Comparative Study of Serum miRNA as A Biomarker for Non-Invasive Diagnosis in Suspected Versus Proven Cases of Endometriosis
Life Sciences-Molecular Biology
DOI:
https://doi.org/10.22376/ijlpr.2023.13.4.L146-L157Keywords:
Endometriosis, Symptoms, Demographic profile, Non-invasive diagnosis, Biomarkers, miRNA, ManagementAbstract
Endometriosis is a chronic systemic inflammatory disorder characterized by endometrial tissue outside the uterine cavity in females. So far, the invasive laparoscopic method is the only gold standard diagnostic option for endometriosis. The study aims to develop a non-invasive diagnosis of endometriosis in patients presenting with one or more symptoms by analyzing the peripheral circulating miRNAs from the serum of the patients. A panel of miRNA 125b-5p, 342-3p, and Let-7b was developed to diagnose endometriosis. We performed the demographic profiling in 56 patients eliciting one or more symptoms of endometriosis without imaging evidence and compared them with 40 patients with the laparoscopically established endometriotic condition. Patients presenting with one or more of the clinical symptoms of endometriosis (n=56) served as the study group, and patients who were proven to be endometriotic by laparoscopy (n=40) served as the training (control) group. The fasting peripheral blood sample was collected, serum was separated, and cryo-preserved. qRT-PCR analysis of the selected miRNAs (miR 125b-5p, miR 342-3p, and Let-7b) was studied in both training (control) and study groups. The results were analyzed using a random forest (RF) approach machine learning algorithm and 10-fold cross-validation. Results indicate significant upregulation of miRNA125b-5p and miRNA 342-3p and downregulation of Let- 7b (p <0.001). Further, the samples derived from the study group with one or more symptoms of endometriosis and the proven endometriotic patients exhibited similar dysregulation of selected miRNAs (miR 125b-5p, miR 342-3p, and Let-7b). Based on our study, we propose the miRNAs panel consisting of miR 125b-5p, miR 342-3p, and Let-7b to be used as an early non-invasive diagnostic marker for endometriosis efficiently without the patients being subjected to invasive laparoscopy, which will reduce the time taken for diagnosis and commence the treatment earlier and prevent morbidity.
References
Greene R, Stratton P, Cleary SD, Ballweg ML, Sinaii N. Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertil Steril. 2009 Jan 1;91(1):32-9. doi: 10.1016/j.fertnstert.2007.11.020, PMID 18367178.
Hudelist G, Fritzer N, Thomas A, Niehues C, Oppelt P, Haas D et al. Diagnostic delay for endometriosis in Austria and Germany: causes and possible consequences. Hum Reprod. 2012 Dec 1;27(12):3412-6. doi: 10.1093/humrep/des316, PMID 22990516.
Roullier C, Sanguin S, Parent C, Lombart M, Sergent F, Foulon A. General practitioners and endometriosis: level of knowledge and the impact of training. J Gynecol Obstet Hum Reprod. 2021 Dec 1;50(10):102227. doi: 10.1016/j.jogoh.2021.102227, PMID 34520875.
Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril. 2008 Nov 1;90(5);Suppl:S260-9. doi: 10.1016/j.fertnstert.2008.08.057, PMID 19007642.
May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010 Nov 1;16(6):651-74. doi: 10.1093/humupd/dmq009, PMID 20462942.
Nouri K, Ott J, Krupitz B, Huber JC, Wenzl R. Family incidence of endometriosis in first-, second-, and third-degree relatives: case-control study. Reprod Biol Endocrinol. 2010 Dec;8(1):85. doi: 10.1186/1477-7827-8-85, PMID 20618992.
Santora E. The Social and Psychological Impact of Endometriosis on Women’s Lives: A Critical Narrative Review2013, by Lorraine Culley. Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, Raine-Fenning N. Embryo project encyclopedia; 2020 Dec 2.
Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco Nardone F, de Cicco Nardone C et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011 Aug 1;96(2):366-373.e8. doi: 10.1016/j.fertnstert.2011.05.090, PMID 21718982.
