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Mohammadi SD, Moeini A, Rastegar T, Amidi F, Saffari M, Zhaeentan S, Akhavan S, Moradi B, Heydarikhah F, Takzare N. Diagnostic accuracy of plasma microRNA as a potential biomarker for detection of endometriosis. Syst Biol Reprod Med 2025; 71:61-75. [PMID: 40053518 DOI: 10.1080/19396368.2025.2465268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 11/24/2024] [Accepted: 02/05/2025] [Indexed: 03/09/2025]
Abstract
Endometriosis is a complex condition with a wide range of clinical manifestations, presenting significant challenges, particularly for young women. Its diverse and often perplexing presentations pose difficulties within the medical community. Laparoscopy remains the gold-standard diagnostic tool for endometriosis. However, alternative diagnostic methods are valuable for monitoring disease progression, assessing the likelihood of recurrence, reducing the need for surgical procedures, and facilitating timely decisions regarding fertility concerns. Recent research highlights the potential of microRNAs (miRNAs) as an alternative diagnostic test for endometriosis. A case-control study was conducted at the infertility unit of Arash Women's Hospital, involving 50 female participants, 25 with endometriosis and 25 without it. Plasma samples were collected and analyzed for the expression levels of 16 miRNAs using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Diagnostic accuracy measures were evaluated to establish a reliable and comparable diagnostic framework. Compared to the control group, downregulation of 11 miRNAs and upregulation of 5 miRNAs were observed in the case group. Regarding expression patterns, evidence from this study indicates that half of the evaluated miRNAs fall into the high-agreement category with similar studies. Sensitivity (SN) of the evaluated miRNAs ranged from 64.0% to 88.0%, while specificity (SP) ranged from 56.0% to 88.0%. The area under the curve (AUC) was reported between 0.619 (miR-135a) and 0.846 (miR-340). These findings suggest that the evaluated miRNAs demonstrate moderate to acceptable diagnostic accuracy for endometriosis.
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Affiliation(s)
- Seyed Danial Mohammadi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ashraf Moeini
- Department of Gynecology and Obstetrics, Infertility Ward, Arash Women`s Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Rastegar
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fardin Amidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Saffari
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahrzad Zhaeentan
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Setareh Akhavan
- Gynecology Oncology Department, Imam Khomeini Hospital Complex, Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnaz Moradi
- Department of Radiology, Yas Women's Hospital, Tehran, Iran
| | - Faezeh Heydarikhah
- Department of Genetics, Islamic Azad University Tehran Medical Branch, Tehran, Iran
| | - Nasrin Takzare
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Arsalan HM, Mumtaz H, Lagana AS. Biomarkers of endometriosis. Adv Clin Chem 2025; 126:73-120. [PMID: 40185537 DOI: 10.1016/bs.acc.2025.01.004] [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] [Indexed: 04/07/2025]
Abstract
Endometriosis represents a diverse disease characterized by three distinct phenotypes: superficial peritoneal lesions, ovarian endometriomas, and deep infiltrating endometriosis. The most widely accepted pathophysiological hypothesis for endometriosis is rooted in retrograde menstruation, a phenomenon observed in most patients. Endometriosis is closely linked to infertility, but having endometriosis does not necessarily imply infertility. The disease can impact fertility through various mechanisms affecting the pelvic cavity, ovaries, and the uterus itself. MicroRNAs (miRNAs) indeed represent a fascinating and essential component of the regulatory machinery within cells. Discovered in the early 1990s, miRNAs have since been identified as critical players in gene expression control. Unfortunately, ovarian endometrioma is a common gynecologic disorder for which specific serum markers are currently lacking. Some have examined urocortin for its ability to differentiate endometriomas from other benign ovarian cysts. Another potential marker, Cancer Antigen 125 (CA-125) is a well-established indicator for epithelial cell ovarian cancer and its levels can be elevated in conditions such as endometriosis. CA-125 is derived from coelomic epithelia, including the endometrium, fallopian tube, ovary, and peritoneum. In this review we examine the pathophysiologic basis for endometriosis and highlight potential markers to more fully characterize the underlying biochemical processes linked to this multifaceted disease state.
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Affiliation(s)
- Hafiz Muhammad Arsalan
- Faculty of General Medicine, Altamimi International Medical University, Bishkek, Kyrgyzstan.
| | - Hina Mumtaz
- Department of Biochemistry, University of Central Punjab, Lahore, Pakistan.
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Guan Y, Chen Y, Lin R, Mo T, Li S, Cao Y, Yin T, Diao L, Li Y. Endometriosis: A new perspective on epigenetics and oxidative stress. J Reprod Immunol 2025; 169:104462. [PMID: 40010026 DOI: 10.1016/j.jri.2025.104462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/07/2025] [Accepted: 02/20/2025] [Indexed: 02/28/2025]
Abstract
As a complex chronic gynecological disorder characterized by multifaceted etiology involving genetics, environment, immunity and inflammation, endometriosis (EM) has long been a significant concern for women of reproductive age worldwide. This review aimed to comprehensively examine the interplay between epigenetics and oxidative stress (OS) in the pathogenesis of EM. Through the integration of cutting-edge research, the response of OS signals to epigenetic modifications was explored. The microbiome exerts an influence on this causal regulatory relationship, and these mechanisms collectively contribute to the pathophysiology of EM. Specifically, this article highlighted the roles of epigenetics and OS in EM and underscored the importance of the microbiome as a regulatory link. A discussion was also held on the future directions of biomarkers and precision medicine, including the application prospects of epigenetic and OS markers in the diagnosis and treatment decision-making of EM, and innovations in therapeutic strategies like targeting epigenetic modifications and antioxidant therapies. Moreover, this review emphasized the potential of multi-omics integrated analysis to deepen the understanding of the disease, guide future therapeutic strategies and promote personalized medicine.
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Affiliation(s)
- Yu Guan
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Yawen Chen
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), China; Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, China
| | - Rong Lin
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), China; Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, China
| | - Tinghui Mo
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Shiyu Li
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Ying Cao
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
| | - Tailang Yin
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
| | - Lianghui Diao
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), China; Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, China.
| | - Yuye Li
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), China; Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-implantation, China.
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Ye L, Dimitriadis E. Endometrial Receptivity-Lessons from "Omics". Biomolecules 2025; 15:106. [PMID: 39858500 PMCID: PMC11764156 DOI: 10.3390/biom15010106] [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: 12/13/2024] [Revised: 01/03/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
The window of implantation (WOI) is a critical phase of the menstrual cycle during which the endometrial lining becomes receptive and facilitates embryo implantation. Drawing on findings from various branches of "omics", including genomics, epigenomics, transcriptomics, proteomics, lipidomics, metabolomics, and microbiomics, this narrative review aims to (1) discuss mechanistic insights on endometrial receptivity and its implication in infertility; (2) highlight advances in investigations for endometrial receptivity; and (3) discuss novel diagnostic and therapeutic strategies that may improve reproductive outcomes.
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Affiliation(s)
- Louie Ye
- Reproductive Service Unit, The Royal Women’s Hospital, Melbourne, VIC 3052, Australia
- Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Melbourne, VIC 3052, Australia;
| | - Evdokia Dimitriadis
- Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Melbourne, VIC 3052, Australia;
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Frisendahl C, Tang Y, Boggavarapu NR, Peters M, Lalitkumar PG, Piltonen TT, Arffman RK, Salumets A, Götte M, Korsching E, Gemzell-Danielsson K. miR-193b-5p and miR-374b-5p Are Aberrantly Expressed in Endometriosis and Suppress Endometrial Cell Migration In Vitro. Biomolecules 2024; 14:1400. [PMID: 39595577 PMCID: PMC11592355 DOI: 10.3390/biom14111400] [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: 09/17/2024] [Revised: 10/27/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
(1) Background: Endometriosis is a highly prevalent gynecological disease affecting 10% of women of reproductive age worldwide. miRNAs may play a role in endometriosis, though their exact function remains unclear. This study aimed to identify differentially expressed miRNAs in endometriosis and study their functions in the disease. (2) Methods: Endometrial tissue was collected from women with endometriosis (n = 15) and non-endometriosis controls (n = 17). Dysregulated miRNAs were identified through small RNA-sequencing, and their biological significance was explored by target gene prediction and pathway analysis. Selected miRNAs were examined in paired ectopic endometriomas and eutopic endometrium (n = 10) using qRT-PCR. Their roles in cell migration and proliferation were further examined in vitro using functional assays. To identify potential target genes, we performed mRNA sequencing on transfected cells and the endometrioma cohort. (3) Results: We identified 14 dysregulated miRNAs in the eutopic endometrium of women with endometriosis compared to endometrial tissue from women without endometriosis. Pathway analysis indicated enrichment in cell migration and proliferation-associated pathways. Further ex vivo studies of miR-193b-5p and miR-374b-5p showed that both miRNAs were upregulated in endometrioma. Overexpression of these two miRNAs in vitro inhibited cell migration, and mRNA sequencing revealed several migration-related genes that are targeted by these miRNAs. (4) Conclusions: Our study identified two key endometrial miRNAs that may be involved in the pathogenesis of endometriosis by regulating cell migration.
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Affiliation(s)
- Caroline Frisendahl
- WHO Collaborating Centre, Division of Neonatology, Obstetrics, Gynecology, and Reproductive Health, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, SE 17176 Stockholm, Sweden; (C.F.); (Y.T.); (N.R.B.); (P.G.L.)
| | - Yiqun Tang
- WHO Collaborating Centre, Division of Neonatology, Obstetrics, Gynecology, and Reproductive Health, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, SE 17176 Stockholm, Sweden; (C.F.); (Y.T.); (N.R.B.); (P.G.L.)
- Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, Medical Research Centre, Oulu University Hospital, University of Oulu, 90220 Oulu, Finland; (T.T.P.); (R.K.A.)
| | - Nageswara Rao Boggavarapu
- WHO Collaborating Centre, Division of Neonatology, Obstetrics, Gynecology, and Reproductive Health, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, SE 17176 Stockholm, Sweden; (C.F.); (Y.T.); (N.R.B.); (P.G.L.)
| | - Maire Peters
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia; (M.P.); (A.S.)
- Celvia CC, Competence Centre on Health Technologies, 50411 Tartu, Estonia
| | - Parameswaran Grace Lalitkumar
- WHO Collaborating Centre, Division of Neonatology, Obstetrics, Gynecology, and Reproductive Health, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, SE 17176 Stockholm, Sweden; (C.F.); (Y.T.); (N.R.B.); (P.G.L.)
| | - Terhi T. Piltonen
- Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, Medical Research Centre, Oulu University Hospital, University of Oulu, 90220 Oulu, Finland; (T.T.P.); (R.K.A.)
| | - Riikka K. Arffman
- Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, Medical Research Centre, Oulu University Hospital, University of Oulu, 90220 Oulu, Finland; (T.T.P.); (R.K.A.)
| | - Andres Salumets
- Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia; (M.P.); (A.S.)
- Celvia CC, Competence Centre on Health Technologies, 50411 Tartu, Estonia
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, and Karolinska University Hospital, SE 17177 Stockholm, Sweden
| | - Martin Götte
- Department of Gynecology and Obstetrics, University Hospital of Münster, University of Münster, 48149 Münster, Germany;
| | - Eberhard Korsching
- Institute of Bioinformatics, University Hospital of Münster, University of Münster, 48149 Münster, Germany;
| | - Kristina Gemzell-Danielsson
- WHO Collaborating Centre, Division of Neonatology, Obstetrics, Gynecology, and Reproductive Health, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, SE 17176 Stockholm, Sweden; (C.F.); (Y.T.); (N.R.B.); (P.G.L.)
