Skip to main content

Advertisement

SpringerLink
Log in

MiR-148a-3p may contribute to flawed decidualization in recurrent implantation failure by modulating HOXC8

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To evaluate whether miR-148a-3p overexpression is associated with disrupted decidualization of recurrent implantation failure (RIF).

Methods

Endometrial miRNA and mRNA expression profiles during the implantation window derived from women with and without RIF were identified using microarray and RT-qPCR. Immortalized human endometrial stromal cells (HESCs) were cultured for proliferation and in vitro decidualization assays after enhancing miR-148a-3p expression or inhibiting putative target gene homeobox C8 (HOXC8) expression. RT-qPCR, western blot, and luciferase reporter assays were used to confirm the relationship between miR-148a-3p and HOXC8 gene.

Results

MiR-148a-3p was significantly upregulated in RIF endometrial tissues. Forced expression of miR-148a-3p notably attenuated HESC in vitro decidualization. Mechanistic studies revealed that miR-148a-3p directly bounds to the HOXC8 3′ untranslated region (3′UTR) and suppressed HOXC8 expressions in both mRNA and protein levels. Further investigations demonstrated that inhibition of HOXC8 in HESCs induced similar effects on decidual process as those induced by miR-148a-3p overexpression.

Conclusion

Taken together, our findings suggested that elevated miR-148a-3p might account for flawed decidualization in RIF by negatively regulating HOXC8, raising the possibility that miR-148a-3p might be a novel therapeutic target in RIF.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Thornhill AR, deDie-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA, et al. ESHRE PGD Consortium Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Hum Reprod. 2005;20(1):35–48.

    PubMed  CAS  Google Scholar 

  2. Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril. 2017;108(1):15–8.

    PubMed  Google Scholar 

  3. Sebastian-Leon P, Garrido N, Remohí J, Pellicer A, Diaz-Gimeno P. Asynchronous and pathological windows of implantation: two causes of recurrent implantation failure. Hum Reprod. 2018;33(4):626–35.

    PubMed  CAS  Google Scholar 

  4. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35(6):851–905.

    PubMed  CAS  Google Scholar 

  5. Ochoa-Bernal MA, Fazleabas AT. Physiologic events of embryo implantation and decidualization in human and non-human primates. Int J Mol Sci. 2020;21(6).

  6. Kliman HJ, Frankfurter D. Clinical approach to recurrent implantation failure: evidence-based evaluation of the endometrium. Fertil Steril. 2019;111(4):618–28.

    PubMed  Google Scholar 

  7. Zhu H, Hou CC, Luo LF, Hu YJ, Yang WX. Endometrial stromal cells and decidualized stromal cells: origins, transformation and functions. Gene. 2014;551(1):1–14.

    PubMed  CAS  Google Scholar 

  8. Berkhout RP, Lambalk CB, Repping S, Hamer G, Mastenbroek S. Premature expression of the decidualization marker prolactin is associated with repeated implantation failure. Gynecol Endocrinol. 2020;36(4):360–4.

    PubMed  CAS  Google Scholar 

  9. Brar AK, Frank GR, Kessler CA, Cedars MI, Handwerger S. Progesterone-dependent decidualization of the human endometrium is mediated by cAMP. Endocrine. 1997;6(3):301–7.

    PubMed  CAS  Google Scholar 

  10. Gellersen B, Brosens J. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J Endocrinol. 2003;178(3):357–72.

    PubMed  CAS  Google Scholar 

  11. Ruan YC, Chen H, Chan HC. Ion channels in the endometrium: regulation of endometrial receptivity and embryo implantation. Hum Reprod Update. 2014;20(4):517–29.

    PubMed  CAS  Google Scholar 

  12. Macklon N. Recurrent implantation failure is a pathology with a specific transcriptomic signature. Fertil Steril. 2017;108(1):9–14.

    PubMed  Google Scholar 

  13. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–67.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Maruyama T, Yoshimura Y. Molecular and cellular mechanisms for differentiation and regeneration of the uterine endometrium. Endocr J. 2008;55(5):795–810.

    PubMed  CAS  Google Scholar 

  15. Vinketova K, Mourdjeva M, Oreshkova T. Human decidual stromal cells as a component of the implantation niche and a modulator of maternal immunity. J Pregnancy. 2016;2016:8689436.

    PubMed  PubMed Central  Google Scholar 

  16. Salilew-Wondim D, Gebremedhn S, Hoelker M, Tholen E, Hailay T, Tesfaye D. The role of microRNAs in mammalian fertility: from gametogenesis to embryo implantation. Int J Mol Sci. 2020;21(2):E585.

    PubMed  Google Scholar 

  17. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.

    PubMed  CAS  Google Scholar 

  18. Engels BM, Hutvagner G. Principles and effects of microRNA-mediated post-transcriptional gene regulation. Oncogene. 2006;25(46):6163–9.

