Skip to main content

Advertisement

SpringerLink
Log in

The Role of 17β-Estrogen in Candida albicans Adhesion on Human Vaginal Epithelial Cells via FAK Phosphorylation

  • Original Article
  • Published:
Mycopathologia Aims and scope Submit manuscript

Abstract

Purposes

To investigate the role of 17β-estrogen in Candida albicans (C. albicans) adhesion on human vaginal epithelial cells in vulvovaginal candidiasis (VVC).

Methods

The vaginal epithelial cell line, VK2/E6E7, was used to study the estrogen-induced molecular events between C. albicans and cells. An adhesion study was performed to evaluate the involvement of the estrogen-dependent focal adhesion kinase (FAK) activation in cell adhesion. The phosphorylation status of FAK and estrogen receptor α (ERα) upon estrogen challenge was assessed by western blotting. Specific inhibitors for ERα were used to validate the involvement of ERα–FAK signaling cascade.

Results

A transient activation of ERα and FAK was observed following the stimulation with 1000 nM estrogen for 48 h, as well as the increased average number of C. albicans adhering to each vaginal epithelial cell. Estrogen-induced activation of ERa and FAK was inhibited by the specific inhibitor of ERα, especially when the inhibitor reached a 10 μM concentration and allowed to act for 12 h. Simultaneously, a decrease in the number of adherent C. albicans was observed. However, this inhibitory effect diminished as the concentration of estrogen increased.

Conclusion

FAK and ERα signaling cascades were involved in the early interaction between the vaginal epithelial cells and C. albicans, which appeared to be linked with the enhanced cell adhesion leading to VVC and promoted by a certain concentration of estrogen.

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
Fig. 5

Similar content being viewed by others

References

  1. Gonçalves B, Ferreira C, Alves CT, et al. Vulvovaginal candidiasis: epidemiology, microbiology and risk factors. Crit Rev Microbiol. 2015;21:1–23.

    Google Scholar 

  2. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1–50.

    Article  Google Scholar 

  3. Takac I. The frequency of bacterial and yeast infection in women with different grades of cervical intraepithelial neoplasia (CIN). Eur J Obstet Gynecol Reprod Biol. 1998;80(2):231–4.

    Article  CAS  Google Scholar 

  4. Thrumurthy SG, Tiew S, Wood N, et al. Candida: an unexpected cause of the acute abdomen. BMJ Case Report, 2010; 2010.

  5. Kranjcić-Zec I, Dzamić A, Mitrović S, et al. The role of parasites and fungi in secondary infertility. Med Pregl. 2004;57(1–2):30–2.

    Article  Google Scholar 

  6. Chung LM, Liang JA, Lin CL, et al. Cancer risk in patients with candidiasis: a nationwide population-based cohort study. Oncotarget. 2017;8(38):63562–73.

    Article  Google Scholar 

  7. Aguin TJ, Sobel JD. Vulvovaginal candidiasis in pregnancy. Curr Infect Dis Rep. 2015;17(6):462.

    Article  CAS  Google Scholar 

  8. Richardson JP, Moyes DL, Ho J, et al. Candida innate immunity at the mucosa. Semin Cell Dev Biol. 2018;89:58–70.

    Article  Google Scholar 

  9. Naglik JR, König A, Hube B, et al. Candida albicans-epithelial interactions and induction of mucosal innate immunity. Curr Opin Microbiol. 2017;40:104–12.

    Article  CAS  Google Scholar 

  10. Kuiper GG, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997;138(3):863–70.

    Article  CAS  Google Scholar 

  11. Dalla Valle L, Ramina A, Vianello S, et al. Potential for estrogen synthesis and action in human normal and neoplastic thyroid tissues. J Clin Endocrinol Metab. 1998;83(10):3702–9.

    CAS  PubMed  Google Scholar 

  12. Schneider B, Cohen E, Stani J, et al. Towards the expression of sex hormone receptors in the human vocal fold. J Voice. 2007;21(4):502–7.

    Article  Google Scholar 

  13. Nyirjesy P, Sobel JD. Vulvovaginal candidiasis. Obstet Gynecol Clin N Am. 2003;30(4):671–84.

    Article  Google Scholar 

  14. Gonçalves B, Azevedo NM, Henriques M, et al. Hormones modulate Candida vaginal isolates biofilm formation and decrease their susceptibility to azoles and hydrogen peroxide. Med Mycol. 2019. https://doi.org/10.1093/mmy/myz070.

    Article  PubMed  Google Scholar 

  15. Zhang X, Essmann M, Burt ET, et al. Estrogen effects on Candida albicans: a potential virulence-regulating mechanism. J Infect Dis. 2000;181(4):1441–6.

    Article  CAS  Google Scholar 

  16. Uma S, Balakrishnan P, Murugavel KG, et al. Bacterial vaginosis in women of low socioeconomic status living in slum areas in Chennai, India. Sex Health. 2006;3(4):297–8.

    Article  Google Scholar 

  17. Netea MG, Joosten LA, van der Meer JW, et al. Immune defence against Candida fungal infections. Nat Rev Immunol. 2015;15:630–42.

    Article  CAS  Google Scholar 

  18. Liu Y, Zhang W, Sileika T, et al. Role of bacterial adhesion in the microbial ecology of biofilms in cooling tower systems. Biofouling. 2009;25(3):241–53.