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Muharam R, Bowolaksono A, Maidarti M, Febri RR, Mutia K, Iffanolida PA, Ikhsan M, Sumapraja K, Pratama G, Harzif AK, Hestiantoro A, Wiweko B. Elevated MMP-9, Survivin, TGB1 and Downregulated Tissue Inhibitor of TIMP-1, Caspase-3 Activities are Independent of the Low Levels miR-183 in Endometriosis. Int J Womens Health 2024; 16:1733-1742. [PMID: 39469031 PMCID: PMC11513572 DOI: 10.2147/ijwh.s469864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/17/2024] [Indexed: 10/30/2024] Open
Abstract
Purpose This study aimed to measure the correlation between miR-183 and gene expression that regulates apoptosis and adhesion mechanism that may be linked to the pathogenesis of endometriosis. Patients and Methods Forty-four subjects, including 22 control subjects, participated in this study. We collected ectopic endometriosis and endometrial samples. For the control, the sample was taken from endometrial tissue through pipelle biopsy. RNA was extracted from all tissues using RNA mini kit, and the expression was assessed using quantitative-real time PCR. Relative mRNA and miRNA expression were presented using the formula of the Livak method. The data were statistically analyzed using GraphPad Prism 8. Results The expression of Caspase-3, Survivin, Integrin β1 (ITGB1), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) (adhesion- and apoptosis-related gene) were calculated using the relative expression method. We found significant differences in Caspase-3, Survivin, ITGB1, MMP-9, and TIMP-1 expression between ectopic endometriosis tissues of women with endometriosis compared to healthy endometrium. MMP-9, Survivin, and ITGB1 was significantly increased in the endometriosis group, while Caspase-3, TIMP-1, and miR-183 were significantly reduced in the endometriosis group. No correlation was found between the expression level of miR-183 and Caspase3, Survivin, ITGB1, and Cadherin in both tissue types. Conclusion Despite the difference in expression levels of miR-183 and associated adhesion- and apoptosis-related genes, there was no significant association between miR-183 with specific adhesion and apoptosis genes in endometriosis tissue.
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Affiliation(s)
- R Muharam
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
| | - Anom Bowolaksono
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Cellular and Molecular Mechanisms in Biological System (CEMBIOS) Research Group, Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok, 16424, Indonesia
| | - Mila Maidarti
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
| | - Ririn Rahmala Febri
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
| | - Kresna Mutia
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
| | - Pritta Ameilia Iffanolida
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
| | - Muhammad Ikhsan
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
| | - Kanadi Sumapraja
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
| | - Gita Pratama
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
| | - Achmad Kemal Harzif
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
| | - Andon Hestiantoro
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
| | - Budi Wiweko
- Human Reproduction, Infertility and Family Planning Research Center, Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia Jakarta, Jakarta, 10430, Indonesia
- Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, DKI Jakarta, 10430, Indonesia
- Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, 10430, Indonesia
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Hon JX, Wahab NA, Karim AKA, Mokhtar NM, Mokhtar MH. Exploring the Role of MicroRNAs in Progesterone and Estrogen Receptor Expression in Endometriosis. Biomedicines 2024; 12:2218. [PMID: 39457531 PMCID: PMC11504708 DOI: 10.3390/biomedicines12102218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/12/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Patients with endometriosis still respond poorly to progestins due to progesterone resistance associated with microRNAs (miRNAs). The aim of this study was to investigate the expression of selected miRNAs, estrogen receptor (ER)α, ERβ, progesterone receptor (PR)-A and PR-B and to determine the target genes of upregulated miRNAs in endometriosis. Methods: In this study, 18 controls, 18 eutopic and 18 ectopic samples were analysed. Profiling and validation of miRNAs associated with functions of endometriosis were performed using next-generation sequencing (NGS) and qRT-PCR. At the same time, the expression of ERα, ERβ, PR-A and PR-B was also determined using qRT-PCR. Target prediction was also performed for miR-199a-3p, miR-1-3p and miR-125b-5p using StarBase. Results: In this study, NGS identified seven significantly differentially expressed miRNAs, of which six miRNAs related to the role of endometriosis were selected for validation by qRT-PCR. The expression of miR-199a-3p, miR-1-3p, miR-146a-5p and miR-125b-5p was upregulated in the ectopic group compared to the eutopic group. Meanwhile, ERα and ERβ were significantly differentially expressed in endometriosis compared to the control group. However, the expressions of PR-A and PR-B showed no significant differences between the groups. The predicted target genes for miR-199a-3p, miR-1-3p and miR-125b-5p are SCD, TAOK1, DDIT4, LASP1, CDK6, TAGLN2, G6PD and ELOVL6. Conclusions: Our findings demonstrated that the expressions of ERα and ERβ might be regulated by miRNAs contributing to progesterone resistance, whereas the binding of miRNAs to target genes could also contribute to the pathogenesis of endometriosis. Therefore, miRNAs could be used as potential biomarkers and for targeted therapy in patients with endometriosis.
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Affiliation(s)
- Jing-Xian Hon
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (J.-X.H.)
| | - Norhazlina Abdul Wahab
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (J.-X.H.)
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Abdul Kadir Abdul Karim
- Department of Obstetrics & Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (J.-X.H.)
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Mohd Helmy Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (J.-X.H.)
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Ochoa Bernal MA, Song Y, Joshi N, Burns GW, Paul EN, Vegter E, Hrbek S, Sempere LF, Fazleabas AT. The Regulation of MicroRNA-21 by Interleukin-6 and Its Role in the Development of Fibrosis in Endometriotic Lesions. Int J Mol Sci 2024; 25:8994. [PMID: 39201680 PMCID: PMC11354763 DOI: 10.3390/ijms25168994] [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: 06/25/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/03/2024] Open
Abstract
Endometriosis is one of the most common causes of chronic pelvic pain and infertility that affects 10% of women of reproductive age. It is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in endometriosis research have some authors believing that endometriosis should be re-defined as "a fibrotic condition in which endometrial stroma and epithelium can be identified". microRNAs (miRNAs) are regulatory molecules that potentially play a role in endometriotic lesion development. There is evidence that suggests that miRNAs, including microRNA-21 (miR-21), participate in fibrotic processes in different organs, including the heart, kidney, liver and lungs. The objective of this study was to understand the role of miR-21 and the mechanisms that can contribute to the development of fibrosis by determining how IL-6 regulates miR-21 expression and how this miRNA regulates the transforming growth factor beta (TGF-β) signaling pathway to promote fibrosis. We investigated the expression of miR-21 in the baboon and mouse model of endometriosis and its correlation with fibrosis. We demonstrated that inflammation and fibrosis are present at a very early stage of endometriosis and that the inflammatory environment in the peritoneal cavity, which includes interleukin 6 (IL-6), can regulate the expression of miR-21 in vitro and in vivo.
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Affiliation(s)
- Maria Ariadna Ochoa Bernal
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
- Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
| | - Yong Song
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
| | - Niraj Joshi
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
| | - Gregory W. Burns
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
| | - Emmanuel N. Paul
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
| | - Erin Vegter
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
| | - Samantha Hrbek
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
| | - Lorenzo F. Sempere
- Precision Health Program and Department of Radiology Michigan State University, East Lansing, MI 48824, USA;
| | - Asgerally T. Fazleabas
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA; (M.A.O.B.); (Y.S.); (N.J.); (G.W.B.); (E.N.P.); (E.V.); (S.H.)
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9
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Hassan M, Shahzadi S, Yasir M, Chun W, Kloczkowski A. Therapeutic Implication of miRNAs as an Active Regulatory Player in the Management of Pain: A Review. Genes (Basel) 2024; 15:1003. [PMID: 39202362 PMCID: PMC11353898 DOI: 10.3390/genes15081003] [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: 11/30/2023] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 09/03/2024] Open
Abstract
Chronic pain is frequently associated with neuropathy, inflammation, or the malfunctioning of nerves. Chronic pain is associated with a significant burden of morbidity due to opioid use, associated with addiction and tolerance, and disability. MicroRNAs (miRs) are emerging therapeutic targets to treat chronic pain through the regulation of genes associated with inflammation, neuronal excitability, survival, or de-differentiation. In this review, we discuss the possible involvement of miRs in pain-related molecular pathways. miRs are known to regulate high-conviction pain genes, supporting their potential as therapeutic targets.
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Affiliation(s)
- Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (S.S.); (A.K.)
| | - Saba Shahzadi
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (S.S.); (A.K.)
| | - Muhammad Yasir
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Wanjoo Chun
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (S.S.); (A.K.)
- Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43205, USA
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
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10
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Kluz N, Kowalczyk E, Wasilewska M, Gil-Kulik P. Diagnostic Value and Molecular Function of MicroRNAs in Endometrial Diseases: A Systematic Review. Cancers (Basel) 2024; 16:2416. [PMID: 39001478 PMCID: PMC11240806 DOI: 10.3390/cancers16132416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
The human endometrium experiences significant cyclic morphological and biochemical changes throughout the menstrual cycle to prepare for embryo implantation. These processes are meticulously regulated by ovarian steroids and various locally expressed genes, encompassing inflammatory reactions, apoptosis, cell proliferation, angiogenesis, differentiation (tissue formation), and tissue remodeling. MicroRNAs (miRNAs) have been recognized as crucial regulators of gene expression, with their altered expression being linked to the onset and progression of various disorders, including cancer. This review examines the expression of miRNAs in the endometrium and their potential regulatory roles under pathological conditions such as endometriosis, recurrent implantation failure and endometrial cancer. Given miRNAs' critical role in maintaining gene expression stability, understanding the regulatory mechanisms of endometrial miRNAs and identifying their specific target genes could pave the way for developing preventive and therapeutic strategies targeting specific genes associated with these reproductive disorders.
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Affiliation(s)
- Natalia Kluz
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland;
| | - Emilia Kowalczyk
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland;
| | - Małgorzata Wasilewska
- Department of Physical Chemistry, Institute of Chemical Sciences, Maria Curie-Sklodowska University, Maria Curie-Sklodowska Sq. 3, 20-031 Lublin, Poland;
| | - Paulina Gil-Kulik
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland;
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11
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Ochoa Bernal MA, Fazleabas AT. The Known, the Unknown and the Future of the Pathophysiology of Endometriosis. Int J Mol Sci 2024; 25:5815. [PMID: 38892003 PMCID: PMC11172035 DOI: 10.3390/ijms25115815] [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: 04/02/2024] [Revised: 05/14/2024] [Accepted: 05/19/2024] [Indexed: 06/21/2024] Open
Abstract
Endometriosis is one of the most common causes of chronic pelvic pain and infertility, affecting 10% of women of reproductive age. A delay of up to 9 years is estimated between the onset of symptoms and the diagnosis of endometriosis. Endometriosis is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in research on endometriosis have some authors believing that endometriosis should be re-defined as "a fibrotic condition in which endometrial stroma and epithelium can be identified". There are several theories on the etiology of the disease, but the origin of endometriosis remains unclear. This review addresses the role of microRNAs (miRNAs), which are naturally occurring post-transcriptional regulatory molecules, in endometriotic lesion development, the inflammatory environment within the peritoneal cavity, including the role that cytokines play during the development of the disease, and how animal models have helped in our understanding of the pathology of this enigmatic disease.
