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Serum miR-451a Levels Are Significantly Elevated in Women With Endometriosis and Recapitulated in Baboons (Papio anubis) With Experimentally-Induced Disease

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Abstract

We have previously demonstrated that human microRNA-451a (miR-451a) endometriotic lesion expression is significantly higher compared to that of the corresponding eutopic endometrium. The objective of the current study was to examine the relationship between lesion and serum content of miR-451a and to determine the utility of serum miR-451a in distinguishing between women with and without visible signs of endometriosis. Eighty-one participants were enrolled in this study, 41 with confirmed endo-metriosis and 40 without visible signs of endometriosis at laparoscopy (n = 20) or symptoms of endometriosis (pain, infertility n = 20). Experimental endometriosis was also induced in 8 baboons. Blood, endometriotic lesions, and eutopic endometrial samples were collected from women undergoing laparoscopy for surgical removal of endometriosis. Blood was also collected from control participants with no signs and symptoms associated with the disease as well as from baboons prior to, and then 1, 3, 6, 9, and 15 months postinduction of endometriosis. MicroRNA-451a was assessed by quantitative real-time polymerase chain reaction in all samples. In humans, serum miR-451a levels positively correlated with endometriotic lesion miR-451a content, and sera levels were significantly higher in these participants compared to controls. The area under the curve (AUC) for miR-451a was 0.8599. In baboons, serum miR-451a reached statistically significant peak levels at 6 months postinduction of endometriosis. We conclude from this study that sera miR-451a levels positively correlated with endometriotic lesion content and are significantly greater compared to sera levels in women without visible signs or symptoms of endometriosis. MicroRNA-451a may serve as a serum diagnostic marker for endometriosis.

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References

  1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799.

    Article  PubMed  Google Scholar 

  2. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64(2):151–154.

    CAS  PubMed  Google Scholar 

  3. Liu DT, Hitchcock A. Endometriosis: its association with retrograde menstruation, dysmenorrhoea and tubal pathology. Br J Obstet Gynaecol. 1986;93(8):859–862.

    Article  CAS  PubMed  Google Scholar 

  4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297.

    Article  CAS  PubMed  Google Scholar 

  5. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318(5858):1931–1934.

    Article  CAS  PubMed  Google Scholar 

  6. Erson AE, Petty EM. MicroRNAs in development and disease. Clin Genet. 2008;74(4):296–306.

    Article  CAS  PubMed  Google Scholar 

  7. Ohlsson Teague EM, Van der Hoek KH, Van der Hoek MB, et al. MicroRNA-regulated pathways associated with endometriosis. Mol Endocrinol. 2009;23(2):265–275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Filigheddu N, Gregnanin I, Proporato PE, et al. Differential expression of microRNAs between eutopic and ectopic endometrium in ovarian endometriosis. J Biomed Biotechnol. 2010;2010: 369549

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Hawkins SM, Creighton CJ, Han DY, et al. Functional microRNA involved in endometriosis. Mol Endocrinol. 2011;25(5):821–832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Braza-Boïls A, Marí-Alexandre J, Gilabert J, et al. MicroRNA expression profile in endometriosis: its relation to angiogenesis and fibrinolytic factors. Hum Reprod. 2014;29(5):978–988.

    Article  CAS  PubMed  Google Scholar 

  11. Shi XY, Gu L, Chen J, Guo XR, Shi YL. Downregulation of miR-183 inhibits apoptosis and enhances the invasive potential of endometrial stromal cells in endometriosis. Int J Mol Med. 2014;33(1):59–67.

    Article  CAS  PubMed  Google Scholar 

  12. Graham A, Falcone T, Nothnick WB. The expression of microRNA-451 in human endometriotic lesions is inversely related to that of macrophage migration inhibitory factor (MIF) and regulates MIF expression and modulation of epithelial cell survival. Hum Reprod. 2015;30(3):642–652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bandres E, Bitarte N, Arias F, et al. microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res. 2009;15(7):2281–2290.

    Article  CAS  PubMed  Google Scholar 

  14. Liu G, Xu Z, Hao D. MicroRNA-451 inhibits neuroblastoma proliferation, invasion and migration by targeting macrophage migration inhibitory factor. Mol Med Rep. 2016;13(3):2253–2260.

