Skip to main content

Advertisement

Log in

Mir-let-7a/g Enhances Uterine Receptivity via Suppressing Wnt/β-Catenin Under the Modulation of Ovarian Hormones

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Microarray has indicated a huge number of miRNAs exist in reproductive tissues and cells. Moreover, the expression of miRNA in the reproductive system varies under the strict monitoring of different regulations. To understand the role of miRNA-mediated post-transcriptional gene regulation in female reproduction, we investigated the level and function of a mir-let-7 family member in both mice and human uterine receptivity. As we observed, mir-let-7 a/g had a higher expression in mouse and human receptive uterine epithelium; the level of mir-let-7a was under the inverse regulation of estrogen and progesterone; upregulated mir-let-7a/g in mouse and human uterine epithelium increased uterine receptivity, thus improved implantation-related embryo attachment and outgrowth ability; the let-7a/g enhanced uterine receptivity through suppressing canonical Wnt signaling. In summary, our findings suggest that mir-let-7 a/g increases uterine receptivity via inhibiting Wnt signaling and under the modulation of ovarian hormones.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yuan DZ, et al. Identification and characterization of progesterone- and estrogen-regulated MicroRNAs in mouse endometrial epithelial cells. Reprod Sci. 2015;22(2):223–34.

    PubMed  PubMed Central  Google Scholar 

  2. Huet-Hudson YM, Andrews GK, Dey SK. Cell type-specific localization of c-myc protein in the mouse uterus: modulation by steroid hormones and analysis of the periimplantation period. Endocrinology. 1989;125(3):1683–90.

    CAS  PubMed  Google Scholar 

  3. Paria BC, Huet-Hudson YM, Dey SK. Blastocyst’s state of activity determines the “window” of implantation in the receptive mouse uterus. Proc Natl Acad Sci U S A. 1993;90(21):10159–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Matsumoto H. Molecular and cellular events during blastocyst implantation in the receptive uterus: clues from mouse models. J Reprod Dev. 2017;63(5):445–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Eulalio A, Huntzinger E, Izaurralde E. Getting to the root of miRNA-mediated gene silencing. Cell. 2008;132(1):9–14.

    CAS  PubMed  Google Scholar 

  6. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9(2):102–14.

    CAS  PubMed  Google Scholar 

  7. Tang F, et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev. 2007;21(6):644–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bahrami A, et al. miRNA-mRNA network involved in folliculogenesis interactome: systems biology approach. Reproduction. 2017;154(1):51–65.

    CAS  PubMed  Google Scholar 

  9. Liang J, Wang S, Wang Z. Role of microRNAs in embryo implantation. Reprod Biol Endocrinol. 2017;15(1):90.

    PubMed  PubMed Central  Google Scholar 

  10. Laurent LC. MicroRNAs in embryonic stem cells and early embryonic development. J Cell Mol Med. 2008;12(6A):2181–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Pasquinelli AE, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408(6808):86–9.

    CAS  PubMed  Google Scholar 

  12. Hertel J, et al. Evolution of the let-7 microRNA family. RNA Biol. 2012;9(3):231–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Landgraf P, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 2007;129(7):1401–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lagos-Quintana M, et al. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853–8.

    CAS  PubMed  Google Scholar 

  15. Liu WM, et al. Involvement of microRNA lethal-7a in the regulation of embryo implantation in mice. PLoS One. 2012;7(5):e37039.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Xia HF, et al. Temporal and spatial regulation of let-7a in the uterus during embryo implantation in the rat. J Reprod Dev. 2010;56(1):73–8.

    CAS  PubMed  Google Scholar 

  17. Wang Y, et al. MicroRNA profiles in spontaneous decidualized menstrual endometrium and early pregnancy decidua with successfully implanted embryos. PLoS One. 2016;11(1):e0143116.

    PubMed  PubMed Central  Google Scholar 

  18. Ramathal CY, et al. Endometrial decidualization: of mice and men. Semin Reprod Med. 2010;28(1):17–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.

    CAS  PubMed  Google Scholar 

  20. Liu C, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108(6):837–47.

    CAS  PubMed  Google Scholar 

  21. Morin PJ, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275(5307):1787–90.

    CAS  PubMed  Google Scholar 

  22. Korinek V, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997;275(5307):1784–7.

    CAS  PubMed  Google Scholar 

  23. Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14(15):1837–51.

    CAS  PubMed  Google Scholar 

  24. Takemaru KI, Moon RT. The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J Cell Biol. 2000;149(2):249–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hecht A, et al. The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J. 2000;19(8):1839–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cai H, et al. Let7b modulates the Wnt/beta-catenin pathway in liver cancer cells via downregulated Frizzled4. Tumour Biol. 2017;39(7):1010428317716076.

    PubMed  Google Scholar 

  27. Sun X, et al. Let-7c blocks estrogen-activated Wnt signaling in induction of self-renewal of breast cancer stem cells. Cancer Gene Ther. 2016;23(4):83–9.

    CAS  PubMed  Google Scholar 

  28. Zhu H, et al. The Lin28/let-7 axis regulates glucose metabolism. Cell. 2011;147(1):81–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cheng TC, et al. Evaluation of mouse blastocyst implantation rate by morphology grading. Chin J Phys. 2004;47(1):43–7.

    Google Scholar 

  30. Chan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod. 2004;70(6):1738–50.

    CAS  PubMed  Google Scholar 

  31. Ebrahimi-Barough S, et al. Differentiation of human endometrial stromal cells into oligodendrocyte progenitor cells (OPCs). J Mol Neurosci. 2013;51(2):265–73.

