reprod Sci 2022; 29:734-742. [PMID: 35075610 DOI: 10.1007/s43032-022-00860-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/19/2022] [Indexed: 01/06/2023]
Abstract
The key relationship between Sampson's theory and the presence of mesenchymal stem cells in the menstrual flow (MenSCs), as well as the changes in post-transcriptional regulatory processes as actors in the etiopathogenesis of endometriosis, are poorly understood. No study to date has investigated the imbalance of miRNAs in MenSCs related to the disease. Thus, through literature and in silico analyses, we selected four predicted miRNAs as regulators of EGR1, SNAI1, NR4A1, NR4A2, ID1, LAMC3, and FOSB involved in pathways of apoptosis, angiogenesis, response to steroid hormones, migration, differentiation, and cell proliferation. These genes are frequently overexpressed in the endometriosis condition in our group studies. They were the trigger for the miRNAs search. Therefore, a case-control study was conducted with MenSCs of women with and without endometriosis (ten samples per group). Crossing information obtained from the STRING, PubMed, miRPathDB, miRWalk, and DIANA TOOLS databases, we chose to explore the expression of miR-21-5p, miR-100-5p, miR-143-3p, and miR-200b-3p by RT-qPCR. We found an upregulation of the miR-200b-3p in endometriosis MenSCs (P = 0.0207), with a 7.93-fold change (ratio of geometric means) compared to control. Overexpression of miR-200b has been associated with increased cell proliferation, stemness, and accentuated mesenchymal-epithelial transition process in eutopic endometrium of endometriosis. We believe that dysregulated miR-200b-3p may establish primary changes in the MenSCs, thus favoring tissue implantation at the ectopic site.
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Affiliation(s)
- Rafael Zucco de Oliveira
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Fabiana de Oliveira Buono
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Ana Clara Lagazzi Cressoni
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Letícia Bruna Corrêa Penariol
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Cristiana Carolina Padovan
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Patricia Aparecida Tozetti
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Omero Benedito Poli-Neto
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
- Laboratory for Translational Data Science, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Rui Alberto Ferriani
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
- National Institute of Hormones and Women's Health (Hormona), CNPq, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil
| | - Maristela Delgado Orellana
- Center for Cell Therapy and Reginal Blood Center, University of São Paulo, Ribeirão Preto, São Paulo, 14051-140, Brazil
| | - Júlio Cesar Rosa-E-Silva
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil
- Laboratory for Translational Data Science, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil
| | - Juliana Meola
- Division of Human Reproduction, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil.
- Laboratory for Translational Data Science, Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil.
- National Institute of Hormones and Women's Health (Hormona), CNPq, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil.
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Mc Cormack BA, González-Cantó E, Agababyan C, Espinoza-Sánchez NA, Tomás-Pérez S, Llueca A, Marí-Alexandre J, Götte M, Gilabert-Estellés J. miRNAs in the Era of Personalized Medicine: From Biomarkers to Therapeutics. Int J Mol Sci 2021; 22:8154. [PMID: 34360918 PMCID: PMC8348078 DOI: 10.3390/ijms22158154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 07/07/2021] [Indexed: 11/17/2022] Open
Abstract
In recent years, interest in personalized medicine has considerably increased [...].
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Affiliation(s)
- Bárbara A. Mc Cormack
- Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Research Foundation of the General University Hospital of Valencia, 46014 Valencia, Spain; (B.A.M.C.); (E.G.-C.); (C.A.); (S.T.-P.); (J.G.-E.)
| | - Eva González-Cantó
- Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Research Foundation of the General University Hospital of Valencia, 46014 Valencia, Spain; (B.A.M.C.); (E.G.-C.); (C.A.); (S.T.-P.); (J.G.-E.)
| | - Cristina Agababyan
- Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Research Foundation of the General University Hospital of Valencia, 46014 Valencia, Spain; (B.A.M.C.); (E.G.-C.); (C.A.); (S.T.-P.); (J.G.-E.)
- Obstetrics and Gynaecology Service, General University Hospital of Valencia Consortium, 46014 Valencia, Spain
| | - Nancy A. Espinoza-Sánchez
- Research Laboratory, Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany;
| | - Sarai Tomás-Pérez
- Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Research Foundation of the General University Hospital of Valencia, 46014 Valencia, Spain; (B.A.M.C.); (E.G.-C.); (C.A.); (S.T.-P.); (J.G.-E.)
| | - Antoni Llueca
- Department of Medicine, University Jaume I, 12071 Castellón, Spain;
- Multidisciplinary Unit of Abdominal Pelvic Oncology Surgery (MUAPOS), General University Hospital of Castellón, 12004 Castellón, Spain
| | - Josep Marí-Alexandre
- Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Research Foundation of the General University Hospital of Valencia, 46014 Valencia, Spain; (B.A.M.C.); (E.G.-C.); (C.A.); (S.T.-P.); (J.G.-E.)
| | - Martin Götte
- Research Laboratory, Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany;
| | - Juan Gilabert-Estellés
- Research Laboratory in Biomarkers in Reproduction, Gynaecology and Obstetrics, Research Foundation of the General University Hospital of Valencia, 46014 Valencia, Spain; (B.A.M.C.); (E.G.-C.); (C.A.); (S.T.-P.); (J.G.-E.)
- Obstetrics and Gynaecology Service, General University Hospital of Valencia Consortium, 46014 Valencia, Spain
- Department of Paediatrics, Obstetrics and Gynaecology, University of Valencia, 46010 Valencia, Spain
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Monnaka VU, Hernandes C, Heller D, Podgaec S. Overview of miRNAs for the non-invasive diagnosis of endometriosis: evidence, challenges and strategies. A systematic review. EINSTEIN-SAO PAULO 2021; 19:eRW5704. [PMID: 33909757 PMCID: PMC8054530 DOI: 10.31744/einstein_journal/2021rw5704] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 09/03/2020] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE The aim of the study was to assess the evidence on miRNAs as biomarkers for the diagnosis of endometriosis, as well as to provide insights into the challenges and strategies associated with the use of these molecules as accessible tools in clinical practice. METHODS Systematic review conducted on PubMed®, Latin American and Caribbean Health Sciences Literature (LILACS), MEDLINE® and Web of Science databases using the search terms endometriosis (all fields) AND miRNA (all fields), evaluating all publication up to May 2019. RESULTS Most miRNAs found to be dysregulated in this study were harvested from tissue samples, which precludes their use as a non-invasive diagnostic test. However, differential expression of 62 miRNAs was reported in samples that may be used for non-invasive diagnosis of endometriosis, such as blood, serum and plasma. CONCLUSION Despite the identification of several candidates, studies are investigatory in nature and have been conducted with small number of samples. Also, no particular miRNA has been validated for diagnostic purposes so far. Studies based primarily on biological samples and applicable to translational research are warranted. Large databases comprising information on sample type and the use of saliva and vaginal fluid for miRNAs identification may prove essential to overcome current barriers to diagnosis of endometriosis.