    Article  PubMed  CAS  Google Scholar 

  15. Joshi NR, Su RW, Chandramouli GV, et al. Altered expression of microRNA-451 in eutopic endometrium of baboons (Papio anubis) with endometriosis. Hum Reprod. 2015;30(12):2881–2891.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang R, Wang ZX, Yang JS, Pan X, De W, Chen LB. MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14). Oncogene 2011;30(23):2644–2658.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang T, Sun Q, Liu T, et al. MiR-451 increases radiosensitivity of nasopharyngeal carcinoma cells by targeting ras-related protein 14 (RAB14). Tumour Biol. 2014;35(12):12593–12599.

    Article  CAS  PubMed  Google Scholar 

  18. Tian Y, Nan Y, Han L, et al. MicroRNA miR-451 downregulates the PI3K/AKT pathway through CAB39 in human glioma. Int J Oncol. 2012;40(4):1105–1112.

    CAS  PubMed  Google Scholar 

  19. Zang WQ, Yang X, Wang T, et al. MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. World J Gastroenterol. 2015;21(19):5867–5876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yin P, Peng R, Peng H, et al. MiR-451 suppresses cell proliferation and metastasis in A549 lung cancer cells. Mol Biotechnol. 2015;57(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  21. Zhu S, Huang Y, Su X. Mir-451 correlates with prognosis of renal cell carcinoma patients and inhibits cellular proliferation of renal cell carcinoma. Med Sci Monit. 2016;22:183–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821.

    Article  Google Scholar 

  23. Hastings J, Fazleabas A. A baboon model for endometriosis: implications for fertility. Reprod Biol Endocrinol. 2006;4(suppl 1):S7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Cho S, Mutlu L, Grechukhina O, Taylor HS. Circulating micro-RNAs as potential biomarkers for endometriosis. Fertil Steril. 2015;103(5):1252–1260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nothnick WB, Healy CA. Estrogen induces distinct patterns of microRNA expression within the mouse uterus. Reprod Sci. 2010;17(11):987–914.

    Article  CAS  PubMed  Google Scholar 

  26. Rathjen T, Nicol C, McConkey G, Dalmay T. 2006. Analysis of short RNAs in the malaria parasite and its red blood cell host. FEBS Lett. 580(22):5185–5188.

    Article  CAS  PubMed  Google Scholar 

  27. Masaki S, Ohtsuka R, Abe Y, Muta K, Umemura T. Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis. Biochem Biophys Res Commun. 2007;364(3):509–514.

    Article  CAS  PubMed  Google Scholar 

  28. 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;106(2):402–409.

    Article  CAS  PubMed  Google Scholar 

  29. Patton PE, Field CS, Harms RW, et al. CA-125 levels in endometriosis. Fertil Steril. 1986;45(6):770–773.

    Article  CAS  PubMed  Google Scholar 

  30. Giudice LC, Jacobs A, Pindeda J, et al. Serum levels of CA-125 in patients with endometriosis: a preliminary report. Fertil Steril. 1986;45(6):876–878.

    Article  CAS  PubMed  Google Scholar 

  31. Pittaway DE, Fayez JA. The use of CA-125 in the diagnosis and management of endometriosis. Fertil Steril. 1986;46(5):790–795.

    Article  CAS  PubMed  Google Scholar 

  32. Santulli P, Streuli I, Melonio I, et al. Increased serum cancer antigen-125 is a marker for severity of deep endometriosis. J Minim Invasive Gynecol. 2015;22(2):275–284.

    Article  PubMed  Google Scholar 

  33. Niloff JM, Knapp RC, Schaetzl E, et al. CA125 antigen levels in obstetric and gynecologic patients. Obstet Gynecol. 1984;64(5):703–707.

    CAS  PubMed  Google Scholar 

  34. Sarandakou A, Protonotariou E, Rizos D. Tumor markers in biological fluids associated with pregnancy. Crit Rev Clin Lab Sci. 2007;44(2):151–178.

    Article  CAS  PubMed  Google Scholar 

  35. Niloff JM, Klug TL, Schaetzl E, et al. Elevation of serum CA125 in carcinomas of the fallopian tube, endometrium, and endocervix. Am J Obstet Gynecol. 1984;148(8):1057–1058.