Hansen KE, Kesmodel US, Baldursson EB, Schultz R, Forman A. The influence of endometriosis-related symptoms on work life and work ability: a study of Danish endometriosis patients in employment. Eur J Obstet Gynecol Reprod Biol. 2013 Jul 1;169(2):331-9. doi: 10.1016/j.ejogrb.2013.03.008, PMID 23537616.
Soliman AM, Taylor HS, Bonafede M, Nelson JK, Castelli-Haley J. Incremental direct and indirect cost burden attributed to endometriosis surgeries in the United States. Fertil Steril. 2017 May 1;107(5):1181-1190.e2. doi: 10.1016/j.fertnstert.2017.03.020, PMID 28476181.
Gruenwald P. Origin of endometriosis from the mesenchyme of the celomic walls. Am J Obstet Gynecol. 1942 Sep 1;44(3):470-4. doi: 10.1016/S0002-9378(42)90484-8.
devi R. T, Kadalmani B, Anchanadevi C. Role of miRNA in non-invasive diagnosis of Endometriosis – A Pilot Study. Al Ameen J Med Sci. 2022;15(4).
Wei S, Xu H, Kuang Y. Systematic enrichment analysis of microRNA expression profiling studies in endometriosis. Iran J Basic Med Sci. 2015 May;18(5):423-9. PMID 26124927.
Cosar E, Mamillapalli R, Ersoy GS, Cho S, Seifer B, Taylor HS. Serum microRNAs as diagnostic markers of endometriosis: a comprehensive array-based analysis. Fertil Steril. 2016 Aug 1;106(2):402-9. doi: 10.1016/j.fertnstert.2016.04.013, PMID 27179784.
Bendifallah S, Suisse S, Puchar A, Delbos L, Poilblanc M, Descamps P, Golfier F, Jornea L, Bouteiller D, Touboul C, Dabi Y. Salivary MicroRNA Signature for Diagnosis of Endometriosis. Journal of Clinical Medicine. 2022 Jan 26;11(3):612.
Bayraktar R, Van Roosbroeck K, Calin GA. Cell‐to‐cell communication: microRNAs as hormones. Mol Oncol. 2017 Dec;11(12):1673-86. doi: 10.1002/1878-0261.12144, PMID 29024380.
Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature. 2017 Feb;542(7642):450-5. doi: 10.1038/nature21365, PMID 28199304.
Min PK, Chan SY. The biology of circulating microRNA s in cardiovascular disease. Eur J Clin Investig. 2015 Aug;45(8):860-74. doi: 10.1111/eci.12475, PMID 26046787.
Chakraborty C, Das S. Profiling cell-free and circulating miRNA: a clinical diagnostic tool for different cancers. Tumour Biol. 2016 May;37(5):5705-14. doi: 10.1007/s13277-016-4907-3, PMID 26831657.
Srivastava SK, Ahmad A, Zubair H, Miree O, Singh S, Rocconi RP et al. MicroRNAs in gynecological cancers: small molecules with big implications. Cancer Lett. 2017 Oct 28;407:123-38. doi: 10.1016/j.canlet.2017.05.011, PMID 28549791.
Wang WT, Zhao YN, Han BW, Hong SJ, Chen YQ. Circulating microRNAs identified in a genome-wide serum microRNA expression analysis as noninvasive biomarkers for endometriosis. J Clin Endocrinol Metab. 2013 Jan 1;98(1):281-9. doi: 10.1210/jc.2012-2415, PMID 23118427.
Wang L, Huang W, Ren C, Zhao M, Jiang X, Fang X et al. Analysis of serum microRNA profile by solexa sequencing in women with endometriosis. Reprod Sci. 2016 Oct;23(10):1359-70. doi: 10.1177/1933719116641761, PMID 27412772.
O DF, Flores I, Waelkens E, D’Hooghe T. Noninvasive diagnosis of endometriosis: review of current peripheral blood and endometrial biomarkers. Best Pract Res Clin Obstet Gynaecol. 2018;50:72-83. doi: 10.1016/j.bpobgyn.2018.04.001, PMID 29778458.