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Affiliation(s)
- Maria Ariadna Ochoa Bernal
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA;
- Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
| | - Asgerally T. Fazleabas
- Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI 49503, USA;
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12
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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. Inflammation 2023; 46:2055-2070. [PMID: 37389684 PMCID: PMC10673760 DOI: 10.1007/s10753-023-01862-x] [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: 04/28/2023] [Revised: 06/04/2023] [Accepted: 06/21/2023] [Indexed: 07/01/2023]
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 was 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 western blot analysis. The elevated secretion of TNFα in EESCs downregulates the expression level of several miRNAs significantly in EESCs compared to NESCs. 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 suppressing the phosphorylation of AKT, ERK, and NF-κB.
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Affiliation(s)
- Saswati Banerjee
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA
| | - Wei Xu
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA
| | - Aaron Doctor
- Department of Obstetrics and Gynecology, Morehouse School of Medicine, 720 Westview Drive Southwest, Atlanta, GA, 30310, USA
| | - Adel Driss
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA
| | - Ceana Nezhat
- Nezhat Medical Center, 5555 Peachtree Dunwoody Road, Atlanta, GA, 30342, USA
| | - Neil Sidell
- Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Robert N Taylor
- Department of Obstetrics and Gynecology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14203, USA
| | - Winston E Thompson
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA
- Department of Obstetrics and Gynecology, Morehouse School of Medicine, 720 Westview Drive Southwest, Atlanta, GA, 30310, USA
| | - Indrajit Chowdhury
- Department of Obstetrics and Gynecology, Morehouse School of Medicine, 720 Westview Drive Southwest, Atlanta, GA, 30310, USA.
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13
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Begum MIA, Chuan L, Hong ST, Chae HS. The Pathological Role of miRNAs in Endometriosis. Biomedicines 2023; 11:3087. [PMID: 38002087 PMCID: PMC10669455 DOI: 10.3390/biomedicines11113087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/13/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Association studies investigating miRNA in relation to diseases have consistently shown significant alterations in miRNA expression, particularly within inflammatory pathways, where they regulate inflammatory cytokines, transcription factors (such as NF-κB, STAT3, HIF1α), and inflammatory proteins (including COX-2 and iNOS). Given that endometriosis (EMS) is characterized as an inflammatory disease, albeit one influenced by estrogen levels, it is natural to speculate about the connection between EMS and miRNA. Recent research has indeed confirmed alterations in the expression levels of numerous microRNAs (miRNAs) in both endometriotic lesions and the eutopic endometrium of women with EMS, when compared to healthy controls. The undeniable association of miRNAs with EMS hints at the emergence of a new era in the study of miRNA in the context of EMS. This article reviews the advancements made in understanding the pathological role of miRNA in EMS and its association with EMS-associated infertility. These findings contribute to the ongoing pursuit of developing miRNA-based therapeutics and diagnostic markers for EMS.
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Affiliation(s)
- Mst Ismat Ara Begum
- Department of Biomedical Sciences, Institute for Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea; (M.I.A.B.); (L.C.)
| | - Lin Chuan
- Department of Biomedical Sciences, Institute for Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea; (M.I.A.B.); (L.C.)
| | - Seong-Tshool Hong
- Department of Biomedical Sciences, Institute for Medical Science, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea; (M.I.A.B.); (L.C.)
| | - Hee-Suk Chae
- Department of Obstetrics and Gynecology, Research Institute of Clinical Medicine, Jeonbuk National University, Jeonju 54907, Republic of Korea
- Biomedical Research Institute, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea
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14
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Hakimi P, Tabatabaei F, Rahmani V, Zakariya NA, Moslehian MS, Bedate AM, Tamadon A, Rahbarghazi R, Mahdipour M. Dysregulated miRNAs in recurrent miscarriage: A systematic review. Gene 2023; 884:147689. [PMID: 37543220 DOI: 10.1016/j.gene.2023.147689] [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: 05/10/2023] [Revised: 07/12/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023]
Abstract
Recurrent miscarriage (RM) is a complex reproductive medicine disease that affects many families. The cause of RM is unclear at this time; however, lifestyle and genetic variables may influence the process. The slight alteration in miRNA expression has enormous consequences for a variety of difficulties, one of which may be RM. The target of this systematic study was to provide a framework of the dysregulated miRNAs in RM. The Prisma guidelines were applied to perform current systematic review pertaining to articles in the seven databases. Thirty-nine papers out of 245 received fulfilled all inclusion requirements. From all the mentioned miRNAs, 40 were up-regulated (65.57 %), whereas 21 were down-regulated (34.43 %). These dysregulated miRNAs contributed to the pathophysiology of RM by influencing key pathways and processes such as apoptosis, angiogenesis, epithelial-mesenchymal transition, and the immune system. Understanding the dysregulation of miRNAs, as well as the pathways and processes that engage these miRNAs and impact disease pathogenesis, may aid in clarifying the unknown underlying mechanisms of RM and the development of novel molecular therapeutic targets and medical domains.
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Affiliation(s)
- Parvin Hakimi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Tabatabaei
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Obstetrics and Gynecology, Division of Gynecologic Laparoscopic, Surgeries, Al-Zahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran; Iranian Society of Minimally Invasive Gynecology, Iran University of Medical, Sciences, Tehran, Iran
| | - Vahideh Rahmani
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nahideh Afshar Zakariya
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Amin Tamadon
- PerciaVista R&D Co, Shiraz, Iran; Department for Scientific Work, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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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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16
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Zhang P, Wang G. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms. Int J Mol Sci 2023; 24:ijms24086992. [PMID: 37108154 PMCID: PMC10138736 DOI: 10.3390/ijms24086992] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/28/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Endometriosis is an estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the uterus. Progestins are currently the most commonly used treatment for endometriosis because of their excellent therapeutic effects and limited side effects. However, progestins have been unsuccessful in some symptomatic patients. The inability of the endometrium to respond properly to progesterone is known as progesterone resistance. An increasing body of evidence suggests the loss of progesterone signaling and the existence of progesterone resistance in endometriosis. The mechanisms of progesterone resistance have received considerable scholarly attention in recent years. Abnormal PGR signaling, chronic inflammation, aberrant gene expression, epigenetic alterations, and environmental toxins are considered potential molecular causes of progesterone resistance in endometriosis. The general objective of this review was to summarize the evidence and mechanisms of progesterone resistance. A deeper understanding of how these mechanisms contribute to progesterone resistance may help develop a novel therapeutic regimen for women with endometriosis by reversing progesterone resistance.
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Affiliation(s)
- Ping Zhang
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan 250021, China
| | - Guoyun Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
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17
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Viganò P, Casalechi M, Vercellini P, Somigliana E. “Shadow of a Doubt”—The Pathogenic Role of Endometrial Defects in Endometriosis Development and Endometriosis-Associated Infertility: Robust Demonstration of Clinical Relevance Is Still Urgently Needed. Biomolecules 2023; 13:biom13040651. [PMID: 37189399 DOI: 10.3390/biom13040651] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Endometriosis is an estrogen-dependent chronic inflammatory disease characterized by the presence of endometrial glands and stroma associated with fibrosis outside the uterine cavity [...]
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Affiliation(s)
- Paola Viganò
- Infertility Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 28, 20122 Milan, Italy
| | - Maíra Casalechi
- Division of Human Reproduction, Hospital das Clínicas-Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil
| | - Paolo Vercellini
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
- Gynecology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Edgardo Somigliana
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
- Gynecology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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18
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Ruiz-Magaña MJ, Puerta JM, Llorca T, Méndez-Malagón C, Martínez-Aguilar R, Abadía-Molina AC, Olivares EG, Ruiz-Ruiz C. Influence of the ectopic location on the antigen expression and functional characteristics of endometrioma stromal cells. Reprod Biomed Online 2023; 46:460-469. [PMID: 36586747 DOI: 10.1016/j.rbmo.2022.12.005] [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: 07/29/2022] [Revised: 10/28/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
RESEARCH QUESTION Are the alterations observed in the endometriotic cells, such as progesterone resistance, already present in the eutopic endometrium or acquired in the ectopic location? DESIGN The response to decidualization with progesterone and cyclic AMP for up to 28 days was compared in different endometrial stromal cell (EnSC) lines established from samples of endometriomas (eEnSC), eutopic endometrium from women with endometriosis (eBEnSC), endometrial tissue from healthy women (BEnSC) and menstrual blood from healthy donors (mEnSC). RESULTS Usual features of decidualized cells, such as changes in cell morphology and expression of prolactin, were similarly observed in the three types of eutopic EnSC studied, but not in the ectopic cells upon decidualization. Among the phenotypic markers analysed, CD105 was down-regulated under decidualization in all cell types (mEnSC, P = 0.005; BEnSC, P = 0.029; eBEnSC, P = 0.022) except eEnSC. mEnSC and BEnSC underwent apoptosis during decidualization, whereas eBEnSC and eEnSC were resistant to the induction of cell death. Lastly, migration studies revealed that mEnSC secreted undetermined factors during decidualization that inhibited cell motility, whereas eEnSC showed a significantly lower ability to produce those migration-regulating factors (P < 0.0001, P < 0.001 and P = 0.0013 for the migration of mEnSC at 24, 48 and 72 h, respectively; P < 0.0001 for the migration of eEnSC at all times studied). CONCLUSIONS This study provides novel insights into the differences between endometriotic and eutopic endometrial cells and reinforces the idea that the microenvironment in the ectopic location plays additional roles in the acquisition of the alterations that characterize the cells of the endometriotic foci.
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Affiliation(s)
- María José Ruiz-Magaña
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain
| | - José M Puerta
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Hospital Quirón Ruber Juan Bravo, Madrid, Spain
| | - Tatiana Llorca
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain
| | - Cristina Méndez-Malagón
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain
| | - Rocío Martínez-Aguilar
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain; Medical Research Council Centre for Reproductive Health, University of Edinburgh, Scotland, UK
| | - Ana Clara Abadía-Molina
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain
| | - Enrique G Olivares
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain; Unidad de Gestión Clínica Laboratorios, Complejo Hospitalario Universitario de Granada, Granada, Spain.
| | - Carmen Ruiz-Ruiz
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain.
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19
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Liu T, Xiao L, Pei T, Luo B, Tan J, Long Y, Huang X, Ouyang Y, Huang W. miR-297 inhibits expression of progesterone receptor and decidualization in eutopic endometria of endometriosis. J Obstet Gynaecol Res 2023; 49:956-965. [PMID: 36572643 DOI: 10.1111/jog.15526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 12/05/2022] [Indexed: 12/28/2022]
Abstract
AIM Progesterone resistance is an epigenetic factor that reduces endometrial receptivity and causes implantation failure in women with endometriosis. In addition, dysregulated miRNAs contribute to the underlying pathogenic mechanisms of endometriosis. This study aimed to determine the effect of miR-297 on the progesterone receptor (PR) expression and on insufficient decidualization of endometrial stromal cells (ESCs) within the eutopic endometria of infertile women with minimal or mild endometriosis. METHODS ESCs were isolated from infertile endometriosis and normal patients and were transfected with miR-297 mimic or miR-297 inhibitor or respective control. qRT-PCR and western blot were conducted to quantify the expression of miR-297 and PR. The effect of miR-297 on ESCs decidualization was investigated by induced decidualization in vitro. RESULTS We observed an increase in miR-297 expression and a decrease in the expression of PR in the ESCs from endometriosis patients. Moreover, the expression of PR, most notably PRB, was found to be downregulated following transfection with miR-297 mimic and upregulated following treatment with miR-297 inhibitor. In addition, overexpressed miR-297 inhibited the decidualization of ESCs in vitro. We further determined that miR-297 exerts direct regulatory effects on PR expression. CONCLUSIONS We demonstrated that miR-297 interferes with fertility by repressing the expression of PR and preventing efficient decidualization in eutopic endometria. Further, miR-297 directly contributes to progesterone resistance in minimal or mild cases of endometriosis. Thus, regulation of miR-297 may prove to be a promising therapeutic strategy for endometriosis.
