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Novel circular RNA expression in the cumulus cells of patients with polycystic ovary syndrome

  • Gynecologic Endocrinology and Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Circular RNAs (circRNAs) mediate the posttranscriptional regulation of multiple genes by functioning as microRNA (miRNA) sponges. This study aimed to detect the novel expression of circRNAs in the cumulus cells (CCs) of polycystic ovary syndrome (PCOS) patients and their potential significance in the pathogenesis of PCOS.

Methods

circRNAs in the CCs from 6 PCOS patients and 6 normal control individuals were collected for microarray analysis, and an independent cohort study including 25 PCOS patients and 25 normal control individuals was conducted to validate the circRNA microarray results using quantitative real-time polymerase chain reaction (qRT-PCR). Spearman’s rank correlation and receiver operating characteristic (ROC) were performed to delineate the potential correlation between novel circRNAs and patients’ clinical characteristics and their potential efficacy for the diagnosis of PCOS. Bioinformatics analysis was applied to investigate the potential roles of circRNAs in the pathogenesis of PCOS.

Results

A total of 286 circRNAs (167 upregulated and 119 downregulated) were identified by microarray that was differentially expressed between the PCOS and non-PCOS groups. After qRT-PCR validation, the expression levels of hsa_circ_0043533 (p < 0.05) and hsa_circ_0043532 (p < 0.01) were significantly higher in the PCOS group, while the expression level of hsa_circ_0097636 (p < 0.01) was prominently lower versus the non-PCOS group. Spearman’s rank correlation indicated that the serum testosterone (T) level positively correlated with the expression of hsa_circ_0043533 and hsa_circ_0097636 in the PCOS group. The ROC curve analysis found that the combination of hsa_circ_0097636 and T resulted in a larger area under the curve (AUC) (0.893) compared with each circRNA alone (0.709, 0.738, and 0.718 for hsa_circ_0043533, hsa_circ_0097636 and hsa_circ_0043532, respectively). Bioinformatics analysis revealed that the dysregulated circRNAs were potentially involved in cell cycle, oocyte meiosis, progesterone-mediated oocyte maturation, the FOXO signaling pathway, phosphatidylinositol signaling and glycerophospholipid metabolism.

Conclusions

The expression of circRNAs in CCs was significantly different between PCOS and normal control individuals. We validated three circRNAs, which could lead to a better understanding of disease pathogenesis and the development of effective therapeutic interventions for PCOS patients.

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References

  1. Yildiz BO, Bozdag G, Yapici Z et al (2012) Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum Reprod 27:3067–3073

    Article  PubMed  Google Scholar 

  2. Broekmans FJ, Knauff EA, Valkenburg O et al (2006) PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and association with metabolic factors. BJOG 113:1210–1217

    Article  CAS  PubMed  Google Scholar 

  3. Diao FY, Xu M, Hu Y et al (2004) The molecular characteristics of polycystic ovary syndrome (PCOS) ovary defined by human ovary cDNA microarray. J Mol Endocrinol 33:59–72

    Article  CAS  PubMed  Google Scholar 

  4. Teede HJ, Misso ML, Deeks AA et al (2011) Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust 195:S65–112

    Article  PubMed  Google Scholar 

  5. Salzman J (2016) Circular RNA expression: its potential regulation and function. Trends Genet 32:309–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Qu S, Yang X, Li X et al (2015) Circular RNA: a new star of noncoding RNAs. Cancer Lett 365:141–148

    Article  CAS  PubMed  Google Scholar 

  7. Rybak-Wolf A, Stottmeister C, Glazar P et al (2015) Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell 58:870–885

    Article  CAS  PubMed  Google Scholar 

  8. Legnini I, Di Timoteo G, Rossi F et al (2017) Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell 66:22–37.e29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shan K, Liu C, Liu BH et al (2017) Circular noncoding RNA HIPK3 mediates retinal vascular dysfunction in diabetes mellitus. Circulation 136:1629–1642

    Article  CAS  PubMed  Google Scholar 

  10. Jeck WR, Sharpless NE (2014) Detecting and characterizing circular RNAs. Nat Biotechnol 32:453–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dang Y, Yan L, Hu B et al (2016) Tracing the expression of circular RNAs in human pre-implantation embryos. Genome Biol 17:130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cheng J, Huang J, Yuan S et al (2017) Circular RNA expression profiling of human granulosa cells during maternal aging reveals novel transcripts associated with assisted reproductive technology outcomes. PLoS One 12:e0177888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rotterdam EA-SPCWG (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25

    Google Scholar 

  14. Huang X, Liu C, Hao C et al (2016) Identification of altered microRNAs and mRNAs in the cumulus cells of PCOS patients: miRNA-509-3p promotes oestradiol secretion by targeting MAP3 K8. Reproduction 151:643–655

    Article  CAS  PubMed  Google Scholar 

  15. You X, Vlatkovic I, Babic A et al (2015) Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci 18:603–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ashwal-Fluss R, Meyer M, Pamudurti NR et al (2014) circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56:55–66

    Article  CAS  PubMed  Google Scholar 

  17. Zhang Y, Zhang XO, Chen T et al (2013) Circular intronic long noncoding RNAs. Mol Cell 51:792–806

    Article  CAS  PubMed  Google Scholar 

  18. Li Z, Huang C, Bao C et al (2015) Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 22:256–264

    Article  CAS  PubMed  Google Scholar 

  19. Yang JL, Zhang CP, Li L et al (2010) Testosterone induces redistribution of forkhead box-3a and down-regulation of growth and differentiation factor 9 messenger ribonucleic acid expression at early stage of mouse folliculogenesis. Endocrinology 151:774–782