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Affiliation(s)
- Vitor Ulisses Monnaka
- Faculdade Israelita de Ciências da Saúde Albert EinsteinHospital Israelita Albert EinsteinSão PauloSPBrazilFaculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
| | - Camila Hernandes
- Hospital Israelita Albert EinsteinSão PauloSPBrazilHospital Israelita Albert Einstein, São Paulo, SP, Brazil.
| | - Debora Heller
- Hospital Israelita Albert EinsteinSão PauloSPBrazilHospital Israelita Albert Einstein, São Paulo, SP, Brazil.
| | - Sérgio Podgaec
- Hospital Israelita Albert EinsteinSão PauloSPBrazilHospital Israelita Albert Einstein, São Paulo, SP, Brazil.
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Identification of candidate microRNA markers of endometriosis with the use of next-generation sequencing and quantitative real-time polymerase chain reaction. Fertil Steril 2021; 113:1232-1241. [PMID: 32482255 DOI: 10.1016/j.fertnstert.2020.01.026] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/07/2020] [Accepted: 01/20/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To identify novel candidate diagnostic microRNA (miRNA) markers of endometriosis by means of an unbiased search with confirmation by means of targeted polymerase chain reaction (PCR). DESIGN Retrospective cohort. SETTING University teaching hospitals. PATIENT(S) Women with endometriosis and control women, confirmed with the use of laparoscopy. INTERVENTIONS(S) Diagnostic laparoscopy and blood sample. MAIN OUTCOME MEASURE(S) Next-generation sequencing (NGS) and quantitative real-time PCR (qRT-PCR). RESULT(S) Candidate miRNAs differentially expressed in women with endometriosis compared with control women were identified by means of NGS and selected for qRT-PCR. Plasma samples from another cohort of women with surgically confirmed endometriosis (n = 53) and disease-free control women (n = 53) were checked for hemolysis using spectrophotometry and the ratio of miR-23a and miR-451 by means of qRT-PCR. MicroRNA signatures were quantified by means of qRT-PCR in hemolysis-free plasma samples of case subjects (n = 25) and control subjects (n = 28) with the use of miRcury LNA miRNA. Circulating levels of eight miRNAs (miR-199a-3p, miR-143-3p, miR-340-5p, let-7b-5p, miR-21-5p, miR-17-5p, miR-20a-5p, and miR-103a-3p) were significantly lower in case subjects compared to control subjects. The sensitivity and specificity for individual miRNAs ranged from 0.36 to 1.00 and from 0.43 to 1.00, respectively, but when combined produced sensitivity and specificity of 0.92 and 0.86 with positive (PPV) and (NPV) predictive values of 0.85 and 0.92, respectively. However, combination of five miRNAs (miR-17-5p, miR-20a-5p, miR-199a-3p, miR-143-3p, and let-7b-5p) produced sensitivity and specificity of 0.96 and 0.79 with PPV and NPV of 0.80 and 0.96, respectively. CONCLUSION(S) We conclude that a panel of candidate miRNAs was comparable to laparoscopy in distinguishing between women with endometriosis and control women.
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Luo Y, Wang D, Chen S, Yang Q. The role of miR-34c-5p/Notch in epithelial-mesenchymal transition (EMT) in endometriosis. Cell Signal 2020; 72:109666. [PMID: 32353411 DOI: 10.1016/j.cellsig.2020.109666] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/19/2020] [Accepted: 04/26/2020] [Indexed: 01/06/2023]
Abstract
Endometriosis, a common benign gynecological disease, has the growth characteristics of malignant tumors, however, the pathogenesis of this disease remains unclear. It is well known that micro ribonucleic acids (miRNAs) are involved in epithelial-mesenchymal transition (EMT), associated with the development of endometriosis. This study investigated the role of a specific miRNA, miR-34c-5p, in endometriosis. High-throughput sequencing (HTS) showed that miR-34c-5p expression was reduced in ectopic endometrium (ecEM) in patients from Northeast Asia with ovarian endometriosis. A wound healing assay and a transwell invasion assay showed that miR-34c-5p inhibits the invasion and migration of Ishikawa and End1/E6E7 endocervical cells. Dual luciferase gene reporter assays revealed that miR-34c-5p specifically targets Notch1 3 'UTR, and Western blot analyses showed that miR-34c-5p promotes E-cadherin expression but inhibits Notch1, N-cadherin and vimentin expression in Ishikawa and End1/E6E7 cell lines. These results were reversed following knockdown of miR-34c-5p. Using quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot analyses, there was a significant reduction in the expression of Notch1 in ecEM compared with eutopic endometrium (euEM). The results of this study indicate that miR-34c-5p inhibits the progression of EMT and cell invasion and migration by targeting the Notch signaling pathway, specifically, Notch1. The findings of this study provide unique insights into the development of EMT in endometriosis and novel, potential therapeutic targets.
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Affiliation(s)
- Yajuan Luo
- Shengjing Hospital, China Medical University, Shenyang, Liaoning 110000, PR China
| | - Dandan Wang
- Shengjing Hospital, China Medical University, Shenyang, Liaoning 110000, PR China
| | - Silei Chen
- Shengjing Hospital, China Medical University, Shenyang, Liaoning 110000, PR China
| | - Qing Yang
- Shengjing Hospital, China Medical University, Shenyang, Liaoning 110000, PR China.