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Affiliation(s)
- Tingting Liu
- Department of Obstetrics and Gynecology, The People's Hospital of Leshan, Leshan, China.,Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Li Xiao
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Tianjiao Pei
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Bin Luo
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Jing Tan
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Ying Long
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Xin Huang
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Yunwei Ouyang
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
| | - Wei Huang
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
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Shan J, Li DJ, Wang XQ. Towards a Better Understanding of Endometriosis-Related Infertility: A Review on How Endometriosis Affects Endometrial Receptivity. Biomolecules 2023; 13:biom13030430. [PMID: 36979365 PMCID: PMC10046640 DOI: 10.3390/biom13030430] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Endometriosis is the most common cause of infertility. Endometrial receptivity has been suggested to contribute to infertility and poor reproductive outcomes in affected women. Even though experimental and clinical data suggest that the endometrium differs in women with endometriosis, the pathogenesis of impaired endometrial receptivity remains incomplete. Therefore, this review summarizes the potential mechanisms that affect endometrial function and contribute to implantation failure. Contemporary data regarding hormone imbalance, inflammation, and immunoregulatory dysfunction will be reviewed here. In addition, genetic, epigenetic, glycosylation, metabolism and microRNA in endometriosis-related infertility/subfertility will be summarized. We provide a brief discussion and perspectives on their future clinical implications in the diagnosis and therapy to improve endometrial function in affected women.
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Affiliation(s)
- Jing Shan
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
| | - Da-Jin Li
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- Department of Obstetrics and Gynecology, Hainan Medical College Affiliated Hospital, Haikou 571100, China
- Correspondence: (D.-J.L.); (X.-Q.W.)
| | - Xiao-Qiu Wang
- Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- Correspondence: (D.-J.L.); (X.-Q.W.)
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21
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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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22
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From Retrograde Menstruation to Endometrial Determinism and a Brave New World of "Root Treatment" of Endometriosis: Destiny or a Fanciful Utopia? Biomolecules 2023; 13:biom13020336. [PMID: 36830705 PMCID: PMC9953699 DOI: 10.3390/biom13020336] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 02/01/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Practically unknown outside of China, the "endometrial determinism" theory was proposed to account for the apparent gap between the relatively low prevalence of endometriosis and nearly universal retrograde menstruation. Attracting uncritical advocacy, the theory culminates in a recent consensus by elite Chinese gynecologists in favor of "root treatment", intended to nip endometriosis in the bud. Correcting endometrial "defects" can gain further momentum by the presence of cancer-driver mutations such as KRAS mutations in the endometrium of women with endometriosis and the recent introduction of therapeutics aiming to rectify the effect of these mutations for cancer treatment. We provide a critical appraisal of evidence for endometrial aberrations in endometriosis and relevant experimental evidence. All available evidence of endometrial "defect" is invariably post hoc and may well be secondary to induced endometriosis. We propose that the theory of "endometrial determinism" needs to demonstrate a clear causal and a phylogenetic relationship between endometrial aberrations and endometriosis. We argue that while it is highly likely that endometriosis is a consequence of retrograde menstruation, the case that molecular aberrations as a sole or a necessary determinant remains to be proven. "Root treatment" is a worthy ambition but as of now it is close to a fanciful Utopia.
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23
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Muharam R, Rahmala Febri R, Mutia K, Ameilia Iffanolida P, Maidarti M, Wiweko B, Hestiantoro A. Down-Regulation of miR-93 Negatively Correlates with Overexpression of VEGFA and MMP3 in Endometriosis: A Cross-Sectional Study. INTERNATIONAL JOURNAL OF FERTILITY & STERILITY 2023; 17:28-33. [PMID: 36617199 PMCID: PMC9807893 DOI: 10.22074/ijfs.2022.543884.1233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Endometriosis is identified as presence of the endometrium outside the uterine cavity. Retrograde menstruation contributes to the endometrial tissue implantation and the establishment of endometriotic lesions at ectopic sites. It has been suggested that the endometriotic lesions are rich in angiogenic growth factors, while they have an essential role in survival and invasion of these cells. We investigated regulation of microRNA-93 (miR-93) and its involvement with vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase (MMP) 3 expression in women with endometriosis. MATERIALS AND METHODS This was a cross-sectional study at Central Surgical Installation, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, between October 2020 and November 2021. Eutopic and ectopic endometrial tissues were collected from 30 subjects with laparoscopically-confirmed endometriotic women. Normal endometrial cells of non-endometriosis women served as controls. Total RNA was isolated from all samples and a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to analyze the expression of miR-93, VEGFA and MMP. RESULTS There was no significant difference in the expression levels of VEGFA (2.14 ± 0.50, P=0.719) and MMP3 (2.99 ± 0.42, P=0.583) between endometriotic lesions of endometriosis women and the healthy endometrium. Expression of miR-93 was significantly lower in the eutopic endometrium (16.7 fold) and ectopic endometriotic lesion (20 fold) compared to the normal endometrium (P<0.001). Furthermore, we also observed a significant correlation between miR-93, VEGFA expression in eutopic endometrium obtained from women with endometriosis (r=-0.544, P=0.029). Expression of the miR-93 was also negatively correlated with MMP3 expression in both eutopic (r=-0.412, P=0.01) and ectopic (r=-0.539, P=0.03) endometrial cells of women with endometriosis. CONCLUSION VEGFA and MMP3 expression levels trended to be increased in both eutopic and ectopic endometrial tissues of endometriosis women, while down-regulation of miR-93 might be involved in the alteration of VEGFA and MMP3 in endometriosis.
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Affiliation(s)
- Raden Muharam
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas
Indonesia, Jakarta, Indonesia,Human Reproduction, Infertility, and Family Planning Research Center, Indonesian Medical Education and Research Institute
(IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia,Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia,Division of Reproductive Endocrinology and InfertilityDepartment of Obstetrics and GynecologyFaculty of MedicineUniversitas IndonesiaJakartaIndonesia
| | - Ririn Rahmala Febri
- Human Reproduction, Infertility, and Family Planning Research Center, Indonesian Medical Education and Research Institute
(IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Kresna Mutia
- Human Reproduction, Infertility, and Family Planning Research Center, Indonesian Medical Education and Research Institute
(IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Pritta Ameilia Iffanolida
- Human Reproduction, Infertility, and Family Planning Research Center, Indonesian Medical Education and Research Institute
(IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Mila Maidarti
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas
Indonesia, Jakarta, Indonesia,Human Reproduction, Infertility, and Family Planning Research Center, Indonesian Medical Education and Research Institute
(IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia,Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
| | - Budi Wiweko
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas
Indonesia, Jakarta, Indonesia,Human Reproduction, Infertility, and Family Planning Research Center, Indonesian Medical Education and Research Institute
(IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia,Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
| | - Andon Hestiantoro
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas
Indonesia, Jakarta, Indonesia,Human Reproduction, Infertility, and Family Planning Research Center, Indonesian Medical Education and Research Institute
(IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia,Yasmin IVF Clinic, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
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24
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Endometriosis Stem Cells as a Possible Main Target for Carcinogenesis of Endometriosis-Associated Ovarian Cancer (EAOC). Cancers (Basel) 2022; 15:cancers15010111. [PMID: 36612107 PMCID: PMC9817684 DOI: 10.3390/cancers15010111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
Endometriosis is a serious recurrent disease impairing the quality of life and fertility, and being a risk for some histologic types of ovarian cancer defined as endometriosis-associated ovarian cancers (EAOC). The presence of stem cells in the endometriotic foci could account for the proliferative, migrative and angiogenic activity of the lesions. Their phenotype and sources have been described. The similarly disturbed expression of several genes, miRNAs, galectins and chaperones has been observed both in endometriotic lesions and in ovarian or endometrial cancer. The importance of stem cells for nascence and sustain of malignant tumors is commonly appreciated. Although the proposed mechanisms promoting carcinogenesis leading from endometriosis into the EAOC are not completely known, they have been discussed in several articles. However, the role of endometriosis stem cells (ESCs) has not been discussed in this context. Here, we postulate that ESCs may be a main target for the carcinogenesis of EAOC and present the possible sequence of events resulting finally in the development of EAOC.
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25
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Arosh JA, Sivakumar KK, Lee J, Banu SK. Effects of selective inhibition of prostaglandin E2 receptors EP2 and EP4 on the miRNA profile in endometriosis. Mol Cell Endocrinol 2022; 558:111728. [PMID: 35944745 DOI: 10.1016/j.mce.2022.111728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/12/2022] [Accepted: 07/13/2022] [Indexed: 12/15/2022]
Abstract
Endometriosis is an estrogen-dependent, progesterone-resistant, chronic inflammatory gynecological disease of reproductive-age women. Two major clinical symptoms of endometriosis are chronic pelvic pain and infertility, which profoundly affect the quality of life in women. Current hormonal therapies to induce a hypoestrogenic state are unsuccessful because of undesirable side effects, reproductive health concerns, and failure to prevent disease recurrence. Prostaglandin E2 (PGE2) plays an important role in the survival and growth of endometriotic lesions. MicroRNAs (miRNAs) are small, noncoding RNAs that control gene expressions through multiple mechanisms and have important roles in the pathogenesis of endometriosis. The objective of the present study is to determine the effects of pharmacological inhibition of PGE2 receptors, EP2 and EP4, on miRNA profile in endometriosis. The novel results collectively indicate that inhibition of PGE2-EP2/EP4 signaling regulated several miRNA clusters associated with cell adhesion, migration, invasion, survival and growth in cell-specific and the chromosome-specific manner and reverses the epigenetic silencing of proapoptotic miRNAs 15a and 34c in the human endometriotic epithelial and stromal cells and experimental endometriotic lesions. Thus, selective inhibition of EP2/EP4 receptors could emerge as a potential nonsteroidal therapy for endometriosis.
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Affiliation(s)
- Joe A Arosh
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA.
| | - Kirthiram K Sivakumar
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA
| | - JeHoon Lee
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA
| | - Sakhila K Banu
- Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, TX, 77843, College Station, USA
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26
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Roles of microRNAs in Regulating Apoptosis in the Pathogenesis of Endometriosis. Life (Basel) 2022; 12:life12091321. [PMID: 36143357 PMCID: PMC9500848 DOI: 10.3390/life12091321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/24/2022] Open
Abstract
Endometriosis is a gynecologic disorder characterized by the presence of endometrial tissues outside the uterine cavity affecting reproductive-aged women. Previous studies have shown that microRNAs and their target mRNAs are expressed differently in endometriosis, suggesting that this molecule may play a role in the development and persistence of endometriotic lesions. microRNA (miRNA), a small non-coding RNA fragment, regulates cellular functions such as cell proliferation, differentiation, and apoptosis by the post-transcriptional modulation of gene expression. In this review, we focused on the dysregulated miRNAs in women with endometriosis and their roles in the regulation of apoptosis. The dysregulated miRNAs and their target genes in this pathophysiology were highlighted. Circulating miRNAs as potential biomarkers for the diagnosis of endometriosis have also been identified. As shown by various studies, miRNAs were reported to be a potent regulator of gene expression in endometriosis; thus, identifying the dysregulated miRNAs and their target genes could help discover new therapeutic targets for treating this disease. The goal of this review is to draw attention to the functions that miRNAs play in the pathophysiology of endometriosis, particularly those that govern cell death.