    Article  CAS  PubMed  Google Scholar 

  20. Chen YX, Zhang XJ, Huang J et al (2016) UHPLC/Q-TOFMS-based plasma metabolomics of polycystic ovary syndrome patients with and without insulin resistance. J Pharm Biomed Anal 121:141–150

    Article  CAS  PubMed  Google Scholar 

  21. Rosenfield RL, Ehrmann DA (2016) The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 37:467–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chazenbalk G, Chen YH, Heneidi S et al (2012) Abnormal expression of genes involved in inflammation, lipid metabolism, and Wnt signaling in the adipose tissue of polycystic ovary syndrome. J Clin Endocrinol Metab 97:E765–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhao Y, Zhang C, Huang Y et al (2015) Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-kappaB signaling in the granulosa cells of PCOS patients. J Clin Endocrinol Metab 100:201–211

    Article  CAS  PubMed  Google Scholar 

  24. Barrett SP, Salzman J (2016) Circular RNAs: analysis, expression and potential functions. Development 143:1838–1847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Memczak S, Jens M, Elefsinioti A et al (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338

    Article  CAS  PubMed  Google Scholar 

  26. Wang K, Long B, Liu F et al (2016) A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur Heart J 37:2602–2611

    Article  CAS  PubMed  Google Scholar 

  27. Piwecka M, Glazar P, Hernandez-Miranda LR et al (2017) Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357:6357

    Article  CAS  Google Scholar 

  28. Chen YH, Heneidi S, Lee JM et al (2013) miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes 62:2278–2286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cai G, Ma X, Chen B et al (2017) MicroRNA-145 negatively regulates cell proliferation through targeting IRS1 in isolated ovarian granulosa cells from patients with polycystic ovary syndrome. Cell Biochem Funct 24:902–910

    CAS  Google Scholar 

  30. Zhang CL, Wang H, Yan CY et al (2017) Deregulation of RUNX2 by miR-320a deficiency impairs steroidogenesis in cumulus granulosa cells from polycystic ovary syndrome (PCOS) patients. Biochem Biophys Res Commun 482:1469–1476

    Article  CAS  PubMed  Google Scholar 

  31. Sen A, Prizant H, Light A et al (2014) Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc Natl Acad Sci USA 111:3008–3013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Long W, Zhao C, Ji C et al (2014) Characterization of serum microRNAs profile of PCOS and identification of novel non-invasive biomarkers. Cell Physiol Biochem 33:1304–1315

    Article  CAS  PubMed  Google Scholar 

  33. Sang Q, Yao Z, Wang H et al (2013) Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J Clin Endocrinol Metab 98:3068–3079

    Article  CAS  PubMed  Google Scholar 

  34. Sirotkin AV, Ovcharenko D, Grossmann R et al (2009) Identification of microRNAs controlling human ovarian cell steroidogenesis via a genome-scale screen. J Cell Physiol 219:415–420

    Article  CAS  PubMed  Google Scholar 

  35. Donadeu FX, Schauer SN, Sontakke SD (2012) Involvement of miRNAs in ovarian follicular and luteal development. J Endocrinol 215:323–334

    Article  CAS  PubMed  Google Scholar 

  36. Yao N, Yang BQ, Liu Y et al (2010) Follicle-stimulating hormone regulation of microRNA expression on progesterone production in cultured rat granulosa cells. Endocrine 38:158–166

    Article  CAS  PubMed  Google Scholar 

  37. Sathyapalan T, David R, Gooderham NJ et al (2015) Increased expression of circulating miRNA 93 in women with polycystic ovary syndrome may represent a novel, non-invasive biomarker for diagnosis. Sci Rep 5:16890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Scalici E, Traver S, Mullet T et al (2016) Circulating microRNAs in follicular fluid, powerful tools to explore in vitro fertilization process. Sci Rep 6(24976):3

    Google Scholar 

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (No. 81671416).

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Authors and Affiliations

  1. Medical College of Qingdao University, Qingdao, Shandong, People’s Republic of China

    Zhi Ma

  2. Centre for Reproductive Medicine, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, People’s Republic of China

    Huishan Zhao, Xiaoyan Liu & Cuifang Hao

  3. Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China

    Yan Zhang

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  1. Zhi Ma
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  2. Huishan Zhao
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  3. Yan Zhang
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  4. Xiaoyan Liu
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  5. Cuifang Hao
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Contributions

ZM: data collection, formal analysis, manuscript writing. HZ: methodology and software supporting. YZ: methodology supporting and manuscript editing. XL: sample collection. CH: project development and manuscript editing.

Corresponding author

Correspondence to Cuifang Hao.

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This study was approved by the Institutional Ethics Review Board, Yantai Yuhuangding Hospital affiliated to Qingdao University.

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Ma, Z., Zhao, H., Zhang, Y. et al. Novel circular RNA expression in the cumulus cells of patients with polycystic ovary syndrome. Arch Gynecol Obstet 299, 1715–1725 (2019). https://doi.org/10.1007/s00404-019-05122-y

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  • DOI: https://doi.org/10.1007/s00404-019-05122-y

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