    PubMed  CAS  Google Scholar 

  19. Chen X, Xie D, Zhao Q, You Z-H. MicroRNAs and complex diseases: from experimental results to computational models. Brief Bioinform. 2019;20(2):515–39.

    PubMed  CAS  Google Scholar 

  20. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74.

    PubMed  CAS  Google Scholar 

  21. Seki N, Hata A. Noncoding RNAs: a new fine-tuner is a key player of human pathogenesis. J Hum Genet. 2017;62(1):1.

    PubMed  CAS  Google Scholar 

  22. Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R, et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell. 2005;122(4):553–63.

    PubMed  CAS  Google Scholar 

  23. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901–6.

    PubMed  CAS  Google Scholar 

  24. Estella C, Herrer I, Moreno-Moya JM, Quinonero A, Martinez S, Pellicer A, et al. miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro. PloS one. 2012;7(7):e41080.

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Kuokkanen S, Chen B, Ojalvo L, Benard L, Santoro N, Pollard JW. Genomic profiling of microRNAs and messenger RNAs reveals hormonal regulation in microRNA expression in human endometrium. Biol Reprod. 2010;82(4):791–801.

    PubMed  CAS  Google Scholar 

  26. Sha AG, Liu JL, Jiang XM, Ren JZ, Ma CH, Lei W, et al. Genome-wide identification of micro-ribonucleic acids associated with human endometrial receptivity in natural and stimulated cycles by deep sequencing. Fertility and sterility. 2011;96(1):150–5.e5.

    PubMed  CAS  Google Scholar 

  27. Zhang Q, Zhang H, Jiang Y, Xue B, Diao Z, Ding L, et al. MicroRNA-181a is involved in the regulation of human endometrial stromal cell decidualization by inhibiting Kruppel-like factor 12. Reproductive biology and endocrinology : RB&E. 2015;13:23.

    Google Scholar 

  28. Chill HH, Dior UP, Kogan L, Revel A. microRNAs and endometrial pathophysiology. Adv Exp Med Biol. 2015;887:143–55.

    PubMed  CAS  Google Scholar 

  29. Galliano D, Pellicer A. MicroRNA and implantation. Fertil Steril. 2014;101(6):1531–44.

    PubMed  CAS  Google Scholar 

  30. Revel A, Achache H, Stevens J, Smith Y, Reich R. MicroRNAs are associated with human embryo implantation defects. Hum Reprod. 2011;26(10):2830–40.

    PubMed  CAS  Google Scholar 

  31. Zhang Q, Li G, Zhang L, Sun X, Zhang D, Lu J, et al. Maternal common variant rs2305957 spanning PLK4 is associated with blastocyst formation and early recurrent miscarriage. Fertility and Sterility. 2017;107(4):1034–40.e5.

    PubMed  CAS  Google Scholar 

  32. Niklaus AL, Aubuchon M, Zapantis G, Li P, Qian H, Isaac B, et al. Assessment of the proliferative status of epithelial cell types in the endometrium of young and menopausal transition women. Hum Reprod. 2007;22(6):1778–88.

    PubMed  CAS  Google Scholar 

  33. Noyes RW, Hertig AT, Rock J. Reprint of: Dating the endometrial biopsy. Fertility and Sterility. 2019;112(4 Suppl1):e93–e115.

    PubMed  CAS  Google Scholar 

  34. Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, et al. Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. Circulation. 2011;124(2):175–84.

    PubMed  CAS  Google Scholar 

  35. Cao C, Sun J, Zhang D, Guo X, Xie L, Li X, et al. The long intergenic noncoding RNA UFC1, a target of MicroRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of β-catenin in HCC cells. Gastroenterology. 2015;148(2):415–26.e18.

    PubMed  CAS  Google Scholar 

  36. Chen Y, Song YX, Wang ZN. The microRNA-148/152 family: multi-faceted players. Mol Cancer. 2013;12:43.

    PubMed  PubMed Central  Google Scholar 

  37. Li Y, Deng X, Zeng X, Peng X. The role of Mir-148a in cancer. J Cancer. 2016;7(10):1233–41.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Wang X, Liang Z, Xu X, Li J, Zhu Y, Meng S, et al. miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer. Cell Death & Disease. 2016;7(12):e2503.

    CAS  Google Scholar 

  39. Cakmak H, Taylor HS. Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update. 2011;17(2):242–53.

    CAS  Google Scholar 

  40. Taylor HS. The role of HOX genes in human implantation. Hum Reprod Update. 2000;6(1):75–9.

    PubMed  CAS  Google Scholar 

  41. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–8.