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27
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Liu Y, Fan L, Jin L, Lu C, Li T, Zhang Z, Xie C, Li S, Zhang Y, Ren J, Lu D. Integrated bioinformatic analysis of dysregulated microRNA-mRNA co-expression network in ovarian endometriosis. Acta Obstet Gynecol Scand 2022; 101:1074-1084. [PMID: 35876135 PMCID: PMC9812100 DOI: 10.1111/aogs.14430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 06/10/2022] [Accepted: 07/11/2022] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Ovarian endometriosis is a frequently occurring gynecological disease with large socioeconomic impact. Accumulating evidence has suggested that aberrant miRNA-mRNA interactions are involved in the pathogenesis and progression of ovarian endometriosis. This study aims to identify key miRNAs in ovarian endometriosis by using integrated bioinformatic analysis of a dysregulated miRNA-mRNA co-expression network. MATERIAL AND METHODS Expression profiling of miRNA and mRNA in three normal endometria and five pairs of ectopic/eutopic endometria from patients with ovarian endometriosis was determined by high-throughput sequencing techniques. The data were then integrated with the public sequencing datasets (GSE105764 and GSE105765) using a non-biased approach and a miRNA-mRNA co-expression regulatory network was constructed by in-depth bioinformatic analysis. RESULTS The constructed miRNA-mRNA network included 87 functionally DEMs, 482 target mRNAs and 1850 paired miRNA-mRNA regulatory interactions. Specifically, five miRNAs (miR-141-3p, miR-363-3p, miR-577, miR-767-5p, miR-96-5p) were gradually decreased and two miRNAs (miR-493-5p, miR-592) were gradually increased from normal endometria to eutopic endometria, and then ectopic endometria tissues. Importantly, miR-141-3p, miR-363-3p and miR-96-5p belonged to the miR-200 family, miR-106a-363 cluster and miR-183/96/182 cluster, respectively. Their target mRNAs were mainly associated with cell adhesion, locomotion and binding, which are suggested to play vital regulatory roles in the pathogenesis of ovarian endometriosis. CONCLUSIONS Integrated bioinformatic analysis of the miRNA-mRNA co-expression network defines the crucial roles of the miR-200 family, miR-106a-363 cluster and miR-183/96/182 cluster in the pathogenesis of ovarian endometriosis. Further in-depth functional studies are needed to unveil the molecular mechanisms of these miRNAs, and may provide clues for the optimization of therapeutic strategies for ovarian endometriosis.
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Affiliation(s)
- Yong Liu
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Linyuan Fan
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Lingge Jin
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Chang Lu
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Ting Li
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Zhan Zhang
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Chengmao Xie
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Shenghui Li
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Yudi Zhang
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Jian Ren
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
| | - Dan Lu
- Department of Gynecology, Beijing Obstetrics and Gynecology HospitalCapital Medical University. Beijing Maternal and Child Health Care HospitalBeijingChina
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28
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Nasu K, Aoyagi Y, Zhu R, Okamoto M, Kai K, Kawano Y. Promising therapeutic targets of endometriosis obtained from microRNA studies. Med Mol Morphol 2022; 55:85-90. [PMID: 34846581 DOI: 10.1007/s00795-021-00308-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/02/2021] [Indexed: 10/19/2022]
Abstract
Endometriosis is a benign tumor that affect 6-10% women of reproductive age. To date, it is suggested that the aberrant microRNA (miRNA) expressions play important roles in the pathogenesis of endometriosis. Reviewing the literature, we found nine overexpressed miRNAs, which were thoroughly investigated in the context of endometriotic tissues and cells. Most of the overexpressed miRNAs induced endometriosis-specific characteristics including inhibition of apoptosis and decidualization, upregulation of fibrogenesis, invasion, migration, cell proliferation, attachment to extracellular matrix, inflammation, and angiogenesis in the endometriotic cells. Then, we found that the downstream target molecules of these miRNAs, such as early growth response protein-1, extracellular signal-regulated kinase, matrix metallopeptidase 1, signal transducer and activator of transcription 3, cyclooxygenase-2, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, and vascular endothelial growth factor-A are promising for the therapeutic targets of endometriosis. Recent findings suggest that complex molecular mechanisms leading to development and progression of endometriosis by miRNAs may exist in endometriosis. The meticulous balance between tumorigenic miRNAs and tumoristatic miRNAs may destine the natural course and response to the surgical, medical, and hormonal treatments of this disease. Further investigations into endometriosis-associated miRNAs may elucidate the pathogenesis of endometriosis and help to develop novel therapeutics.
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Affiliation(s)
- Kaei Nasu
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan.
- Division of Obstetrics and Gynecology, Support System for Community Medicine, Faculty of Medicine, Oita University, Oita, Japan.
| | - Yoko Aoyagi
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Ruofei Zhu
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Mamiko Okamoto
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Kentaro Kai
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Yasushi Kawano
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
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29
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Sabina S, Panico A, Mincarone P, Leo CG, Garbarino S, Grassi T, Bagordo F, De Donno A, Scoditti E, Tumolo MR. Expression and Biological Functions of miRNAs in Chronic Pain: A Review on Human Studies. Int J Mol Sci 2022; 23:ijms23116016. [PMID: 35682695 PMCID: PMC9181121 DOI: 10.3390/ijms23116016] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 02/01/2023] Open
Abstract
Chronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management.
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Affiliation(s)
- Saverio Sabina
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
| | - Alessandra Panico
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
| | - Pierpaolo Mincarone
- Institute for Research on Population and Social Policies, National Research Council, c/o ex Osp. Di Summa, Piazza Di Summa, 72100 Brindisi, Italy;
| | - Carlo Giacomo Leo
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
| | - Sergio Garbarino
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal/Child Sciences, University of Genoa, 16132 Genoa, Italy;
| | - Tiziana Grassi
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
| | - Francesco Bagordo
- Department of Pharmacy-Pharmaceutical Science, University of Bari Aldo Moro, Via Edoardo Orabona, 70126 Bari, Italy;
| | - Antonella De Donno
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
| | - Egeria Scoditti
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
- Correspondence: ; Tel.: +39-(08)-3229-8860
| | - Maria Rosaria Tumolo
- Institute of Clinical Physiology, National Research Council, Via Monteroni, 73100 Lecce, Italy; (S.S.); (C.G.L.); (M.R.T.)
- Department of Biological and Environmental Sciences and Technology, University of Salento, Via Monteroni, 73100 Lecce, Italy; (A.P.); (T.G.); (A.D.D.)
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30
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Li J, Yan S, Li Q, Huang Y, Ji M, Jiao X, Yuan M, Wang G. Macrophage Associated Immune Checkpoint CD47 Blocking Ameliorates Endometriosis. Mol Hum Reprod 2022; 28:6566307. [PMID: 35404426 DOI: 10.1093/molehr/gaac010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/28/2022] [Indexed: 11/14/2022] Open
Abstract
Abstract
Peritoneal macrophages play a significant role in the progression of endometriosis (EM), but their functional differentiation is still unclear, and their phagocytic ability is weak. CD47-SIRPα and PD-L1-PD-1 are considered immune checkpoints associated with macrophage phagocytosis. A specific blockade of these two pathways had been shown to increase the phagocytic clearance of cancer cells by macrophages in most cancers. We hypothesized that targeting CD47/PD-L1 in EM could improve the phagocytosis of macrophages, thereby delaying the progression of EM. From localization to quantification, from mRNA to protein, we comprehensively evaluated the expression of CD47 and PD-L1 in EM. We demonstrated that the CD47 expression in ectopic endometrium from patients with EM was significantly increased, but PD-L1was not. We performed direct co-culture experiments of endometrial stromal cells with macrophages in vitro and in vivo to assess whether ectopic endometrial stromal cells escape macrophage phagocytosis through the CD47-SIRPα signaling pathway. The results showed that targeting CD47 increased the phagocytic capacity of macrophages. Interestingly, we also found that the reduction of CD47 expression promoted apoptosis of ESCs. In conclusion, these data suggested that targeting CD47 can effectively target ectopic endometrial stromal cells through a dual mechanism of increased phagocytosis of macrophages and induced apoptosis of ectopic endometrial stromal cells. Thus, immunotherapy based on the CD47-SIRPa signaling pathway has some potential in treating EM, but further mechanistic studies are needed to explore more effective and specific antibodies.
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Affiliation(s)
- Jing Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Shumin Yan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Qiuju Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Yufei Huang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Miaomiao Ji
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Xue Jiao
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Ming Yuan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Guoyun Wang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
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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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Nasu K, Aoyagi Y, Zhu R, Okamoto M, Yano M, Kai K, Kawano Y. Role of repressed microRNAs in endometriosis. Med Mol Morphol 2022; 55:1-7. [PMID: 34463829 DOI: 10.1007/s00795-021-00303-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023]
Abstract
Endometriosis is a common, estrogen-dependent benign tumor that affect 3-10% women of reproductive age, and is characterized by the ectopic growth of endometrial tissue, which is found primarily in the rectovaginal septum, ovaries, and pelvic peritoneum. To date, accumulating evidence suggests that various epigenetic aberrations, including the expression of aberrant microRNAs (miRNAs), play definite roles in the pathogenesis of endometriosis. This review summarizes the recent findings on the aberrantly repressed miRNAs, as well as their potential roles regarding the pathogenesis of endometriosis.
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Affiliation(s)
- Kaei Nasu
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan.
- Division of Obstetrics and Gynecology, Support System for Community Medicine, Faculty of Medicine, Oita University, Oita, Japan.
| | - Yoko Aoyagi
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Ruofei Zhu
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Mamiko Okamoto
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Mitsutake Yano
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Kentaro Kai
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
| | - Yasushi Kawano
- Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan
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Srivastava P, Bamba C, Chopra S, Mandal K. Role of miRNA polymorphism in recurrent pregnancy loss: a systematic review and meta-analysis. Biomark Med 2022; 16:101-115. [PMID: 35026953 DOI: 10.2217/bmm-2021-0568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
There are a plethora of publications on the role of miRNA gene polymorphism and its association with recurrent pregnancy loss (RPL), but a lack of uniformity in the studies available due to the variable subject population, heterogeneity and contrary results of significance. Rigorous data mining was done through PubMed, SCOPUS, Cochrane library, Elsevier and Google Scholar to extract the studies of interest published until June 2021. A total of eight SNPs of miRNAs have been included, where ≥2 studies per SNPs were available. Analysis was done on the basis of pooled odds ratios and 95% CI. This is the first meta-analysis on miRNA SNPs in RPL that suggests that rs11614913, rs3746444 and rs2292832 biomarkers may decrease the risk of RPL under different genetic models.
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Affiliation(s)
- Priyanka Srivastava
- Genetic Metabolic Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education & Research, Sector-12, Chandigarh, 160012, India
| | - Chitra Bamba
- Genetic Metabolic Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education & Research, Sector-12, Chandigarh, 160012, India
| | - Seema Chopra
- Department of Obstetric & Gynaecology, Post Graduate Institute of Medical Education & Research, Sector-12, Chandigarh, 160012, India
| | - Kausik Mandal
- Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Bareli Road, Lucknow, 226014, Uttar Pradesh, India
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Jaafar SO, Jaffar JO, Ibrahim SA, Jarjees KK. MicroRNA Variants miR-27a rs895819 and miR-423 rs6505162, but not miR-124-1 rs531564, are Linked to Endometriosis and its Severity. Br J Biomed Sci 2022; 79:10207. [PMID: 35996508 PMCID: PMC8915672 DOI: 10.3389/bjbs.2021.10207] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 12/02/2021] [Indexed: 12/20/2022]
Abstract
Background: While different studies have investigated the association of SNPs with female reproductive disorders, a limited number of studies have investigated the effect of microRNAs variants in endometriosis. In this study, we evaluated the prevalence and the association of three different miRNAs variants including, miR-27a rs895819, miR-124-1 rs531564, and miR-423 rs6505162 with endometriosis to help further elucidate the importance of these variants in female reproductive disorders. Methods: A total number of 440 women (220 cases and 220 controls) were included. DNA was extracted and genotyping of the SNPs was carried out by PCR. Results: The results showed that rs895819 and rs6505162 had a significant association with endometriosis under the dominant, recessive, co-dominant, and allelic model, but rs531564 was not linked to endometriosis. Our results also imply a protective effect on endometriosis severity for AG genotype and G allele in rs895819 (p < 0.001), and also for AA and AC genotypes in rs6505162 with severity in endometriosis (p < 0.001). Moreover, Hardy–Weinberg equilibrium, haplotype frequency, and linkage disequilibrium between SNPs were performed. Conclusion: miR-27a rs895819 and miR-423 rs6505162, but not miR-124-1 rs531564, are linked to endometriosis.