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Integrated Bioinformatics Analysis Reveals Function and Regulatory Network of miR-200b-3p in Endometriosis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3962953. [PMID: 32802844 PMCID: PMC7414375 DOI: 10.1155/2020/3962953] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/01/2020] [Accepted: 07/16/2020] [Indexed: 12/12/2022]
Abstract
Objective MicroRNAs play vital roles in the development of endometriosis. It is reported that miR-200b-3p is downregulated in endometriosis, although its mechanisms in this disease remain still unclear. Therefore, the purpose of this study was to explore the function and potential regulatory network of miR-200b-3p in endometriosis through database analysis. Methods The endometriosis gene expression profiles were downloaded from the GEO database to screen differentially expressed genes (DEGs). The predicted and validated target genes of miR-200b-3p were obtained from miRWalk and miRTarBase database. Then, a comparison was performed between miR-200b-3p target genes and DEGs. GO enrichment and KEGG pathway analysis of the target genes was performed using clusterProfiler package. STRING was used to predict the protein-protein interaction among the proteins encoded by the target genes. Then, TransmiR, LncBase, StarBase, PROMO, and AnimalTFDB were employed to identify interactive transcription factors and lncRNAs of miR-200b-3p. Results miR-200b-3p was associated with the transcription factors DNMT1, EZH2, HNF1B, JUN, MYB, ZEB1, and ZEB2 during the pathogenesis of endometriosis. The downstream 110 target genes were involved in the biological processes of positive regulation of MAPK cascade, muscle cell proliferation, organ growth, vasculogenesis, and axon development. KEGG analysis revealed that the main pathways related to miR-200b-3p were microRNAs in cancer, PI3K-Akt signaling pathway, colorectal cancer, and tight junction. In addition, four lncRNAs such as MALAT1, NEAT1, SNHG22, and XIST interacted with miR-200b-3p and were associated with transcription factors FOXP3 and YY1. Conclusion The predicted target genes and molecular regulatory network of miR-200b-3p in endometriosis not only revealed its biological function but also provided a valuable guideline for further research.
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Quintero-Ronderos P, Laissue P. Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches. Reprod Sci 2020; 27:1541-1552. [PMID: 32430708 DOI: 10.1007/s43032-020-00187-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Recurrent pregnancy loss (RPL) affects up to 5% of couples. It is believed that genetic factors contribute to the disease's etiology and pathophysiology. Hundreds of genes represent coherent RPL candidates due to mammalian implantation's inherent complexity. Sanger sequencing (direct sequencing) of candidate genes has identified potential RPL causative genes (and variants), including those regulating embryo implantation and pregnancy maintenance. Although this approach is a reliable technique, the simultaneous analysis of large genomic regions is challenging. Next-generation sequencing (NGS) technology has thus emerged as a useful alternative for determining genetic variants and transcriptomic disturbances contributing to monogenic and polygenic diseases pathogenesis. However, interpreting results remains challenging as NGS experiments provide an enormous amount of complex data. The molecular aspects of specific diseases must be fully understood for accurate interpretation of NGS data. This review was thus aimed at describing (for the first time) the most relevant studies involving Sanger and NGS sequencing, leading to the description of variants related to RPL pathogenesis. Successful RPL-related NGS initiatives (including RNAseq-based studies) and future challenges are discussed. We consider that the information given here should be useful for clinicians, scientists, and students to enable a better understanding of RPL etiology. It may also provide a basis for the development of diagnostic/prognostic approaches contributing toward translational medicine.
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Affiliation(s)
- Paula Quintero-Ronderos
- Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 N° 63C-69, Bogotá, 1100100, Colombia
| | - Paul Laissue
- Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 N° 63C-69, Bogotá, 1100100, Colombia.
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Circulating non-coding RNAs as non-invasive diagnostic markers of endometriosis: a comprehensive meta-analysis. Arch Gynecol Obstet 2019; 300:1099-1112. [PMID: 31605183 DOI: 10.1007/s00404-019-05290-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 09/03/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Circulating non-coding RNAs have great potential for diagnosing endometriosis as non-invasive markers. We have assessed the potential accuracy and utility for diagnosis of endometriosis. METHODS We searched many bases to identify the included literature, which included English bases, such as, Pubmed, Embase, Web of Science, Cochrane library and Chinese bases, for instance, CNKI, Wang Fang, VIP, DuXiu, ChaoXing. We also calculated the general sensitivity and specificity, negative likelihood ratio, positive likelihood ratio, diagnostic odds ratio, ROC curve plotting and so on with Stata 15. I2 could test the heterogeneity of the meta-analysis, the funnel plot valuated whether meta-analysis had a publication bias. Regression analysis could explore heterogeneity in studies. RESULT Comprehensive reading and integrating extracted data, we included 11 published papers. The total number of people included in the case group was 453, and the control group was 362. We, respectively, calculated the general sensitivity and general specificity which were 0.81 (95% CI 0.76-0.85) and 0.77 (95% CI 0.71-0.82) by bivariate analysis. The area under the ROC curve was 0.86 (95% CI 0.83-0.89). There was significant heterogeneity in studies which is I2 = 89.62% (95% CI 87.41%-91.83%). In addition, the results of meta-regression and subgroup analysis showed that the heterogeneity might come from gold standard, evaluation standard, experimental group size, experimental sample and race CONCLUSION: The circulating non-coding RNAs have great ability of diagnosing endometriosis as non-invasive markers which were performed robustly and accurately.
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Quintero-Ronderos P, Laissue P. Genetic Variants Contributing to Early Recurrent Pregnancy Loss Etiology Identified by Sequencing Approaches. Reprod Sci 2019:1933719119831769. [PMID: 30879428 DOI: 10.1177/1933719119831769] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Recurrent pregnancy loss (RPL) affects up to 5% of couples. It is believed that genetic factors contribute to the disease's etiology and pathophysiology. Hundreds of genes represent coherent RPL candidates due to mammalian implantation's inherent complexity. Sanger sequencing (direct sequencing) of candidate genes has identified potential RPL causative genes (and variants), including those regulating embryo implantation and pregnancy maintenance. Although this approach is a reliable technique, the simultaneous analysis of large genomic regions is challenging. Next-generation sequencing (NGS) technology has thus emerged as a useful alternative for determining genetic variants and transcriptomic disturbances contributing to monogenic and polygenic diseases pathogenesis. However, interpreting results remains challenging as NGS experiments provide an enormous amount of complex data. The molecular aspects of specific diseases must be fully understood for accurate interpretation of NGS data. This review was thus aimed at describing (for the first time) the most relevant studies involving Sanger and NGS sequencing, leading to the description of variants related to RPL pathogenesis. Successful RPL-related NGS initiatives (including RNAseq-based studies) and future challenges are discussed. We consider that the information given here should be useful for clinicians, scientists, and students to enable a better understanding of RPL etiology. It may also provide a basis for the development of diagnostic/prognostic approaches contributing toward translational medicine.
