Skip to main content

Advertisement

SpringerLink
Log in

Hypoxia Promotes Invasion of Endometrial Stromal Cells via Hypoxia-Inducible Factor 1α Upregulation-Mediated β-Catenin Activation in Endometriosis

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

Abstract

Endometriosis is a common benign gynecological disease defined as the presence of endometrial tissue outside the uterine cavity. The aim of this study was to identify the molecular mechanism underlying hypoxia-induced increases in invasive ability of human endometrial stromal cells (HESCs). Herein, we show that the expression levels of hypoxia-inducible factor lα (HIF-1α) and β-catenin were greater in ectopic endometriotic tissue compared with eutopic tissue from controls. Exposure of eutopic endometrial stromal cells under hypoxic conditions or treated with desferrioxamine (DFO, chemical hypoxia) resulted in a time-dependent increase in β-catenin expression and its dephosphorylation. Hypoxia/HIF-1α also activated the β-catenin/T-cell factor (TCF) signaling pathway and the expression of target genes, vascular endothelial growth factor and matrix metalloproteinase 9, and knockdown of HIF-1α or β-catenin abrogated hypoxia-induced increases in HESC invasiveness. These results suggest that HIF-1α interacting with β-catenin/TCF signaling pathway, which is activated by hypoxia, may provide new insights into the etiology of endometriosis.

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

Similar content being viewed by others

References

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

    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. Olive DL, Pritts EA. Treatment of endometriosis. N Engl J Med. 2001; 345(4):266–275.

    CAS  PubMed  Google Scholar 

  4. Figueira PG, Abrao MS, Krikun G, Taylor HS. Stem cells in endometrium and their role in the pathogenesis of endometriosis. Ann N Y Acad Sci. 2011; 1221:10–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kao AP, Wang KH, Chang CC, et al. Comparative study of human eutopic and ectopic endometrial mesenchymal stem cells and the development of an in vivo endometriotic invasion model. Fertil Steril. 2011; 95(4):1308–1315.

    CAS  PubMed  Google Scholar 

  6. Wu MH, Chen KF, Lin SC, Lgu CW, Tsai SJ. Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1 alpha. Am J Pathology. 2007; 170(2):590–598.

    CAS  Google Scholar 

  7. Sharkey AM, Day K, McPherson A, et al. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab. 2000; 85(1):402–409.

    CAS  PubMed  Google Scholar 

  8. Krikun G, Schatz F, Finlay T, et al. Expression of angiopoietin-2 by human endometrial endothelial cells:regulation by hypoxia and inflammation. Biochem Biophys Res Commun. 2000; 275(1):159–163.

    CAS  PubMed  Google Scholar 

  9. Lu Z, Zhang W, Jiang S, Zou J, Li Y. Effect of oxygen tensions on the proliferation and angiogenesis of endometriosis heterograft in severe combined immunodeficiency mice. Fertil Steril. 2014; 101(2):568–576.

    CAS  PubMed  Google Scholar 

  10. Hsiao KY, Chang N, Lin SC, Li YH, Wu MH. Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis. Hum Reprod. 2014; 29(12):2747–2755.

    CAS  PubMed  Google Scholar 

  11. Lin SC, Wang CC, Wu MH, Yang SH, Li YH, Tsai SJ. Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. J Clin Endocrinol Metab. 2012; 97(8):E1515–E1523.

    Google Scholar 

  12. Ulukus M, Cakmak H, Arici A. The role of endometrium in endometriosis. J Soc Gynecol Invest. 2006; 13(7):467–476.

    CAS  Google Scholar 

  13. Harada T, Kaponis A, Iwabe T, et al. Apoptosis in human endometrium and endometriosis. Hum Reprod Update. 2004; 10(1):29–38.

    CAS  PubMed  Google Scholar 

  14. Bassi MA, Podgaec S, Dias Junior JA, Sobrado CW, N DAF. [Bowel endometriosis:a benign disease?]. Rev Assoc Med Bras. 2009; 55(5):611–616.

    PubMed  Google Scholar 

  15. Bumey RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012; 98(3):511–519.

    Google Scholar 

  16. Rogers PA, D’Hooghe TM, Fazleabas A, et al. Defining future directions for endometriosis research:workshop report from the 2011 World Congress of Endometriosis In Montpellier, France. Reprod Sci. 2013; 20(5):483–499.

    PubMed  PubMed Central  Google Scholar 

  17. Willert K, Nusse R. Beta-catenin:a key mediator of Wnt signaling. Curr Opin Genet Dev. 1998; 8(1):95–102.

    CAS  PubMed  Google Scholar 

  18. Matsuzaki S, Darcha C. In vitro effects of a small-molecule antagonist of the Tcf/ss-catenin complex on endometrial and endometriotic cells of patients with endometriosis. PloS One. 2013; 8(4):e61690.