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Affiliation(s)
- S. O. Jaafar
- Department of Obstetrics and Gynecology, College of Medicine, Hawler Medical University, Erbil, Iraq
| | - J. O. Jaffar
- Department of Obstetrics and Gynecology, Erbil Maternity Teaching Hospital, Erbil, Iraq
- *Correspondence: J. O. Jaffar, ,
| | - S. A. Ibrahim
- Department of Obstetrics and Gynecology, Erbil Maternity Teaching Hospital, Erbil, Iraq
| | - K. K. Jarjees
- Department of Food Technology, College of Agricultural Engineering Sciences, University of Salahaddin-Erbil, Erbil, Iraq
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miRNAs and lncRNAs: Potential Non-Invasive Biomarkers for Endometriosis. Biomedicines 2021; 9:biomedicines9111662. [PMID: 34829891 PMCID: PMC8615815 DOI: 10.3390/biomedicines9111662] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 12/12/2022] Open
Abstract
Many studies have tried to understand the mechanism of endometriosis and its manner of manifestation. However, the only method of diagnosis considered as the gold standard in endometriosis is an invasive method called exploratory laparoscopy. Hence, there is a need to identify non-invasive or minimally invasive methods to minimize patients' suffering, thus increasing their addressability at the earliest possible staging of the disease, and to diagnose this condition as soon as possible. miRNAs (microRNAs) and lncRNAs (long-noncoding RNAs) are potential non-invasive diagnostic methods for endometriosis. Multiple clinical trials indicate that miRNA can be used as a non-invasive method in the diagnosis and differentiation of endometriosis stages.
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Kolanska K, Bendifallah S, Canlorbe G, Mekinian A, Touboul C, Aractingi S, Chabbert-Buffet N, Daraï E. Role of miRNAs in Normal Endometrium and in Endometrial Disorders: Comprehensive Review. J Clin Med 2021; 10:jcm10163457. [PMID: 34441754 PMCID: PMC8396961 DOI: 10.3390/jcm10163457] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/15/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
The molecular responses to hormonal stimuli in the endometrium are modulated at the transcriptional and post-transcriptional stages. Any imbalance in cellular and molecular endometrial homeostasis may lead to gynecological disorders. MicroRNAs (miRNAs) are involved in a wide variety of physiological mechanisms and their expression patterns in the endometrium are currently attracting a lot of interest. miRNA regulation could be hormone dependent. Conversely, miRNAs could regulate the action of sexual hormones. Modifications to miRNA expression in pathological situations could either be a cause or a result of the existing pathology. The complexity of miRNA actions and the diversity of signaling pathways controlled by numerous miRNAs require rigorous analysis and findings need to be interpreted with caution. Alteration of miRNA expression in women with endometriosis has been reported. Thus, a potential diagnostic test supported by a specific miRNA signature could contribute to early diagnosis and a change in the therapeutic paradigm. Similarly, specific miRNA profile signatures are expected for RIF and endometrial cancer, with direct implications for associated therapies for RIF and adjuvant therapies for endometrial cancer. Advances in targeted therapies based on the regulation of miRNA expression are under evaluation.
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Affiliation(s)
- Kamila Kolanska
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
- Correspondence:
| | - Sofiane Bendifallah
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Geoffroy Canlorbe
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Service de Chirurgie et Cancérologie Gynécologique et Mammaire, Hôpitaux Universitaires Pitié-Salpêtrière, Charles-Foix, Sorbonne Université, 47/83, Boulevard de l’Hôpital, 75013 Paris, France
| | - Arsène Mekinian
- Service de Médecine Interne, Hôpital Saint Antoine, AP-HP, 184 Rue du Faubourg Saint Antoine, Sorbonne Université, 75012 Paris, France;
| | - Cyril Touboul
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Selim Aractingi
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Faculté de Médecine Paris 5 Descartes, 12 Rue de l’Ecole de Médecine, 75006 Paris, France
| | - Nathalie Chabbert-Buffet
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Emile Daraï
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
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Romero R. Giants in Obstetrics and Gynecology Series: a profile of Linda C. Giudice, MD, PhD, MSc. Am J Obstet Gynecol 2021; 225:113-119. [PMID: 34332715 PMCID: PMC10568801 DOI: 10.1016/j.ajog.2021.04.230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 11/25/2022]
Affiliation(s)
- Roberto Romero
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services, Detroit, MI.
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38
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Circulating miRNA 27a and miRNA150-5p; a noninvasive approach to endometrial carcinoma. Mol Biol Rep 2021; 48:4351-4360. [PMID: 34076790 DOI: 10.1007/s11033-021-06450-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/27/2021] [Indexed: 01/28/2023]
Abstract
The search for novel non-invasive biomarkers such as epigenetic molecular markers is new hope for common and burdensome cancers. We aim to assess serum expression of miRNA 27a and miRNA150-5p in endometrial cancer patients. Serum was drawn for 36 un-intervened endometrial cancer patients scheduled for hysterectomy and 35 controls. miRNA 27a and miRNA150-5p were measured by real time reverse transcription polymerase chain reaction. Significant overexpression of both miRNA in patients (p < 0.001). At cutoffs 0.2872 & > 1.02, miRNA 27a showed 100% sensitivity, specificity, positive and negative predictive values. miRNA150-5p showed 88.89% sensitivity, 100% specificity, 100% positive and 78.9% negative predictive values. Areas under curve were 1.0 for miRNA 27a, 0.982 for miRNA 150 performing much better than Ca125. miRNA 27a was significantly associated with type I endometroid endometrial cancer. Conclusion: miRNA 27a and miRNA-150-5P can be suggested as promising biomarkers of endometrial cancer possibly part of a miRNA panel for management.
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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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Zafari N, Tarafdari AM, Izadi P, Noruzinia M, Yekaninejad MS, Bahramy A, Mohebalian A. A Panel of Plasma miRNAs 199b-3p, 224-5p and Let-7d-3p as Non-Invasive Diagnostic Biomarkers for Endometriosis. Reprod Sci 2021; 28:991-999. [PMID: 33398851 DOI: 10.1007/s43032-020-00415-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 11/25/2020] [Indexed: 11/29/2022]
Abstract
The objective of this study was to investigate whether the combination of miR-224-5p, miR-199-3p, and let-7d-3p is a suitable diagnostic panel for endometriosis. Twenty-five women with endometriosis (case) and twenty-five women without any sign of endometriosis (controls) were included. Peripheral blood specimens were collected from all these women who were a proper candidate for laparoscopy before surgery. Total RNA was isolated to synthesize complementary DNA. Expression of miR-199b-3p, miR-224-5p, and let-7d-3p was analyzed by RT-qPCR. To estimate the performance of the identified miRNAs for endometriosis diagnosis, we performed ROC curves analysis. There was an upregulation of miRNAs 199b-3p (P value < 0.001) and down-regulation of 224-5p (P value < 0.001) and miRNA let-7d-3p (P value < 0.05) in women with endometriosis compared to non-endometriosis women. The diagnostic accuracy of miRNAs 199b-3p, 224-5p, and let-7d-3p was measured by AUC which was 0.843 (sensitivity = 96% and specificity = 80%), 0.914 (sensitivity = 84% and specificity = 80%), and 0.696 (sensitivity = 80% and specificity = 56%) for miRNAs 199b-3p, 224-5p, and let-7d-3p, respectively. In combination, they showed the highest accuracy with the AUC 0.992 (sensitivity = 96% and specificity = 100%). In conclusion(s) the levels of miRNAs 199b-3p, 224-5p, and Let-7d-3p in plasma are potential diagnostic biomarkers for endometriosis patients.
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Affiliation(s)
- Narges Zafari
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Manshadi Tarafdari
- Department of Gynecology and Obstetrics, Tehran University of Medical Sciences, Tehran, Iran
| | - Pantea Izadi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mehrdad Noruzinia
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mir Saead Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Afshin Bahramy
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Mohebalian
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Cong S, Li J, Zhang J, Feng J, Zhang A, Pan L, Ma J. Construction of circRNA-miRNA-mRNA Network for Exploring Underlying Mechanisms of Lubrication Disorder. Front Cell Dev Biol 2021; 9:580834. [PMID: 33777926 PMCID: PMC7991743 DOI: 10.3389/fcell.2021.580834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/17/2021] [Indexed: 12/13/2022] Open
Abstract
Lubrication disorder is a common health issue that manifests as insufficient sexual arousal at the beginning of sex. It often causes physical and psychological distress. However, there are few studies on lubrication disorder, and the complexity of circular RNA (circRNA) and the related competing endogenous RNA (ceRNA) network in lubrication disorder is still poorly known. Therefore, this study aims to build a regulatory circRNA-micro (mi)RNA-mRNA network and explore potential molecular markers of lubrication disorder. In the study, 12 subjects were recruited, including 6 in the lubrication disorder group and 6 in the normal control group. RNA sequencing was exploited to identify the expression profiles of circRNA, miRNA and mRNA between two groups, and then to construct the circRNA-miRNA-mRNA networks. The enrichment analyses of the differentially expressed (DE)-mRNAs were examined via Gene Set Enrichment Analysis (GSEA). Furthermore, the expression level and interactions among circRNA, miRNA, and mRNA were validated using real-time quantitative polymerase chain reaction (RT-qPCR) and dual-luciferase reporter assays. In the results, 73 circRNAs, 287 miRNAs, and 354 target mRNAs were differentially expressed between two groups when taking | Log2 (fold change)| > 1 and P-value < 0.05 as criteria, and then the results of GSEA revealed that DE-mRNAs were linked with "vascular smooth muscle contraction," "aldosterone regulated sodium reabsorption," "calcium signaling pathway," etc. 19 target relationships among 5 circRNAs, 4 miRNAs, and 7 mRNAs were found and constructed the ceRNA network. Among them, hsa-miR-212-5p and hsa-miR-874-3p were demonstrated to be related to the occurrence of lubrication disorder. Eventually, consistent with sequencing, RT-qPCR showed that hsa_circ_0026782 and ASB2 were upregulated while hsa-miR-874-3p was downregulated, and dual-luciferase reporter assays confirmed the interactions among them. In summary, the findings indicate that the circRNA-miRNA-mRNA regulatory network is presented in lubrication disorder, and ulteriorly provide a deeper understanding of the specific regulatory mechanism of lubrication disorder from the perspective of the circRNA-miRNA-mRNA network.