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Affiliation(s)
- Paula Quintero-Ronderos
- 1 Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Paul Laissue
- 1 Center For Research in Genetics and Genomics (CIGGUR), GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
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Cai H, Zhu XX, Li ZF, Zhu YP, Lang JH. MicroRNA Dysregulation and Steroid Hormone Receptor Expression in Uterine Tissues of Rats with Endometriosis during the Implantation Window. Chin Med J (Engl) 2018; 131:2193-2204. [PMID: 30203794 PMCID: PMC6144856 DOI: 10.4103/0366-6999.240808] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background: Estrogen receptor (ER) and progesterone receptor (PR) are involved in endometriosis, but the involvement of microRNAs (miRNAs) is unknown. The aim of the study was to explore the correlation between miRNA and ER/PR in uterine tissues of rats with endometriosis during the implantation window. Methods: Twenty female Sprague-Dawley rats were randomized in three groups: endometriosis (n = 7), fat tissue control (n = 6), and normal (n = 7) groups. The female rats were mated and sacrificed on day 5 (implantation). Uterine tissues were obtained for hematoxylin-eosin staining, immunohistochemistry, and miRNA expression. Reverse transcription polymerase chain reaction (RT-PCR) was used to validate the expression of rno-miR-29c-3p, rno-miR-34c-5p, rno-miR-141-5p, rno-miR-24-1-5p, and rno-miR-490-5p. Results: The 475 miRNAs were found to differentially express between the endometriosis and normal control groups, with 127 being upregulated and 348 being downregulated. Expression of five miRNAs (rno-miR-29c-3p, rno-miR-34c-5p, rno-miR-141-5p, rno-miR-24-1-5p, and rno-miR-490-5p) were validated by RT-PCR and found to be differentially expressed among the three groups. Expression of ER and PR proteins (immunohistochemistry) in the glandular epithelium and endometrial stroma was significantly different among the three groups (all P < 0.05). Five miRNAs were involved in pathways probably taking part in implantation and fertility. Conclusions: The results suggested that miRNAs, ER, and PR could play important roles in the embryo implantation period of rats with endometriosis. These miRNAs might play a role in endometrial receptivity in endometriosis.
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Affiliation(s)
- Han Cai
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100005, China
| | - Xin-Xin Zhu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100005, China
| | - Zhan-Fei Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100005, China
| | - Ya-Pei Zhu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100005, China
| | - Jing-He Lang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100005, China
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Differentially-Expressed miRNAs in Ectopic Stromal Cells Contribute to Endometriosis Development: The Plausible Role of miR-139-5p and miR-375. Int J Mol Sci 2018; 19:ijms19123789. [PMID: 30487429 PMCID: PMC6321240 DOI: 10.3390/ijms19123789] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/16/2018] [Accepted: 11/24/2018] [Indexed: 02/06/2023] Open
Abstract
microRNA (miRNA) expression level alterations between endometrial tissue and endometriotic lesions indicate their involvement in endometriosis pathogenesis. However, as both endometrium and endometriotic lesions consist of different cell types in various proportions, it is not clear which cells contribute to variability in miRNA levels and the overall knowledge about cell-type specific miRNA expression in ectopic cells is scarce. Therefore, we utilized fluorescence-activated cell sorting to isolate endometrial stromal cells from paired endometrial and endometrioma biopsies and combined it with high-throughput sequencing to determine miRNA alterations in endometriotic stroma. The analysis revealed 149 abnormally expressed miRNAs in endometriotic lesions, including extensive upregulation of miR-139-5p and downregulation of miR-375 compared to eutopic cells. miRNA transfection experiments in the endometrial stromal cell line ST-T1b showed that the overexpression of miR-139-5p resulted in the downregulation of homeobox A9 (HOXA9) and HOXA10 expression, whereas the endothelin 1 (EDN1) gene was regulated by miR-375. The results of this study provide further insights into the complex molecular mechanisms involved in endometriosis pathogenesis and demonstrate the necessity for cell-type-specific analysis of ectopic tissues to understand the interactions between different cell populations in disease onset and progression.
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A Two-Cohort RNA-seq Study Reveals Changes in Endometrial and Blood miRNome in Fertile and Infertile Women. Genes (Basel) 2018; 9:genes9120574. [PMID: 30477193 PMCID: PMC6315937 DOI: 10.3390/genes9120574] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/07/2018] [Accepted: 11/07/2018] [Indexed: 12/16/2022] Open
Abstract
The endometrium undergoes extensive changes to prepare for embryo implantation and microRNAs (miRNAs) have been described as playing a significant role in the regulation of endometrial receptivity. However, there is no consensus about the miRNAs involved in mid-secretory endometrial functions. We analysed the complete endometrial miRNome from early secretory (pre-receptive) and mid-secretory (receptive) phases from fertile women and from patients with recurrent implantation failure (RIF) to reveal differentially expressed (DE) miRNAs in the mid-secretory endometrium. Furthermore, we investigated whether the overall changes during early to mid-secretory phase transition and with RIF condition could be reflected in blood miRNA profiles. In total, 116 endometrial and 114 matched blood samples collected from two different population cohorts were subjected to small RNA sequencing. Among fertile women, 91 DE miRNAs were identified in the mid-secretory vs. early secretory endometrium, while no differences were found in the corresponding blood samples. The comparison of mid-secretory phase samples between fertile and infertile women revealed 21 DE miRNAs from the endometrium and one from blood samples. Among discovered novel miRNAs, chr2_4401 was validated and showed up-regulation in the mid-secretory endometrium. Besides novel findings, we confirmed the involvement of miR-30 and miR-200 family members in mid-secretory endometrial functions.
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Wahid B, Rafique S, Ali A, Waqar M, Nabi G, Wasim M, Idrees M. Biomarkers for diagnosis of pre-eclampsia and endometriosis. Biomark Med 2018; 12:1161-1173. [PMID: 30191726 DOI: 10.2217/bmm-2018-0058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Gynecological disorders are leading public health problems in developing countries with substantial impact on women's quality of life. Significant proportion of maternal mortality and reproductive morbidity is attributed to misdiagnosis and mismanagement of pregnancy related lethal pathological conditions and affect women's health. Timely diagnosis is necessary to prevent maternal deaths and to manage complications. Biomarker development will create a wide window of opportunity for early diagnosis. This review discusses the current status of biomarkers and recent advances in 'omics' technology for early screening of endometriosis and pre-eclampsia because of significant global bioburden associated with these disorders. This review will also give baseline data for future biomarker development strategies.