    Article  CAS  PubMed  Google Scholar 

  36. Asher V, Hammond R, Duncan TJ. Pelvic mass associated with raised CA125 for benign condition: a case report. World J Surg Oncol. 2010;8:28.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Vodolazkaia A, El-Aalamat Popovic D, et al. Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endometriosis. Hum Reprod. 2012;27(9):2698–2711.

    Article  CAS  PubMed  Google Scholar 

  38. Borrelli GM, Abrão MS, Mechsner S. Can chemokines be used as biomarkers for endometriosis? A systematic review. Hum Reprod. 2014;29(2):253–266.

    Article  CAS  PubMed  Google Scholar 

  39. Nothnick WB, Al-Hendy A, Lue JR. Circulating micro-RNAs as diagnostic biomarkers for endometriosis: privation and promise. J Minim Invasive Gynecol. 2015;22(5):719–726.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 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;98(1):281–289.

    Article  CAS  PubMed  Google Scholar 

  41. Hsu CY, Hsieh TH, Tsai CF, et al. miRNA-199a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. J Pathol. 2014;232(3):330–343.

    Article  CAS  PubMed  Google Scholar 

  42. Jia SZ, Yang Y, Lang J, et al. Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis. Hum Reprod. 2013;28(2):322–330.

    Article  CAS  PubMed  Google Scholar 

  43. Suryawanshi S, Vlad AM, Lin HM, et al. Plasma microRNAs as novel biomarkers for endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res. 2013;19(5):1213–1224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rekker K, Saare M, Roost AM, et al. Circulating miR-200-family micro-RNAs have altered plasma levels in patients with endometriosis and vary with blood collection time. Fertil Steril. 2015;104(4):938–946.

    Article  CAS  PubMed  Google Scholar 

  45. Yamada H, Suzuki K, Ichino N, et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta. 2013;424:99–103.

    Article  CAS  PubMed  Google Scholar 

  46. Churov AV, Oleinik EK, Knip M. MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun Rev. 2015;14(11):1029–1037.

    Article  CAS  PubMed  Google Scholar 

  47. Redova M, Poprach A, Nekvindova J, et al. Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J Transl Med. 2012;10:55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Markou A, Sourvinou I, Vorkas PA, Yousef GM, Lianidou E. Clinical evaluation of microRNA expression profiling in non-small cell lung cancer. Lung Cancer. 2013;81(3):388–396.

    Article  CAS  PubMed  Google Scholar 

  49. Ling S, Ruiqin M, Guohong Z, Ying W. Expression and prognostic significance of microRNA-451 in human epithelial ovarian cancer. Eur J Gynaecol Oncol. 2015;36(4):463–468.

    CAS  PubMed  Google Scholar 

  50. Harris HR, Costenbader KH, Mu F, et al. Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses’ Health Study II. Ann Rheum Dis. 2016;75(7):1279–1284.

    Article  CAS  PubMed  Google Scholar 

  51. Nielsen NM1, Jørgensen KT, Pedersen BV, Rostgaard K, Frisch M. The co-occurrence of endometriosis with multiple sclerosis, systemic lupus erythematosus and Sjogren syndrome. Hum Reprod. 2011;26(6):1555–1559.

    Article  PubMed  Google Scholar 

  52. Nothnick W, Alali Z. Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment. F1000Res. 2016;17:5.

    Google Scholar 

  53. Taylor RN, Kane MA, Sidell N. Pathogenesis of endometriosis: roles of retinoids and inflammatory pathways. Semin Reprod Med. 2015;33(4):246–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Smigielska-Czepiel K, van den Berg A, Jellema P, et al. Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs. Genes Immun. 2014;15(2):115–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Warren B. Nothnick PhD, HCLD.

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Nothnick, W.B., Falcone, T., Joshi, N. et al. Serum miR-451a Levels Are Significantly Elevated in Women With Endometriosis and Recapitulated in Baboons (Papio anubis) With Experimentally-Induced Disease. Reprod. Sci. 24, 1195–1202 (2017). https://doi.org/10.1177/1933719116681519

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