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Affiliation(s)
- Shengnan Cong
- School of Nursing, Nanjing Medical University, Jiangsu, China
| | - Jinlong Li
- Department of Laboratory Medicine, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingjing Zhang
- Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jingyi Feng
- High School Affiliated To Nanjing Normal University International Department, Nanjing, China
| | - Aixia Zhang
- School of Nursing, Nanjing Medical University, Jiangsu, China.,Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Lianjun Pan
- Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
| | - Jiehua Ma
- Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China
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42
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Joshi NR, Kohan-Ghadr HR, Roqueiro DS, Yoo JY, Fru K, Hestermann E, Yuan L, Ho SM, Jeong JW, Young SL, Lessey BA, Fazleabas AT. Genetic and epigenetic changes in the eutopic endometrium of women with endometriosis: association with decreased endometrial αvβ3 integrin expression. Mol Hum Reprod 2021; 27:6163298. [PMID: 33693877 DOI: 10.1093/molehr/gaab018] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 02/09/2021] [Indexed: 01/10/2023] Open
Abstract
About 40% of women with infertility and 70% of women with pelvic pain suffer from endometriosis. The pregnancy rate in women undergoing IVF with low endometrial integrin αvβ3 (LEI) expression is significantly lower compared to the women with high endometrial integrin αvβ3 (HEI). Mid-secretory eutopic endometrial biopsies were obtained from healthy controls (C; n=3), and women with HEI (n=4) and LEI (n=4) and endometriosis. Changes in gene expression were assessed using human gene arrays and DNA methylation data were derived using 385 K Two-Array Promoter Arrays. Transcriptional analysis revealed that LEI and C groups clustered separately with 396 differentially expressed genes (DEGs) (P<0.01: 275 up and 121 down) demonstrating that transcriptional and epigenetic changes are distinct in the LEI eutopic endometrium compared to the C and HEI group. In contrast, HEI vs C and HEI vs LEI comparisons only identified 83 and 45 DEGs, respectively. The methylation promoter array identified 1304 differentially methylated regions in the LEI vs C comparison. The overlap of gene and methylation array data identified 14 epigenetically dysregulated genes and quantitative RT-PCR analysis validated the transcriptomic findings. The analysis also revealed that aryl hydrocarbon receptor (AHR) was hypomethylated and significantly overexpressed in LEI samples compared to C. Further analysis validated that AHR transcript and protein expression are significantly (P<0.05) increased in LEI women compared to C. The increase in AHR, together with the altered methylation status of the 14 additional genes, may provide a diagnostic tool to identify the subset of women who have endometriosis-associated infertility.
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Affiliation(s)
- Niraj R Joshi
- Michigan State University, College of Human Medicine, Grand Rapids, MI, USA
| | | | | | - Jung Yoon Yoo
- Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea
| | - Karenne Fru
- Coastal Reproductive Endocrinology and Infertility, Wilmington, NC, USA
| | | | - Lingwen Yuan
- University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Shuk-Mei Ho
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jae-Wook Jeong
- Michigan State University, College of Human Medicine, Grand Rapids, MI, USA
| | - Steven L Young
- University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Gaia-Oltean AI, Braicu C, Gulei D, Ciortea R, Mihu D, Roman H, Irimie A, Berindan-Neagoe I. Ovarian endometriosis, a precursor of ovarian cancer: Histological aspects, gene expression and microRNA alterations (Review). Exp Ther Med 2021; 21:243. [PMID: 33603851 PMCID: PMC7851621 DOI: 10.3892/etm.2021.9674] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 12/17/2020] [Indexed: 12/24/2022] Open
Abstract
Ovarian endometriosis is a frequent chronic gynecological disease with an uncertain evolution regarding its progression or association with ovarian malignant lesions. The present review summarized the histological aspects, gene expression and microRNA (miRNA/miR) alterations associated with ovarian endometriosis and cancer and their possible interaction. The endometriosis-ovarian cancer interaction has been proposed by certain researchers as a single entity. Histological results indicated that endometriosis has been in different circumstances coexisting with ovarian cancer, with reference to endometrioid and clear cell carcinoma. Endometriosis with moderate and severe atypia can influence cell proliferation and architecture, resulting in a possible malignant transformation. Gene expression analysis indicated that the pathologies of both endometriosis and ovarian cancer are characterized by genetic instability from a molecular point of view, as several important genetic mutations, including ARID1A, PI3KCA, PTEN, BRCA1, BRCA2, TP53 and KRAS genes, were identified. miRNA alterations have been implicated in the regulation of gene expression. Common dysregulated miRNAs, such as miR-331, miR-335, miR-891, miR-548, miR-124, miR-148, miR-215, miR-192, miR-337, miR-153, miR-155, miR-144, miR-221 and miR-3688 were extensively investigated in understanding endometriosis and ovarian cancer evolution. From a combined viewpoint including histological aspects, gene expression and miRNA alterations, it is reasonable to speculate that endometriosis is associated with ovarian cancer. Ovarian endometriosis lesions may present a risk for ovarian malignant lesions, which supports a model of endometriosis as a malignant precursor. However, the endometriosis-ovarian cancer association is not widely accepted in the literature and additional studies are required to validate this association.
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Affiliation(s)
- Adriana Ioana Gaia-Oltean
- Department of Oncological Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Cornelia Braicu
- Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 40015 Cluj-Napoca, Romania
| | - Diana Gulei
- MedFuture-Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 40015 Cluj-Napoca, Romania
| | - Razvan Ciortea
- Second Department of Obstetrics and Gynecology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj-Napoca, Romania
| | - Dan Mihu
- Second Department of Obstetrics and Gynecology, Iuliu Hatieganu University of Medicine and Pharmacy, 400124 Cluj-Napoca, Romania
| | - Horace Roman
- Center of Endometriosis, Clinique Tivoli-Ducos, 33000 Bordeaux, France
| | - Alexandru Irimie
- Department of Oncological Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.,Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 40015 Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 40015 Cluj-Napoca, Romania.,MedFuture-Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 40015 Cluj-Napoca, Romania.,Department of Functional Genomics and Experimental Pathology, Oncology Institute 'Prof. Dr. Ion Chiricuta', 400015 Cluj-Napoca, Romania
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44
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Yong PJ, Talhouk A, Anglesio MS. Somatic Genomic Events in Endometriosis: Review of the Literature and Approach to Phenotyping. Reprod Sci 2021; 28:2743-2757. [PMID: 33469880 DOI: 10.1007/s43032-020-00451-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/29/2020] [Indexed: 12/17/2022]
Abstract
In this review, we provide a survey and appraisal of research into somatic genomic events in endometriosis. Methodologies have evolved from conventional cytogenetics to next-generation sequencing, with findings ranging from chromosome imbalances to recurrent somatic cancer driver mutations. Somatic cancer driver mutations have been described in a range of endometriosis lesions, dominated by recurrent mutations in KRAS and PIK3CA as well as loss of PTEN and BAF250a (ARID1A). These somatic events appear to be largely restricted to the endometriosis glandular epithelium. Somatic mutations, particularly PTEN loss, have also been observed in eutopic (uterine) endometrium, although at lower mutant allele frequencies compared with ectopic lesions. Systematic studies of the potential clinical phenotype of these somatic genomic events have yet to be performed. Thus, we propose a framework to investigate the potential clinical phenotype associated with somatic genomic events in endometriosis. Technical requirements include pathology review of histological endometriosis, microdissection for tissue enrichment, orthogonal validation of whole genome/exome sequencing, and a germline sample for confirmation of somatic origin. Clinical requirements include annotation of surgical findings; patient demographics; cross-sectional and prospective data on pain and fertility; consideration of sampling multiple lesions in each patient, mutant allele frequency, and somatic events in the eutopic endometrium; and confirmation of any associations with mechanistic studies. Given the multifactorial nature of endometriosis-associated symptoms, it is likely that somatic events have small (or at most, moderate) effect sizes, and thus careful consideration will have to be given to future study design.
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Affiliation(s)
- Paul J Yong
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada. .,BC Women's Centre for Pelvic Pain and Endometriosis, F2 - 4500 Oak Street, Vancouver, British Columbia, V6H3N1, Canada.
| | - Aline Talhouk
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael S Anglesio
- Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada
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45
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Azhari F, Pence S, Hosseini MK, Balci BK, Cevik N, Bastu E, Gunel T. The role of the serum exosomal and endometrial microRNAs in recurrent implantation failure. J Matern Fetal Neonatal Med 2020; 35:815-825. [PMID: 33249960 DOI: 10.1080/14767058.2020.1849095] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE It has been identified that endometrium specific microRNAs have different expression levels in endometrial tissues and maternal serum during endometrial cycle. The aim of this study was to analyze microRNA expression levels in recurrent implantation failure patients and healthy controls endometrial samples for enlightening the aetiopathogenesis of the disease. The second aim was to search for a potential noninvasive molecular biomarker in early diagnosis and treatment of Recurrent Implantation Failure (RIF) patients. METHODS Endometrium and serum samples in two different phases (PP; proliferative phase and SP; secretory phase) from the same cases (RIF; n = 12 and Control; n = 8) were obtained. The expression levels of the microRNA by RT-qPCR method were measured. The expression levels of the healthy controls and study group were compared. Lastly performed target genes analysis of significantly dysregulated miRNA by target analyze databases for obtained related biological pathways. RESULTS This study showed that has-miR-145, has-miR-23b, has-miR-31 and has-miR-30b were significantly up-regulated in PP and down-regulated in SP endometrium samples. In serum samples, has-miR-145 and hsa-miR-23b were significantly down-regulated in both of PP and SP. Target gene and pathway analysis for dysregulated miRNAs identified important, validated and predicted genes for the implantation process. CONCLUSIONS This study is the first study to obtain endometrium and serum samples in two different phases from the same cases and measure the candidate miRNAs expression. Our finding suggests that expression level of four candidate miRNAs may be involved in RIF development in women. Furthermore, these miRNAs can be potential biomarker for early diagnosis of RIF patients.
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Affiliation(s)
- Fatemeh Azhari
- Department of Molecular Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sadrettin Pence
- Department of Molecular Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mohammad Kazem Hosseini
- Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, Turkey
| | | | - Nazife Cevik
- Department of Computer Engineering, Engineering-Architecture Faculty, Arel University, Istanbul, Turkey
| | - Ercan Bastu
- Department of Obstetrics and Gynecology, Acibadem University School of Medicine, Istanbul, Turkey
| | - Tuba Gunel
- Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, Turkey
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46
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Dong L, Zhang L, Liu H, Xie M, Gao J, Zhou X, Zhao Q, Zhang S, Yang J. Circ_0007331 knock-down suppresses the progression of endometriosis via miR-200c-3p/HiF-1α axis. J Cell Mol Med 2020; 24:12656-12666. [PMID: 32960511 PMCID: PMC7686986 DOI: 10.1111/jcmm.15833] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/05/2020] [Accepted: 08/18/2020] [Indexed: 12/14/2022] Open
Abstract
Endometriosis is considered a benign gynaecological disease with cancer-like characterizations, which has a high incidence among women of reproductive age. However, this disease has so far lacked timely diagnosis and effective treatment owing to its unclear aetiology. In this study, we identified aberrant high expression of circ_0007331 in ectopic endometrial cells by comparing the endometrial samples from patients with and without endometriosis. Further functional experiments revealed that circ_0007331 knock-down effectively suppressed the viability, proliferation and invasive capacity of ectopic endometrial cells. Additionally, we attempted to define the molecular mechanism of circ_0007331 in the initiation and progression of endometriosis. Circ_0007331 acted as a miRNA sponge for miR-200c-3p to indirectly regulate the function of HIF-1α, which plays a key role in the local angiogenesis and hypoxic mechanisms of ectopic endometrium. A final in vivo experiment confirmed that circ_0007331 knock-down could suppress the development of endometriosis through down-regulating the expression of HIF-1α. Collectively, we preliminarily characterized the role and possible insights of circ_0007331/miR-200c-3p/HIF-1α axis in the proliferation and invasion of ectopic endometrial cells. We hope that by exploring the potential function and molecular mechanism of circ_0007331, we can increase our biological insight into the pathogenesis of endometriosis, which will bring the new ways for the diagnosis and therapy of this disease.