    Google Scholar 

  19. Matsuzaki S, Darcha C. Involvement of the Wnt/beta-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis. PloS One. 2013; 8(10):e76808.

    Google Scholar 

  20. Matsuzaki S, Darcha C, Maleysson E, Canis M, Mage G. Impaired down-regulation of E-cadherin and beta-catenin protein expression in endometrial epithelial cells in the mid-secretory endometrium of infertile patients with endometriosis. J Clin Endocrinol Metabol. 2010; 95(7):3437–3445.

    CAS  Google Scholar 

  21. Liu L, Zhu XD, Wang WQ, et al. Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clin Cancer Res. 2010; 16(10):2740–2750.

    CAS  PubMed  Google Scholar 

  22. Cui XP, Xing Y, Chen JM, Dong SW, Ying DJ, Yew DT. Wnt/ beta-catenin is involved in the proliferation of hippocampal neural stem cells induced by hypoxia. Irish J Med Sci. 2011; 180(2):387–393.

    CAS  PubMed  Google Scholar 

  23. Guillemin K, Krasnow MA. The hypoxic response:huffing and HIFing. Cell. 1997; 89(1):9–12.

    CAS  PubMed  Google Scholar 

  24. Jiang QY, Wu RJ. Growth mechanisms of endometriotic cells in implanted places:a review. Gynecol Endocrinol. 2012; 28(7):562–567.

    PubMed  Google Scholar 

  25. Spuijbroek MD, Dunselman GA, Menheere PP, Evers JL. Early endometriosis invades the extracellular matrix. Fertil Steril. 1992; 58(5):929–833.

    CAS  PubMed  Google Scholar 

  26. Bruner KL, Matrisian LM, Rodgers WH, Gorstein F, Osteen KG. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997; 99(12):2851–2857.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Chung HW, Wen Y, Chun SH, Nezhat C, Woo BH, Lake Polan M. Matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis:a rationale for endometriotic invasiveness. Fertil Siril. 2001; 75(1):152–159.

    CAS  Google Scholar 

  28. Collette T, Maheux R, Mailloux J, Akoum A. Increased expression of matrix metalloproteinase-8 in the eutopic endometrial tissue of women with endometriosis. Hum Reprod. 2006; 21(12):3059–3067.

    CAS  PubMed  Google Scholar 

  29. Groothuis PG, Nap AW, Winterhager E, Grummer R. Vascular development in endometriosis. Angiogenesis. 2005; 8(2):147–156.

    CAS  PubMed  Google Scholar 

  30. Liang JY, Li CD, Zhang WY. [Effects of activating and inhibiting Wnt/beta-catenin signaling pathway on murine model of eutopic endometrium and endometriosis]. Zhonghua yi xue za zhi. 2012; 92(19):1352–1356.

    CAS  PubMed  Google Scholar 

  31. Franke WW. Discovering the molecular components of intercellular junctions-a historical view. Cold Spring Harbor Perspect Biol. 2009; 1(3):003061.

    Google Scholar 

  32. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cad-herin pathways. Science. 2004; 303(5663):1483–1487.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Ann Rev Cell Dev Biol. 1998; 14:59–88.

    CAS  Google Scholar 

  34. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling:components, mechanisms, and diseases. Dev Cell. 2009; 17(1):9–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC. Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis:Wnt you like to know? Endocrine Rev. 2005; 26(7):898–915.

    CAS  Google Scholar 

  36. Akiyama T. Wnt/beta-catenin signaling. Cytokine Growth Factor Rev. 2000; 11(4):273–282.

    CAS  PubMed  Google Scholar 

  37. Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogen-esis-a look outside the nucleus. Science. 2000; 287(5458):1606–1609.

    CAS  PubMed  Google Scholar 

  38. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010; 40(2):294–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Revised American Society for Reproductive Medicine classification of endometriosis:1996. Fertility and Sterility. 1997; 67(5):817–821.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China

    Wenqian Xiong MD, Ling Zhang MD, Yao Xiong MD, Hengwei Liu MD & Yi Liu PhD

Authors
  1. Wenqian Xiong MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Zhang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yao Xiong MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hengwei Liu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Liu PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Liu PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiong, W., Zhang, L., Xiong, Y. et al. Hypoxia Promotes Invasion of Endometrial Stromal Cells via Hypoxia-Inducible Factor 1α Upregulation-Mediated β-Catenin Activation in Endometriosis. Reprod. Sci. 23, 531–541 (2016). https://doi.org/10.1177/1933719115607999

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719115607999

Keywords

Search

Navigation