    PubMed  CAS  Google Scholar 

  42. Choi Y, Kim HR, Lim EJ, Park M, Yoon JA, Kim YS, et al. Integrative analyses of uterine transcriptome and microRNAome reveal compromised LIF-STAT3 signaling and progesterone response in the endometrium of patients with recurrent/repeated implantation failure (RIF). PLoS One. 2016;11(6):e0157696.

    PubMed  PubMed Central  Google Scholar 

  43. Kang YJ, Lees M, Matthews LC, Kimber SJ, Forbes K, Aplin JD. MiR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R. J Cell Sci. 2015;128(4):804–14.

    PubMed  CAS  Google Scholar 

  44. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010;10(5):361–71.

    PubMed  CAS  Google Scholar 

  45. Lei H, Wang H, Juan AH, Ruddle FH. The identification of Hoxc8 target genes. Proc Natl Acad Sci U S A. 2005;102(7):2420–4.

    PubMed  PubMed Central  CAS  Google Scholar 

  46. Shah M, Cardenas R, Wang B, Persson J, Mongan NP, Grabowska A, et al. HOXC8 regulates self-renewal, differentiation and transformation of breast cancer stem cells. Mol Cancer. 2017;16(1):38.

    PubMed  PubMed Central  Google Scholar 

  47. Liu H, Zhang M, Xu S, Zhang J, Zou J, Yang C, et al. HOXC8 promotes proliferation and migration through transcriptional up-regulation of TGFbeta1 in non-small cell lung cancer. Oncogenesis. 2018;7(2):1.

    PubMed  PubMed Central  Google Scholar 

  48. Coutifaris C, Myers ER, Guzick DS, Diamond MP, Carson SA, Legro RS, et al. Reprint of: Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertility and Sterility. 2019;112(4 Suppl1):e116–e24.

    PubMed  Google Scholar 

Download references

Acknowledgments

We thank Prof. Haibin Wang and colleagues at Xiamen University, Xiamen, China, for constructive insight and valuable advice. The authors expressed gratitude to all participants involved in this study.

Funding

The work was supported by National Key Research & Development Program of China (2016YFC1000202, 2018YFC1002804), Major Program of National Natural Science Foundation of China (81490743), General Program of National Natural Science Foundation of China (81671522, 81571406), Shandong Provincial Key Research and Development Program (2016GGH4522), and the Special Fund of Taishan Scholars Program of Shandong Province.

Author information

Author notes

  1. Qian Zhang and Tianxiang Ni contributed equally to this work.

Authors and Affiliations

  1. Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, No. 157 Jingliu Road, Jinan, 250012, Shandong, China

    Qian Zhang, Tianxiang Ni, Yujie Dang, Lingling Ding, Jingjing Jiang, Jing Li, Mingdi Xia, Na Yu, Jinlong Ma, Junhao Yan & Zi-Jiang Chen

  2. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, Shandong, China

    Qian Zhang, Tianxiang Ni, Yujie Dang, Lingling Ding, Jingjing Jiang, Jing Li, Mingdi Xia, Na Yu, Jinlong Ma, Junhao Yan & Zi-Jiang Chen

  3. Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China

    Qian Zhang, Tianxiang Ni, Yujie Dang, Lingling Ding, Jingjing Jiang, Jing Li, Mingdi Xia, Na Yu, Jinlong Ma, Junhao Yan & Zi-Jiang Chen

  4. Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, Shandong, China

    Qian Zhang, Tianxiang Ni, Yujie Dang, Lingling Ding, Jingjing Jiang, Jing Li, Mingdi Xia, Na Yu, Jinlong Ma, Junhao Yan & Zi-Jiang Chen

  5. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetic, Shanghai, 200127, China

    Zi-Jiang Chen

  6. Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Zi-Jiang Chen

Authors
  1. Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tianxiang Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yujie Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lingling Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingjing Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mingdi Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Na Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jinlong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Junhao Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zi-Jiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Junhao Yan designed the study and finally approved the version to be submitted; Qian Zhang and Tianxiang Ni performed the study, analyzed the data, and wrote the paper; Yujie Dang performed the study; Lingling Ding and Jingjing Jiang collected samples and analyzed the data; Jing Li, Mingdi Xia, and Na Yu analyzed the data; and Jinlong Ma and Zi-Jiang Chen revised the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Junhao Yan.

Ethics declarations

The study was approved by the Institutional Review Board of Center for Reproductive Medicine, Shandong University. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Supplemental Table 1.

Primers for RT-qPCR (DOCX 16 kb)

Supplemental Fig 1.

Lentivirus-mediated miR-148a-3p overexpression or HOXC8 inhibition in HESCs (PNG 230 kb)

High Resolution (TIF 1959 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Q., Ni, T., Dang, Y. et al. MiR-148a-3p may contribute to flawed decidualization in recurrent implantation failure by modulating HOXC8. J Assist Reprod Genet 37, 2535–2544 (2020). https://doi.org/10.1007/s10815-020-01900-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-020-01900-9

Keywords

Search

Navigation