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Affiliation(s)
- Braira Wahid
- Genome Center for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore Pakistan.,Center for Applied Molecular Biology (CAMB), University of the Punjab, 87-West Canal Bank Road Thokar Niaz Baig, Lahore, Pakistan
| | - Shazia Rafique
- Division of Molecular Virology & Diagnostics Center of Excellence in Molecular Biology (CEMB), University of the Punjab, 87-West Canal Bank Road Thokar Niaz Baig, Lahore, Pakistan
| | - Amjad Ali
- Center for Applied Molecular Biology (CAMB), University of the Punjab, 87-West Canal Bank Road Thokar Niaz Baig, Lahore, Pakistan
| | - Muhammad Waqar
- Genome Center for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore Pakistan.,Center for Applied Molecular Biology (CAMB), University of the Punjab, 87-West Canal Bank Road Thokar Niaz Baig, Lahore, Pakistan
| | - Ghulam Nabi
- Institue of Hydrobiology, Chinese Academy of Sciences, Wuhan, PR China
| | - Muhammad Wasim
- Department of Medicine, Khyber Teaching Hospital, Peshawar, Pakistan
| | - Muhammad Idrees
- Genome Center for Molecular Based Diagnostics & Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore Pakistan.,Center for Applied Molecular Biology (CAMB), University of the Punjab, 87-West Canal Bank Road Thokar Niaz Baig, Lahore, Pakistan.,Division of Molecular Virology & Diagnostics Center of Excellence in Molecular Biology (CEMB), University of the Punjab, 87-West Canal Bank Road Thokar Niaz Baig, Lahore, Pakistan.,Department of Medicine, Khyber Teaching Hospital, Peshawar, Pakistan
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24
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Klemmt PA, Starzinski-Powitz A. Molecular and Cellular Pathogenesis of Endometriosis. CURRENT WOMEN'S HEALTH REVIEWS 2018; 14:106-116. [PMID: 29861704 PMCID: PMC5925869 DOI: 10.2174/1573404813666170306163448] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 02/06/2017] [Accepted: 02/15/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND A substantial body of studies supports the view that molecular and cellular features of endometriotic lesions differ from those of eutopic endometrium. Apart from that, evidence exists that the eutopic endometrium from pa-tients with endometriosis differs from that of females without endometriosis. OBJECTIVE Aberrant expression profiles include a number of non-steroid signaling pathways that exert their putative influ-ence on the pathogenesis of endometriosis at least in part via crosstalk(s) with estrogen-mediated mechanisms. A rational to focus research on non-steroid signal pathways is that they might be remunerative targets for the development and selection of novel therapeutics to treat endometriosis possibly without affecting estrogen levels. RESULTS AND CONCLUSION In this article, we describe molecular and cellular features of endometriotic lesions and focus on the canonical WNT/β-signaling pathway, a key regulatory system in biology (including stem cell homeostasis) and often in pathophysiological conditions such as endometriosis. Recently emerged novel biological concepts in signal transduction and gene regulation like exosomes and microRNAs are discussed in their putative role in the pathogenesis of endometriosis.
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Affiliation(s)
- Petra A.B. Klemmt
- Department of Molecular Cell Biology and Human Genetics, Institute of Cell Biology and Neuroscience, Johann Wolfgang Goethe University of Frankfurt, Max-von-Laue-Str. 13, D-60438Frankfurt am Main, Germany
| | - Anna Starzinski-Powitz
- Department of Molecular Cell Biology and Human Genetics, Institute of Cell Biology and Neuroscience, Johann Wolfgang Goethe University of Frankfurt, Max-von-Laue-Str. 13, D-60438Frankfurt am Main, Germany
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25
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Zhao L, Gu C, Ye M, Zhang Z, Li L, Fan W, Meng Y. Integration analysis of microRNA and mRNA paired expression profiling identifies deregulated microRNA-transcription factor-gene regulatory networks in ovarian endometriosis. Reprod Biol Endocrinol 2018; 16:4. [PMID: 29357938 PMCID: PMC5776778 DOI: 10.1186/s12958-017-0319-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 12/25/2017] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND The etiology and pathophysiology of endometriosis remain unclear. Accumulating evidence suggests that aberrant microRNA (miRNA) and transcription factor (TF) expression may be involved in the pathogenesis and development of endometriosis. This study therefore aims to survey the key miRNAs, TFs and genes and further understand the mechanism of endometriosis. METHODS Paired expression profiling of miRNA and mRNA in ectopic endometria compared with eutopic endometria were determined by high-throughput sequencing techniques in eight patients with ovarian endometriosis. Binary interactions and circuits among the miRNAs, TFs, and corresponding genes were identified by the Pearson correlation coefficients. miRNA-TF-gene regulatory networks were constructed using bioinformatic methods. Eleven selected miRNAs and TFs were validated by quantitative reverse transcription-polymerase chain reaction in 22 patients. RESULTS Overall, 107 differentially expressed miRNAs and 6112 differentially expressed mRNAs were identified by comparing the sequencing of the ectopic endometrium group and the eutopic endometrium group. The miRNA-TF-gene regulatory network consists of 22 miRNAs, 12 TFs and 430 corresponding genes. Specifically, some key regulators from the miR-449 and miR-34b/c cluster, miR-200 family, miR-106a-363 cluster, miR-182/183, FOX family, GATA family, and E2F family as well as CEBPA, SOX9 and HNF4A were suggested to play vital regulatory roles in the pathogenesis of endometriosis. CONCLUSION Integration analysis of the miRNA and mRNA expression profiles presents a unique insight into the regulatory network of this enigmatic disorder and possibly provides clues regarding replacement therapy for endometriosis.