Migliore C, Giordano S. Resistance to targeted therapies: a role for microRNAs? Trends Mol Med. 2013;19(10):633-42. doi: 10.1016/j.molmed.2013.08.002, PMID 24012193.
Karkia R, Wali S, Payne A, Karteris E, Chatterjee J. Diagnostic accuracy of liquid biomarkers for the non-invasive diagnosis of endometrial cancer: A systematic review and meta-analysis. Cancers. 2022 Sep 25;14(19):4666. doi: 10.3390/cancers14194666, PMID 36230588.
Mishra VV, Gaddagi RA, Aggarwal R, Choudhary S, Sharma U, Patel U. Prevalence; characteristics and management of endometriosis amongst infertile women: a one year retrospective study. J Clin Diagn Res. 2015 Jun;9(6):QC01-3. doi: 10.7860/JCDR/2015/13687.6125, PMID 26266170.
Gajendra S. Tomar HP 3 Shweta Gupta. Endometriosis in infertility; prevalence, clinical profile and diagnosis. Int J Med Health Res;3(1):1-4.
Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014 May;10(5):261-75. doi: 10.1038/nrendo.2013.255, PMID 24366116.
Tang Y, Zhao M, Lin L, Gao Y, Chen GQ, Chen S et al. Is body mass index associated with the incidence of endometriosis and the severity of dysmenorrhoea: a case–control study in China? BMJ Open. 2020 Sep 1;10(9):e037095. doi: 10.1136/bmjopen-2020-037095, PMID 32895278.
Saha R, Kuja-Halkola R, Tornvall P, Marions L. Reproductive and lifestyle factors associated with endometriosis in a large cross-sectional population sample. J Womens Health (Larchmt). 2017 Feb 1;26(2):152-8. doi: 10.1089/jwh.2016.5795, PMID 27632570.
Tsuji I, Ami K, Miyazaki A, Hujinami N, Hoshiai H. Benefit of diagnostic laparoscopy for patients with unexplained infertility and normal hysterosalpingography findings. Tohoku J Exp Med. 2009;219(1):39-42. doi: 10.1620/tjem.219.39, PMID 19713683.
Rajeswari M, Ramanidevi T, Kadalmani B. Cohort study of endometriosis in south Indian district. Int J Reprod Contracept Obstet Gynecol. 2016:3883-8. doi: 10.18203/2320-1770.ijrcog20163858.
Mokhtar S, Hassan MS HA, Mahdy N. Elkhwsky F, Shehata G. Risk factors for primary and secondary female infertility in Alexandria: a hospital-based case-control study. J Med Res Inst;27(4):255-61.
Maheshwari A, Hamilton M, Bhattacharya S. Effect of female age on the diagnostic categories of infertility. Hum Reprod. 2008 Mar 1;23(3):538-42. doi: 10.1093/humrep/dem431, PMID 18308834.
Chapron C, Marcellin L, Borghese B, Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 2019 Nov;15(11):666-82. doi: 10.1038/s41574-019-0245-z, PMID 31488888.
Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009 Jul 1;15(4):441-61. doi: 10.1093/humupd/dmp007, PMID 19279046.
Fourquet J, Gao X, Zavala D, Orengo JC, Abac S, Ruiz A et al. Patients’ report on how endometriosis affects health, work, and daily life. Fertil Steril. 2010;93(7):2424-8. doi: 10.1016/j.fertnstert.2009.09.017, PMID 19926084.
Cui D, Ma J, Liu Y, Lin K, Jiang X, Qu Y et al. Analysis of long non-coding RNA expression profiles using RNA sequencing in ovarian endometriosis. Gene. 2018;673:140-8. doi: 10.1016/j.gene.2018.06.046, PMID 29920364.
Saare M, Rekker K, Laisk-Podar T, Sõritsa D, Roost AM, Simm J et al. High-throughput sequencing approach uncovers the miRNome of peritoneal endometriotic lesions and adjacent healthy tissues. PLOS ONE. 2014;9(11):e112630. doi: 10.1371/journal.pone.0112630, PMID 25386850.