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Affiliation(s)
- Lan Dong
- Department of GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Lu Zhang
- Department of ObstetricsRenmin Hospital of Wuhan UniversityWuhanChina
| | - Hua Liu
- Department of GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Meiting Xie
- Department of ObstetricsRenmin Hospital of Wuhan UniversityWuhanChina
| | - Jing Gao
- Ultrasound Department of Obstetrics and GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Xiaoyan Zhou
- Ultrasound Department of Obstetrics and GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Qinghong Zhao
- Ultrasound Department of Obstetrics and GynecologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Silin Zhang
- Reproductive Medical CenterRenmin Hospital of Wuhan UniversityWuhanChina
| | - Jing Yang
- Reproductive Medical CenterRenmin Hospital of Wuhan UniversityWuhanChina
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Borisov E, Knyazeva M, Novak V, Zabegina L, Prisyazhnaya T, Karizkiy A, Berlev I, Malek A. Analysis of Reciprocally Dysregulated miRNAs in Eutopic Endometrium Is a Promising Approach for Low Invasive Diagnostics of Adenomyosis. Diagnostics (Basel) 2020; 10:E782. [PMID: 33022981 PMCID: PMC7601074 DOI: 10.3390/diagnostics10100782] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/26/2020] [Accepted: 10/01/2020] [Indexed: 01/07/2023] Open
Abstract
Endometriosis is a chronic disease characterized by the growth of endometrial tissue outside of the uterine cavity. Endometriosis affects up to 10% of women of reproductive age and has great social impact. The diagnostics of endometriosis are based on clinical appearance, ultrasound, and magnetic resonance imaging (MRI); however, a diagnosis is frequently hampered by the absence of objective criteria. Adenomyosis (AM) is a particular type of endometriosis wherein the spread of the ectopic endometrial gland is limited by the uterine myometrium. Alteration of the microRNA expression profile in the eutopic endometrium can be associated with AM, and may be assayed for diagnostic purposes. In the presented study, we aimed to explore the diagnostic potency of this approach. Eutopic endometrium specimens were collected from patients (n = 33) and healthy women (n = 30). The microRNA expression was profiled to select individual microRNAs with AM-associated expression alterations. A new method of two-tailed RT-qPCR microRNA analysis was applied to assay potential markers. The expression ratios of reciprocally dysregulated microRNAs were calculated, and the diagnostic potency of these parameters was evaluated by receiver operation curve (ROC) analysis. Mir-10b, miR-200c and miR-191 were significantly dysregulated in the eutopic endometrium of AM patients. The expression ratio of reciprocally dysregulated microRNAs allowed us to diagnose AM with a range of sensitivity from 65% to 74%, and of specificity from 72% to 86%. The analysis of microRNAs from the eutopic endometrium might present a promising low-invasive method of AM diagnostics.
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Affiliation(s)
- Evgeny Borisov
- Subcellular Technology Lab., N.N. Petrov National Medical Research Center of Oncology, 197758 Saint-Petersburg, Russia; (E.B.); (M.K.); (L.Z.); (I.B.)
- Oncosystem Ltd., 121205 Moscow, Russia
| | - Margarita Knyazeva
- Subcellular Technology Lab., N.N. Petrov National Medical Research Center of Oncology, 197758 Saint-Petersburg, Russia; (E.B.); (M.K.); (L.Z.); (I.B.)
- Oncosystem Ltd., 121205 Moscow, Russia
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 Saint-Petersburg, Russia
| | - Veronika Novak
- Department of Obstetrics and Gynecology, North-Western State Medical University Named after I.I. Mechnikov, 195067 Saint-Petersburg, Russia; (V.N.); (T.P.)
| | - Lidia Zabegina
- Subcellular Technology Lab., N.N. Petrov National Medical Research Center of Oncology, 197758 Saint-Petersburg, Russia; (E.B.); (M.K.); (L.Z.); (I.B.)
- Oncosystem Ltd., 121205 Moscow, Russia
- Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251 Saint-Petersburg, Russia
| | - Tatyana Prisyazhnaya
- Department of Obstetrics and Gynecology, North-Western State Medical University Named after I.I. Mechnikov, 195067 Saint-Petersburg, Russia; (V.N.); (T.P.)
| | - Aleksey Karizkiy
- Information Technologies and Programming Faculty, Information Technologies, Mechanics and Optics University, 197101 Saint-Petersburg, Russia;
| | - Igor Berlev
- Subcellular Technology Lab., N.N. Petrov National Medical Research Center of Oncology, 197758 Saint-Petersburg, Russia; (E.B.); (M.K.); (L.Z.); (I.B.)
- Department of Obstetrics and Gynecology, North-Western State Medical University Named after I.I. Mechnikov, 195067 Saint-Petersburg, Russia; (V.N.); (T.P.)
| | - Anastasia Malek
- Subcellular Technology Lab., N.N. Petrov National Medical Research Center of Oncology, 197758 Saint-Petersburg, Russia; (E.B.); (M.K.); (L.Z.); (I.B.)
- Oncosystem Ltd., 121205 Moscow, Russia
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Mariani LL, Mancarella M, Fuso L, Baino S, Biglia N, Menato G. Endometrial thickness in the evaluation of clinical response to medical treatment for deep infiltrating endometriosis: a retrospective study. Arch Gynecol Obstet 2020; 303:161-168. [PMID: 32926208 DOI: 10.1007/s00404-020-05794-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 09/05/2020] [Indexed: 11/29/2022]
Abstract
PURPOSE Deep infiltrating endometriosis (DIE) is associated with severe pelvic pain and functional impairment of bowel, urinary, and sexual functions. Though hormone therapy with progestins, either as single agents or combined with estrogens, is effective in managing symptoms, some patients may experience a suboptimal response. Endometrial thickness assessed by transvaginal ultrasound examination, reflecting the overall estrogen stimulation, may correlate with the clinical response to hormonal treatments. METHODS A retrospective study was carried out on 61 women with DIE affecting the bowel or the recto-vaginal septum, undergoing hormone treatment. The symptoms of patients were evaluated at the baseline and after 12 months of therapy, calculating a global Visual Analogue Scale score (gVAS) encompassing dysmenorrhea, dyspareunia, chronic pelvic pain, dyschezia, abdominal pain and dysuria. Patients were divided into two subgroups using, as a calculated cut-off value, the mean endometrial thickness in our population at 12 months. The change in gVAS score during the 12 months of treatment was then compared between the two groups. RESULTS Women with a thinner endometrium (< 3.3 mm) showed a better response to treatment in terms of symptoms control as compared to patients with a thicker endometrium (mean gVAS score reduction 9.2 ± 1.3 vs. 5.2 ± 1.3, p = 0.036). The correlation between endometrial thickness and symptomatic response was also confirmed (p = 0.041) on multivariate linear regression analysis including as covariates age, size of lesions of DIE, presence of uterine adenomyosis, ovarian endometriosis and type of medical treatment. CONCLUSION Endometrial thickness on ultrasound transvaginal examination is correlated with better response rates to hormone therapy in terms of symptoms control. A thinner endometrium, probably resulting from a more efficient suppression of estrogen stimulation, is associated with improved symptoms. These results may aid clinicians in monitoring and tailoring hormonal treatments during follow-up of women with symptomatic DIE.
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Affiliation(s)
- Luca Liban Mariani
- Obstetrics and Gynecology University Department, Mauriziano Umberto I Hospital, Largo Turati 62, 10128, Torino, Italy
| | - Matteo Mancarella
- Obstetrics and Gynecology University Department, Mauriziano Umberto I Hospital, Largo Turati 62, 10128, Torino, Italy
| | - Luca Fuso
- Obstetrics and Gynecology University Department, Mauriziano Umberto I Hospital, Largo Turati 62, 10128, Torino, Italy
| | - Sara Baino
- Obstetrics and Gynecology University Department, Mauriziano Umberto I Hospital, Largo Turati 62, 10128, Torino, Italy
| | - Nicoletta Biglia
- Obstetrics and Gynecology University Department, Mauriziano Umberto I Hospital, Largo Turati 62, 10128, Torino, Italy. .,Department of Surgical Sciences, University of Turin, Corso Dogliotti 14, 10126, Torino, Italy.
| | - Guido Menato
- Department of Surgical Sciences, University of Turin, Corso Dogliotti 14, 10126, Torino, Italy
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Shomali N, Hemmatzadeh M, Yousefzadeh Y, Soltani-Zangbar MS, Hamdi K, Mehdizadeh A, Yousefi M. Exosomes: Emerging biomarkers and targets in folliculogenesis and endometriosis. J Reprod Immunol 2020; 142:103181. [PMID: 32717674 DOI: 10.1016/j.jri.2020.103181] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 06/14/2020] [Accepted: 07/18/2020] [Indexed: 12/31/2022]
Abstract
An appropriate connection of the cells in the ovary follicles is vital for a healthy ovule maturation and fertilization, and also for endometrium preparation for implantation that can cause endometriosis. Cellular communication within the follicle and endometrial epithelium involve many signaling molecules. Recent studies indicate that cellular communication can be enclosed by secretion and absorption of small membrane carriers which are named extracellular vesicles including exosomes and microvesicles. Understanding and defining these EVs (Extracellular vesicles) population are important for future studies and clinical translation. Here, we describe the various important cargos which are carried by exosomes during folliculogenesis and endometriosis. Additionally, the current knowledge of exosomes and their cargo within the FF (Follicular fluid) during the folliculogenesis and also in the intrauterine cavity which are involved in endometriosis lesions have also been summarized. Considering the potential importance of this form of the cell to cell communication in the reproductive system, the vital issues under discussion lead to a new insight in this rapidly expanding field and it may be an interesting approach for diagnostic, prognostic and especially therapeutic strategies in the field of infertility and assisted reproductive technology (ART).
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Affiliation(s)
- Navid Shomali
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Hemmatzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yousef Yousefzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Kobra Hamdi
- Reproductive Biology Department, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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50
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Bjorkman S, Taylor HS. MicroRNAs in endometriosis: biological function and emerging biomarker candidates†. Biol Reprod 2020; 100:1135-1146. [PMID: 30721951 DOI: 10.1093/biolre/ioz014] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 12/21/2018] [Accepted: 01/31/2019] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs), a class of small noncoding RNA molecules, have been recognized as key post-transcriptional regulators associated with a multitude of human diseases. Global expression profiling studies have uncovered hundreds of miRNAs that are dysregulated in several diseases, and yielded many candidate biomarkers. This review will focus on miRNAs in endometriosis, a common chronic disease affecting nearly 10% of reproductive-aged women, which can cause pelvic pain, infertility, and a myriad of other symptoms. Endometriosis has delayed time to diagnosis when compared to other chronic diseases, as there is no current accurate, easily accessible, and noninvasive tool for diagnosis. Specific miRNAs have been identified as potential biomarkers for this disease in multiple studies. These and other miRNAs have been linked to target genes and functional pathways in disease-specific pathophysiology. Highlighting investigations into the roles of tissue and circulating miRNAs in endometriosis, published through June 2018, this review summarizes new connections between miRNA expression and the pathophysiology of endometriosis, including impacts on fertility. Future applications of miRNA biomarkers for precision medicine in diagnosing and managing endometriosis treatment are also discussed.
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Affiliation(s)
- Sarah Bjorkman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
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