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Affiliation(s)
- Luyang Zhao
- Department of Gynecology and Obstetrics, People’s Liberation Army (PLA) Medical School, Chinese PLA General Hospital, Beijing, 100853 China
- Department of Gynecology and Obstetrics, Peking University People’s Hospital, Beijing, China
| | - Chenglei Gu
- Department of Gynecology and Obstetrics, People’s Liberation Army (PLA) Medical School, Chinese PLA General Hospital, Beijing, 100853 China
- Department of Gynecology and Obstetrics, the 309th Hospital of Chinese PLA, Beijing, China
| | - Mingxia Ye
- Department of Gynecology and Obstetrics, People’s Liberation Army (PLA) Medical School, Chinese PLA General Hospital, Beijing, 100853 China
| | - Zhe Zhang
- Department of Gynecology and Obstetrics, People’s Liberation Army (PLA) Medical School, Chinese PLA General Hospital, Beijing, 100853 China
| | - Li’an Li
- Department of Gynecology and Obstetrics, People’s Liberation Army (PLA) Medical School, Chinese PLA General Hospital, Beijing, 100853 China
| | - Wensheng Fan
- Department of Gynecology and Obstetrics, People’s Liberation Army (PLA) Medical School, Chinese PLA General Hospital, Beijing, 100853 China
| | - Yuanguang Meng
- Department of Gynecology and Obstetrics, People’s Liberation Army (PLA) Medical School, Chinese PLA General Hospital, Beijing, 100853 China
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26
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Challenges in endometriosis miRNA studies — From tissue heterogeneity to disease specific miRNAs. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2282-2292. [DOI: 10.1016/j.bbadis.2017.06.018] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 06/06/2017] [Accepted: 06/22/2017] [Indexed: 12/31/2022]
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27
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Furuya M, Masuda H, Hara K, Uchida H, Sato K, Sato S, Asada H, Maruyama T, Yoshimura Y, Katabuchi H, Tanaka M, Saya H. ZEB1 expression is a potential indicator of invasive endometriosis. Acta Obstet Gynecol Scand 2017; 96:1128-1135. [PMID: 28597474 DOI: 10.1111/aogs.13179] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 05/31/2017] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Although endometriosis is a benign disease, it shares some features with cancers, such as invasiveness and the potential to metastasize. This study sought to investigate the epithelial-mesenchymal transition status in human endometriotic lesions. MATERIAL AND METHODS Thirteen endometriosis patients and 10 control women without endometriosis undergoing surgery for benign indications were recruited. We examined the expression of E-cadherin, vimentin, and epithelial-mesenchymal transition-induced transcriptional factors, such as Snail and ZEB1, by immunohistochemistry. We evaluated the expression of each marker in epithelial cells of both endometriotic lesions (ovarian endometrioma, deep infiltrating endometriosis, adenomyosis) and normal endometria. The correlation between ZEB1 expression and serum level of CA125 was also investigated. RESULTS Immunohistochemical analysis revealed that although E-cadherin, vimentin, and Snail were expressed in epithelia of normal endometria and endometriotic lesions, ZEB1 expression was only expressed in epithelia of endometriotic lesions. Additionally, ZEB1 was most frequently observed in epithelial cells of invasive endometriosis. The endometriosis patients with high serum CA125 level were more likely to have ZEB1-positive lesions. CONCLUSIONS This is the first observation of ZEB1 expression in epithelial cells of benign disease. The preferential expression of ZEB1 in epithelial cells of endometriotic lesions suggests that these cells may have, at least in part, a higher level of mesenchymal features possibly via ZEB1-driven epithelial-mesenchymal transition than normal endometria and that ZEB1 can be a potential indicator of invasiveness or severity of endometriosis.
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Affiliation(s)
- Masataka Furuya
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Hirotaka Masuda
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | | | - Hiroshi Uchida
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Kenji Sato
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Suguru Sato
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Hironori Asada
- Department of Obstetrics, Gynecology and Gynecologic Minimally Invasive Surgery, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Tetsuo Maruyama
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Yasunori Yoshimura
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Hidetaka Katabuchi
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Mamoru Tanaka
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Saya
- Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
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28
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Logan PC, Yango P, Tran ND. Endometrial Stromal and Epithelial Cells Exhibit Unique Aberrant Molecular Defects in Patients With Endometriosis. Reprod Sci 2017; 25:140-159. [PMID: 28490276 DOI: 10.1177/1933719117704905] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
CONTEXT Endometriosis is a chronic inflammatory disease that causes pain and infertility in women of reproductive age. OBJECTIVE To investigate the pathologic pathways in endometrial stromal and epithelial cells that contribute to the manifestation of endometriosis. DESIGN In vitro cellular and molecular analyses of isolated eutopic endometrial stromal and epithelial cells. METHODS Eutopic stromal and epithelial cells from endometriotic and normal patients were isolated by fluorescence-activated cell sorting for paired sibling RNA sequencing and microRNA microarray. Aberrant pathways were identified using ingenuity pathway analysis networks and confirmed with in vitro modulation of the affected pathways in stromal and epithelial cell cultures. RESULTS Both stromal versus epithelial cell types and paired endometriotic versus normal samples exhibited distinct hierarchical clustering. Compared to normal samples, there were 151 and 215 differentially expressed genes in the endometriotic stromal and epithelial populations, respectively, and concomitantly 9 and 16 differentially expressed microRNAs. Overall, endometriotic stromal and epithelial cells revealed distinct defects. In endometriotic stromal cells, key decidualization genes Zinc finger E-box Binding protein 1 (ZEB1), Heart And Neural crest Derivatives expressed 2 (HAND2), WNT4, and Interleukin 15 (IL-15) were found to be downregulated and Periostin (POSTN) and Matrix Metallopeptidase 7 (MMP7) were upregulated. Specifically, ZEB1 was downregulated in stromal cells by aberrant elevation in miR-200b. In contrast, ZEB1 was found to be upregulated in endometriotic epithelial cells through associated upregulation of transforming growth factor β1 (TGFβ1), inducer of the TGFβ1-Bone Morphogenetic Protein 2 (BMP2)-MMP2-Prostaglandin-endoperoxide Synthase 2 (COX2)-ZEB1 pathway, which activates epithelial-mesenchymal transition. CONCLUSION Manifestation of endometriosis involves dysregulation of unique molecular pathways within the diseased endometrial stromal and epithelial cells in the endometrium. Targeting the cell type-specific defects may offer a novel approach to treating endometriosis.