Kiesel L, Sourouni M. Diagnosis of endometriosis in the 21st century. Climacteric. 2019;22(3):296-302. doi: 10.1080/13697137.2019.1578743, PMID 30905186.
Jia SZ, Yang YP, Lang JH, Sun PR, Leng JH. Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis. Hum Reprod. 2013;28(2):322-30. doi: 10.1093/humrep/des413, PMID 23203215.
Maged AM, Deeb WS, El Amir A, Zaki SS, El Sawah H, Al Mohamady M et al. Diagnostic accuracy of serum miR-122 and miR-199a in women with endometriosis. Int J Gynaecol Obstet. 2018;141(1):14-9. doi: 10.1002/ijgo.12392, PMID 29149541.
Nisenblat V, Sharkey DJ, Wang Z, Evans SF, Healey M, Ohlsson Teague EMC et al. Plasma miRNAs display limited potential as diagnostic tools for endometriosis. J Clin Endocrinol Metab. 2019;104(6):1999-2022. doi: 10.1210/jc.2018-01464, PMID 30608536.
Pateisky P, Pils D, Szabo L, Kuessel L, Husslein H, Schmitz A et al. hsa-miRNA-154-5p expression in plasma of endometriosis patients is a potential diagnostic marker for the disease. Reprod Biomed Online. 2018;37(4):449-66. doi: 10.1016/j.rbmo.2018.05.007, PMID 29857988.
Nisenblat V, Bossuyt PM, Shaikh R, Farquhar C, Jordan V, Scheffers CS et al. Blood biomarkers for the non‐invasive diagnosis of endometriosis. Cochrane Database Syst Rev. 2016;2016(5):CD012179. doi: 10.1002/14651858.CD012179, PMID 27132058.
Moustafa S, Burn M, Mamillapalli R, Nematian S, Flores V, Taylor HS. Accurate diagnosis of endometriosis using serum microRNAs. Am J Obstet Gynecol. 2020 Oct 1;223(4):557.e1-557.e11. doi: 10.1016/j.ajog.2020.02.050, PMID 32165186.
Pokrovenko DA, Vozniuk V, Medvediev MV. MicroRNA let-7: A promising non-invasive biomarker for diagnosing and treating external genital endometriosis. Turk J Obstet Gynecol. 2021 Dec;18(4):291-7. doi: 10.4274/tjod.galenos.2021.07277, PMID 34955008.
Wu Y, Zhong JL, Hou N, Sun Y, Ma B, Nisar MF et al. MicroRNA let-7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2. Exp Dermatol. 2017;26(2):116-23. doi: 10.1111/exd.13164, PMID 27513293.
Wang Y, Pang X, Wu J, Jin L, Yu Y, Gobin R et al. MicroRNA hsa-let-7b suppresses the odonto/osteogenic differentiation capacity of stem cells from apical papilla by targeting MMP1. J Cell Biochem. 2018;119(8):6545-54. doi: 10.1002/jcb.26737, PMID 29384216.
Rasheed Z, Rasheed N, Abdulmonem WA, Khan MI. MicroRNA-125b-5p regulates IL-1β induced inflammatory genes via targeting TRAF6-mediated MAPKs and NF-κBsignaling in human osteoarthritic chondrocytes Zafar Rasheed, Naila Rasheed. Sci Rep. 2019;9(1):6882. doi: 10.1038/s41598-019-42601-3, PMID 31053727.
Vodolazkaia A, Yesilyurt BT, Kyama CM, Bokor A, Schols D, Huskens D et al. Vascular endothelial growth factor pathway in endometriosis: genetic variants and plasma biomarkers. Fertil Steril. 2016 Apr 1;105(4):988-96. doi: 10.1016/j.fertnstert.2015.12.016, PMID 26773192.
Published
How to Cite
Issue
Section
Copyright (c) 2023 Dr. T. Ramanidevi, Dr. C. Anchana Devi, Dr. B. Kadalmani, Dr. Hari Balaji
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