    CAS  PubMed  Google Scholar 

  32. Duan ZY, et al. U6 can be used as a housekeeping gene for urinary sediment miRNA studies of IgA nephropathy. Sci Rep. 2018;8(1):10875.

    PubMed  PubMed Central  Google Scholar 

  33. Crossland RE, et al. Evaluation of optimal extracellular vesicle small RNA isolation and qRT-PCR normalisation for serum and urine. J Immunol Methods. 2016;429:39–49.

    CAS  PubMed  Google Scholar 

  34. Pang RT, et al. MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells. Carcinogenesis. 2010;31(6):1037–44.

    CAS  PubMed  Google Scholar 

  35. Deb K, Reese J, Paria BC. Methodologies to study implantation in mice. Methods Mol Med. 2006;121:9–34.

    PubMed  Google Scholar 

  36. Altmae S, et al. MicroRNAs miR-30b, miR-30d, and miR-494 regulate human endometrial receptivity. Reprod Sci. 2013;20(3):308–17.

    PubMed  PubMed Central  Google Scholar 

  37. Weimar CH, et al. In-vitro model systems for the study of human embryo-endometrium interactions. Reprod BioMed Online. 2013;27(5):461–76.

    CAS  PubMed  Google Scholar 

  38. Harduf H, Goldman S, Shalev E. Human uterine epithelial RL95-2 and HEC-1A cell-line adhesiveness: the role of plexin B1. Fertil Steril. 2007;87(6):1419–27.

    CAS  PubMed  Google Scholar 

  39. Bhagwat SR, et al. Endometrial receptivity: a revisit to functional genomics studies on human endometrium and creation of HGEx-ERdb. PLoS One. 2013;8(3):e58419.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rahnama F, et al. Epigenetic regulation of E-cadherin controls endometrial receptivity. Endocrinology. 2009;150(3):1466–72.

    CAS  PubMed  Google Scholar 

  41. Ho H, et al. A high-throughput in vitro model of human embryo attachment. Fertil Steril. 2012;97(4):974–8.

    PubMed  Google Scholar 

  42. Somkuti SG, et al. Epidermal growth factor and sex steroids dynamically regulate a marker of endometrial receptivity in Ishikawa cells. J Clin Endocrinol Metab. 1997;82(7):2192–7.

    CAS  PubMed  Google Scholar 

  43. Kuokkanen S, et al. Genomic profiling of microRNAs and messenger RNAs reveals hormonal regulation in microRNA expression in human endometrium. Biol Reprod. 2010;82(4):791–801.

    CAS  PubMed  Google Scholar 

  44. Nei H, et al. Nuclear localization of beta-catenin in normal and carcinogenic endometrium. Mol Carcinog. 1999;25(3):207–18.

    CAS  PubMed  Google Scholar 

  45. Wang J, Mayernik L, Armant DR. Trophoblast adhesion of the peri-implantation mouse blastocyst is regulated by integrin signaling that targets phospholipase C. Dev Biol. 2007;302(1):143–53.

    CAS  PubMed  Google Scholar 

  46. Xie H, et al. Inactivation of nuclear Wnt-beta-catenin signaling limits blastocyst competency for implantation. Development. 2008;135(4):717–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li R, et al. MicroRNA array and microarray evaluation of endometrial receptivity in patients with high serum progesterone levels on the day of hCG administration. Reprod Biol Endocrinol. 2011;9:29.

    PubMed  PubMed Central  Google Scholar 

  48. Xia HF, et al. MicroRNA expression and regulation in the uterus during embryo implantation in rat. FEBS J. 2014;281(7):1872–91.

    CAS  PubMed  Google Scholar 

  49. Chakrabarty A, et al. MicroRNA regulation of cyclooxygenase-2 during embryo implantation. Proc Natl Acad Sci U S A. 2007;104(38):15144–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Hu SJ, et al. MicroRNA expression and regulation in mouse uterus during embryo implantation. J Biol Chem. 2008;283(34):23473–84.

    CAS  PubMed  Google Scholar 

  51. Lee H, et al. Biogenesis and regulation of the let-7 miRNAs and their functional implications. Protein Cell. 2016;7(2):100–13.

    CAS  PubMed  Google Scholar 

  52. Duchartre Y, Kim YM, Kahn M. The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol. 2016;99:141–9.

    PubMed  Google Scholar 

  53. Wang Y, et al. Let-7b contributes to hepatocellular cancer progression through Wnt/beta-catenin signaling. Saudi J Biol Sci. 2018;25(5):953–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Inyawilert W, et al. Let-7-mediated suppression of mucin 1 expression in the mouse uterus during embryo implantation. J Reprod Dev. 2015;61(2):138–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Cho S, et al. Circulating microRNAs as potential biomarkers for endometriosis. Fertil Steril. 2015;103(5):1252–60 e1.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cho S, et al. Aromatase inhibitor regulates let-7 expression and let-7f-induced cell migration in endometrial cells from women with endometriosis. Fertil Steril. 2016;106(3):673–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sahin C, et al. microRNA Let-7b: a novel treatment for endometriosis. J Cell Mol Med. 2018;22(11):5346–53.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We are sincerely grateful to Prof. George Q. Daley of Harvard Stem Cell Institute for providing ES cells carrying a let-7g Stem/mir-21loop sequence, and all the reviewers for their helpful comments on this article, and those who offer kind help during the whole project.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Weimin LIU.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

LI, Q., LIU, W., CHIU, P.C. et al. Mir-let-7a/g Enhances Uterine Receptivity via Suppressing Wnt/β-Catenin Under the Modulation of Ovarian Hormones. Reprod. Sci. 27, 1164–1174 (2020). https://doi.org/10.1007/s43032-019-00115-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-019-00115-3

Keywords

Navigation