    Article  CAS  Google Scholar 

  19. Shi Z, Stack MS. Molecules of cell adhesion and extracellular matrix proteolysis in oral squamous cell carcinoma. Histol Histopathol. 2010;25(7):917–32.

    CAS  PubMed  Google Scholar 

  20. Goni GM, Epifano C, Boskovic J, et al. Phosphatidylinositol 4, 5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. PNAS. 2014;111:E3177–86.

    Article  CAS  Google Scholar 

  21. Stone RL, Baggerly KA, Armaiz-Pena GN, et al. Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer. Cancer Biol Ther. 2014;15:919–29.

    Article  CAS  Google Scholar 

  22. Shi J, Zeng X, Zhou M, et al. Activation of ERK–FAK signaling pathway and enhancement of cell migration involved in the early interaction between oral keratinocytes and Candida albicans. Mycopathologia. 2009;167(1):1–7.

    Article  Google Scholar 

  23. Segura-Uribe JJ, Pinto-Almazán R, Coyoy-Salgado A, et al. Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system. Neural Regen Res. 2017;12(8):1231–40.

    Article  Google Scholar 

  24. Klinge CM. Estrogens regulate life and death in mitochondria. J Bioenerg Biomembr. 2017;49(4):307–24.

    Article  CAS  Google Scholar 

  25. Shapiro LF, Freeman K. The relationship between estrogen, estrogen receptors and periodontal disease in adult women: a review of the literature. N Y State Dent J. 2014;80(3):30–4.

    PubMed  Google Scholar 

  26. Sanchez AM, Flamini MI, Zullino S, et al. Estrogen receptor-α promotes endothelial cell motility through focal adhesion kinase. Mol Hum Reprod. 2011;17(4):219–26.

    Article  CAS  Google Scholar 

  27. Calderone RA, Fonzi WA. Virulence factors of Candida albicans. Trends Microbiol. 2001;9(7):327–35.

    Article  CAS  Google Scholar 

  28. Cole JN, Barnett TC, Nizet V, et al. Molecular insight into invasive group A streptococcal disease. Nat Rev Microbiol. 2011;9(10):724–36.

    Article  CAS  Google Scholar 

  29. Kalo A, Segal E. Interaction of Candida albicans with genital mucosa: effect of sex hormones on adherence of yeasts in vitro. Can J Microbiol. 1988;34(3):224–8.

    Article  CAS  Google Scholar 

  30. Zhang JE, Luo D, Chen RY, Yang YP, Zhou Y, Fan YM. Feasibility of histological scoring and colony count for evaluating infective severity in mouse vaginal candidiasis. Exp Anim. 2013;62(3):205–10.

    Article  CAS  Google Scholar 

  31. Nakamura T, Miyagawa S, Katsu Y, et al. Wnt family genes and their modulation in the ovary-independent and persistent vaginal epithelial cell proliferation and keratinization induced by neonatal diethylstilbestrol exposure in mice. Toxicology. 2012;296(1–3):13–9.

    Article  CAS  Google Scholar 

  32. Li S, Herrera GG, Tam KK, et al. Estrogen action in the epithelial cells of the mouse vagina regulates neutrophil infiltration and vaginal tissue integrity. Sci Rep. 2018;8(1):11247.

    Article  Google Scholar 

  33. Matsuda S, Kawamoto K, Miyamoto K, et al. PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity. Sci Rep. 2017;7:45545.

    Article  CAS  Google Scholar 

  34. Sieg DJ, Hauck CR, Ilic D, et al. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol. 2000;2(5):249–56.

    Article  CAS  Google Scholar 

  35. Rigiracciolo DC, Santolla MF, Lappano R, et al. Focal adhesion kinase (FAK) activation by estrogens involves GPER in triple-negative breast cancer cells. J Exp Clin Cancer Res. 2019;38(1):58.

    Article  Google Scholar 

  36. Golubovskaya VM, Kweh FA, Cance WG. Focal adhesion kinase and cancer. Histol Histopathol. 2009;24(4):503–10.

    CAS  PubMed  Google Scholar 

  37. Mantovani A. Molecular pathways linking inflammation and cancer. Curr Mol Med. 2010;10(4):369–73.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was financially supported by National Natural Science Foundation of China (81671410, 81871474, 81501341) and Nanjing medical science and technique development foundation (QRX17072).

Author information

Author notes

  1. Ting Luan and Xia Liu have contributed equally to this paper.

Authors and Affiliations

  1. Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, People’s Republic of China

    Ting Luan, Pengyuan Mao, Xinyan Wang, Can Rui, Lina Yan, Chong Fan, Ping Li & Xin Zeng

  2. Department of Obstetrics and Gynecology, Jiangsu Taizhou People’s Hospital, Taizhou, Jiangsu, People’s Republic of China

    Xia Liu

  3. Department of Internal Medicine, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China

    Yiquan Wang

Authors
  1. Ting Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pengyuan Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Can Rui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lina Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yiquan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chong Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xin Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ping Li or Xin Zeng.

Additional information

Handling Editor: Anamelia Lorenzetti Bocca.

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luan, T., Liu, X., Mao, P. et al. The Role of 17β-Estrogen in Candida albicans Adhesion on Human Vaginal Epithelial Cells via FAK Phosphorylation. Mycopathologia 185, 425–438 (2020). https://doi.org/10.1007/s11046-020-00440-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11046-020-00440-1

Keywords

Search

Navigation