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Affiliation(s)
- Philip C Logan
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Pamela Yango
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Nam D Tran
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA
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Shi W, Bruce J, Lee M, Yue S, Rowe M, Pintilie M, Kogo R, Bissey PA, Fyles A, Yip KW, Liu FF. MiR-449a promotes breast cancer progression by targeting CRIP2. Oncotarget 2017; 7:18906-18. [PMID: 26934316 PMCID: PMC4951339 DOI: 10.18632/oncotarget.7753] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/14/2016] [Indexed: 12/12/2022] Open
Abstract
The identification of prognostic biomarkers and their underlying mechanisms of action remain of great interest in breast cancer biology. Using global miRNA profiling of 71 lymph node-negative invasive ductal breast cancers and 5 normal mammary epithelial tissues, we identified miR-449a to be highly overexpressed in the malignant breast tissue. Its expression was significantly associated with increased incidence of patient relapse, decreased overall survival, and decreased disease-free survival. In vitro, miR-449a promoted breast cancer cell proliferation, clonogenic survival, migration, and invasion. By utilizing a tri-modal in silico approach for target identification, Cysteine-Rich Protein 2 (CRIP2; a transcription factor) was identified as a direct target of miR-449a, corroborated using qRT-PCR, Western blot, and luciferase reporter assays. MDA-MB-231 cells stably transfected with CRIP2 demonstrated a significant reduction in cell viability, migration, and invasion, as well as decreased tumor growth and angiogenesis in mouse xenograft models. Our data revealed that overexpression of miR-449a suppresses CRIP2, which then affects the tumor vasculature, likely via NF-κB/p65 complex-mediated transcription of VEGF. These finding define an oncogenic function of miR-449a in human breast cancer, and highlight the importance of this pathway in driving aggressive behaviour.
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Affiliation(s)
- Wei Shi
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Jeff Bruce
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Matthew Lee
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Shijun Yue
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Matthew Rowe
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Melania Pintilie
- Division of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Ryunosuke Kogo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | | | - Anthony Fyles
- Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada
| | - Kenneth W Yip
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Fei-Fei Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.,Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
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30
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Kiba A, Banno K, Yanokura M, Asada M, Nakayama Y, Aoki D, Watanabe T. Differential micro ribonucleic acid expression profiling in ovarian endometrioma with leuprolide acetate treatment. J Obstet Gynaecol Res 2016; 42:1734-1743. [PMID: 27709720 DOI: 10.1111/jog.13137] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 07/17/2016] [Indexed: 01/27/2023]
Abstract
AIM Micro ribonucleic acids (miRNAs) play an important pathological role in endometriosis. Leuprolide acetate, an analog of gonadotropin-releasing hormone, is widely used to treat endometriosis; however, the molecular mechanisms involved in endometriotic tissue regression remain unclear. We performed miRNA expression profiling of clinical ovarian endometrioma to obtain insight into the effects of leuprolide acetate treatment. METHODS We obtained clinical samples from nine normal eutopic endometrium, eight ovarian endometriotic, and 12 leuprolide acetate-treated endometriotic tissues. We compared the miRNA expression profiles of the three groups by performing TaqMan Array MicroRNA Card and bioinformatic analysis. RESULTS Two miRNAs, miR-939 and miR-154, were upregulated in endometriotic tissue and downregulated in leuprolide acetate-treated endometriotic tissue. Five miRNAs (miR-146a, miR-142-3p, miR-136*, miR-125b-1* and miR-15b*) were unchanged in endometriotic tissue but were upregulated under leuprolide acetate treatment. Ingenuity pathway analysis using predicted target genes for the seven identified miRNAs suggested the involvement of a range of pathways, including axonal guidance, bone morphogenetic protein, phosphatase and tensin homolog and nitric oxide signaling; molecular mechanisms of cancer; and the adipogenesis and signal transducer and activator of transcription 3 (STAT3) pathways. CONCLUSIONS To our knowledge, this is the first report profiling the miRNAs of endometrioma under leuprolide acetate treatment. The expression of seven miRNAs was modulated, concomitant with the disease state. This result gives new insight into the effects of leuprolide acetate treatment. Further investigation using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry will allow us to validate the results of this study and to explore new therapeutic targets and biomarkers of endometriosis.
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Affiliation(s)
- Atsushi Kiba
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Kouji Banno
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Megumi Yanokura
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Mari Asada
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Yusuke Nakayama
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
| | - Tatsuya Watanabe
- Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
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31
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Marí-Alexandre J, Barceló-Molina M, Olcina-Guillem M, García-Oms J, Braza-Boïls A, Gilabert-Estellés J. MicroRNAs: New players in endometriosis. World J Obstet Gynecol 2016; 5:28-38. [DOI: 10.5317/wjog.v5.i1.28] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/14/2015] [Accepted: 01/07/2016] [Indexed: 02/05/2023] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disorder that limits the quality of life of affected women. This pathology affects 10% of reproductive-age women, although the prevalence in those patients experiencing pain, infertility or both is as high as 35%-50%. Endometriosis is characterized by endometrial-like tissue outside the uterus, primarily on the pelvic peritoneum, ovaries and the pouch of Douglas. Despite extensive research endeavours, a unifying theory regarding the exact etiopathogenic mechanism of this high prevalent and incapacitating condition is still lacking, although it has been suggested that epigenetics could be involved. MicroRNAs (miRNAs), one of the epigenetic players, are small non-coding RNAs that can act as post-transcriptional regulators of gene expression, reducing the expression of their target mRNAs either inhibiting its translation or promoting its degradation. MiRNA expression profiles are specific of tissue and cell type. Abnormal miRNA expression has been described in different pathological conditions, such as a myriad of oncological, cardiovascular and inflammatory diseases and gynecological pathologies. In endometriosis, miRNA expression patterns of eutopic endometrium from patients and control women and from different endometriotic lesions have been described. These small non-coding molecules have become attractive candidates as novel biomarkers for an early non-invasive diagnosis of the disease, which could suppose a valuable benefit to the patients in terms of improvement of prognosis and reduction of the ratio of recurrence. In this systematic review we will focus on the role of miRNAs in the pathophisiology of endometriosis.
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32
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Götte M, Kiesel L. Pathophysiologie der Endometriose. GYNAKOLOGISCHE ENDOKRINOLOGIE 2016. [DOI: 10.1007/s10304-015-0047-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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33
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Eggers JC, Martino V, Reinbold R, Schäfer SD, Kiesel L, Starzinski-Powitz A, Schüring AN, Kemper B, Greve B, Götte M. microRNA miR-200b affects proliferation, invasiveness and stemness of endometriotic cells by targeting ZEB1, ZEB2 and KLF4. Reprod Biomed Online 2016; 32:434-45. [PMID: 26854065 DOI: 10.1016/j.rbmo.2015.12.013] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 12/18/2015] [Accepted: 12/22/2015] [Indexed: 02/06/2023]
Abstract
Endometriosis is characterized by growth of endometrial tissue at ectopic locations. Down-regulation of microRNA miR-200b is observed in endometriosis and malignant disease, driving tumour cells towards an invasive state by enhancing epithelial-to-mesenchymal transition (EMT). miR-200b up-regulation may inhibit EMT and invasive growth in endometriosis. To study its functional impact on the immortalized endometriotic cell line 12Z, the stromal cell line ST-T1b, and primary endometriotic stroma cells, a transient transfection approach with microRNA precursors was employed. Expression of bioinformatically predicted targets of miR-200b was analysed by qPCR. The cellular phenotype was monitored by Matrigel invasion assays, digital-holographic video microscopy and flow cytometry. qPCR revealed significant down-regulation of ZEB1 (P < 0.05) and ZEB2 (P < 0.01) and an increase in E-cadherin (P < 0.01). miR-200b overexpression decreased invasiveness (P < 0.0001) and cell motility (P < 0.05). In contrast, cell proliferation (P < 0.0001) and the stemness-associated side population phenotype (P < 0.01) were enhanced following miR-200b transfection. These properties were possibly due to up-regulation of the pluripotency-associated transcription factor KLF4 (P < 0.05) and require attention when considering therapeutic strategies. In conclusion, up-regulation of miR-200b reverts EMT, emerging as a potential therapeutic approach to inhibit endometriotic cell motility and invasiveness.
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Affiliation(s)
- Julia C Eggers
- Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany
| | - Valentina Martino
- Institute of Biomedical Technologies, National Research Council, 20090 Segrate-Milan, Italy
| | - Rolland Reinbold
- Institute of Biomedical Technologies, National Research Council, 20090 Segrate-Milan, Italy
| | - Sebastian D Schäfer
- Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany
| | - Ludwig Kiesel
- Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany
| | - Anna Starzinski-Powitz
- Institute of Anthropology and Human Genetics for Biologists, Johann-Wolfgang-Goethe University of Frankfurt, Frankfurt, Germany
| | - Andreas N Schüring
- Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany
| | - Björn Kemper
- Biomedical Technology Center, University of Muenster, 48149 Muenster, Germany
| | - Burkhard Greve
- Klinik für Strahlentherapie - Radioonkologie, Universitätsklinikum Münster, D-48149 Münster, Germany.
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, D-48149 Münster, Germany.
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Circulating miR-200-family micro-RNAs have altered plasma levels in patients with endometriosis and vary with blood collection time. Fertil Steril 2015. [PMID: 26206343 DOI: 10.1016/j.fertnstert.2015.06.029] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To determine whether circulating micro-RNA (miR) 200a, miR-200b, and miR-141 have altered levels in patients with endometriosis compared with control individuals. DESIGN Experimental laboratory study. SETTING University. PATIENT(S) Patients with endometriosis (n = 61), laparoscopically confirmed endometriosis-free women (n = 35), and self-reported healthy women (n = 30) were included in the study. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Plasma miRNA levels in endometriosis patients and control subjects. RESULT(S) We found that the levels of studied miRNAs varied with blood collection time, being lower in the morning than in the evening. When blood collection time was taken into account, the results revealed significantly lower levels of miR-200a and miR-141 in the evening plasma samples of women with endometriosis compared with surgically confirmed disease-free patients. However, the evening-sample levels of all three miRNAs were significantly lower in patients with stage I-II endometriosis than in endometriosis-free control subjects. In cases of stage III-IV endometriosis, only miR-200a levels were significantly lower compared with patients without endometriosis. Circulating miR-200a showed the best discriminative power to differentiate women with endometriosis from patients with similar complaints but without the disease. CONCLUSION(S) Our findings suggest that miR-200a and miR-141 have a potential as novel noninvasive biomarkers for endometriosis. In addition, we found that the plasma miR-200a, miR-200b and miR-141 levels vary with blood sampling time, so it is important to take the sample collection time into account when studying miRNAs as biomarkers.
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Nothnick WB, Al-Hendy A, Lue JR. Circulating Micro-RNAs as Diagnostic Biomarkers for Endometriosis: Privation and Promise. J Minim Invasive Gynecol 2015; 22:719-26. [PMID: 25757811 DOI: 10.1016/j.jmig.2015.02.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/25/2015] [Accepted: 02/26/2015] [Indexed: 12/20/2022]
Abstract
Endometriosis represents a major medical concern in women of reproductive age. One of the remaining major hurdles for successful treatment of endometriosis is the limitation of the process of timely disease diagnosis. A simple blood test for endometriosis-specific biomarkers would offer a more timely accurate diagnosis for the disease, thus allowing for earlier treatment intervention. Although there have been considerable efforts to identify such biomarkers, no clear choice for such noninvasive diagnostic tools has been identified. Micro-RNAs are small noncoding RNAs that have been evaluated intensively as biomarkers for several diseases, and they may hold promise for a diagnosis of endometriosis. In this review, we highlight the need for noninvasive testing for endometriosis, discuss the potential use of micro-RNAs as diagnostic tools for this disease, and consider potential limitations in the use of these small RNA molecules as diagnostic markers for endometriosis.
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Affiliation(s)
- Warren B Nothnick
- Department of Molecular and Integrative Physiology, Center for Reproductive Sciences, Institute of Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas.
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, Georgia
| | - John R Lue
- Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, Georgia
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36
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Small RNAs: Their Possible Roles in Reproductive Failure. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 868:49-79. [PMID: 26178845 DOI: 10.1007/978-3-319-18881-2_3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Posttranscriptional gene regulation is a regulatory mechanism which occurs "above the genome" and confers different phenotypes and functions within a cell. Transcript and protein abundance above the level of transcription can be regulated via noncoding ribonucleic acid (ncRNA) molecules, which potentially play substantial roles in the regulation of reproductive function. MicroRNA (miRNA), endogenous small interfering RNA (endo-siRNA), and PIWI-interacting RNA (piRNA) are three primary classes of small ncRNA. Similarities and distinctions between their biogenesis and in the interacting protein machinery that facilitate their function distinguish these three classes. Characterization of the expression and importance of the critical components for the biogenesis of each class in different tissues contributes a clearer understanding of their contributions in specific reproductive tissues and their ability to influence fertility in both males and females. This chapter discusses the expression and potential roles of miRNA, endo-siRNA, and piRNA in the regulation of reproductive function. Additionally, this chapter elaborates on investigations aimed to address and characterize specific mechanisms through which miRNA may influence infertility and the use of miRNA as biomarkers associated with several reproductive calamities such as defective spermatogenesis in males, polycystic ovarian failure, endometriosis and obesity, and chemical-induced subfertility.
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