Skip to main content

Advertisement

SpringerLink
Log in

Sprouty4 mediates amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells

  • Original Article
  • Published:
Tumor Biology

Abstract

Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase (RTK)-mediated activation of cellular signaling pathways. The down-regulation of SPRY4 expression has been reported in human ovarian cancer. However, the specific roles and mechanisms by which SPRY4 affects ovarian cancer progression are completely unknown. Amphiregulin (AREG) binds exclusively to the epidermal growth factor receptor (EGFR) and has been considered to be a dominant autocrine/paracrine EGFR ligand in ovarian cancer. In the present study, we first examined the effects of AREG on SPRY4 expression and the possible underlying molecular mechanisms involved in this process in two human ovarian cancer cell lines. Our results demonstrated that treatment with AREG up-regulated SPRY4 expression by activating the ERK1/2 signaling pathway. In addition, we showed that small interfering RNA (siRNA)-mediated knockdown of SPRY4 attenuated the AREG-induced down-regulation of E-cadherin by inhibiting the expression of SNAIL but not SLUG. In contrast, overexpression of SPRY4 enhanced AREG-induced down-regulation of E-cadherin by increasing the expression of SNAIL. Moreover, SPRY4 knockdown attenuated AREG-induced cell migration and invasion. Overexpression of SPRY4 enhanced AREG-induced cell invasion. This study reveals that SPRY4 is involved in EGFR-mediated human ovarian cancer progression.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA. Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the drosophila airways. Cell. 1998;92:253–63.

    Article  CAS  PubMed  Google Scholar 

  2. Minowada G, Jarvis LA, Chi CL, Neubuser A, Sun X, Hacohen N, et al. Vertebrate sprouty genes are induced by FGF signaling and can cause chondrodysplasia when overexpressed. Development. 1999;126:4465–75.

    CAS  PubMed  Google Scholar 

  3. Zhang S, Lin Y, Itaranta P, Yagi A, Vainio S. Expression of sprouty genes 1, 2 and 4 during mouse organogenesis. Mech Dev. 2001;109:367–70.

    Article  CAS  PubMed  Google Scholar 

  4. Guy GR, Jackson RA, Yusoff P, Chow SY. Sprouty proteins: modified modulators, matchmakers or missing links? J Endocrinol. 2009;203:191–202.

    Article  CAS  PubMed  Google Scholar 

  5. Masoumi-Moghaddam S, Amini A, Morris DL. The developing story of sprouty and cancer. Cancer Metastasis Rev. 2014;33:695–720.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bartlett JM, Langdon SP, Simpson BJ, Stewart M, Katsaros D, Sismondi P, et al. The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer. Br J Cancer. 1996;73:301–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    Article  CAS  PubMed  Google Scholar 

  8. Yotsumoto F, Yagi H, Suzuki SO, Oki E, Tsujioka H, Hachisuga T, et al. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun. 2008;365:555–61.

    Article  CAS  PubMed  Google Scholar 

  9. Yagi H, Miyamoto S, Tanaka Y, Sonoda K, Kobayashi H, Kishikawa T, et al. Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer. Br J Cancer. 2005;92:1737–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Qiu X, Cheng JC, Klausen C, Fan Q, Chang HM, So WK, et al. Transforming growth factor-alpha induces human ovarian cancer cell invasion by down-regulating e-cadherin in a snail-independent manner. Biochem Biophys Res Commun. 2015;461:128–35.

    Article  CAS  PubMed  Google Scholar 

  11. So WK, Fan Q, Lau MT, Qiu X, Cheng JC, Leung PC. Amphiregulin induces human ovarian cancer cell invasion by down-regulating e-cadherin expression. FEBS Lett. 2014;588:3998–4007.

    Article  CAS  PubMed  Google Scholar 

  12. Cheng JC, Auersperg N, Leung PC. EGF-induced EMT and invasiveness in serous borderline ovarian tumor cells: a possible step in the transition to low-grade serous carcinoma cells? PLoS ONE. 2012;7, e34071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cheng JC, Chang HM, Leung PC. Egr-1 mediates epidermal growth factor-induced downregulation of e-cadherin expression via slug in human ovarian cancer cells. Oncogene. 2013;32:1041–9.

    Article  CAS  PubMed  Google Scholar 

  14. Cheng JC, Chang HM, Leung PC. Epidermal growth factor induces human oviductal epithelial cell invasion by down-regulating e-cadherin expression. J Clin Endocrinol Metab. 2012;97:E1380–1389.

    Article  CAS  PubMed  Google Scholar 

  15. Masoumi-Moghaddam S, Amini A, Wei AQ, Robertson G, Morris DL. Sprouty 2 protein, but not sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer. Int J Cancer J Int Cancer. 2015;137:560–70.

    Article  CAS  Google Scholar 

  16. So WK, Cheng JC, Fan Q, Wong AS, Huntsman DG, Gilks CB, et al. Loss of sprouty2 in human high-grade serous ovarian carcinomas promotes EGF-induced e-cadherin down-regulation and cell invasion. FEBS Lett. 2015;589:302–9.

    Article  CAS  PubMed  Google Scholar 

  17. Inoue Y, Miyamoto S, Fukami T, Shirota K, Yotsumoto F, Kawarabayashi T. Amphiregulin is much more abundantly expressed than transforming growth factor-alpha and epidermal growth factor in human follicular fluid obtained from patients undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2009;91:1035–41.

    Article  CAS  PubMed  Google Scholar 

  18. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505–16.

    Article  CAS  PubMed  Google Scholar 

  19. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–28.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng JC, Klausen C, Leung PC. Hydrogen peroxide mediates EGF-induced down-regulation of e-cadherin expression via p38 MAPK and snail in human ovarian cancer cells. Mol Endocrinol. 2010;24:1569–80.

    Article  CAS  PubMed  Google Scholar 

  21. Mayer CE, Haigl B, Jantscher F, Siegwart G, Grusch M, Berger W, et al. Bimodal expression of sprouty2 during the cell cycle is mediated by phase-specific Ras/MAPK and c-Cbl activities. Cell Mol Life Sci: CMLS. 2010;67:3299–311.

    Article  CAS  PubMed  Google Scholar 

  22. Ozaki K, Kadomoto R, Asato K, Tanimura S, Itoh N, Kohno M. ERK pathway positively regulates the expression of sprouty genes. Biochem Biophys Res Commun. 2001;285:1084–8.

    Article  CAS  PubMed  Google Scholar 

  23. Sasaki A, Taketomi T, Wakioka T, Kato R, Yoshimura A. Identification of a dominant negative mutant of sprouty that potentiates fibroblast growth factor- but not epidermal growth factor-induced ERK activation. J Biol Chem. 2001;276:36804–8.

    Article  CAS  PubMed  Google Scholar 

  24. Doriguzzi A, Haigl B, Gsur A, Sutterluty-Fall H. The increased sprouty4 expression in response to serum is transcriptionally controlled by specific protein 1. Int J Biochem Cell Biol. 2015;64:220–8.

    Article  CAS  PubMed  Google Scholar 

  25. Mason JM, Morrison DJ, Basson MA, Licht JD. Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol. 2006;16:45–54.

    Article  CAS  PubMed  Google Scholar 

  26. Taniguchi K, Ayada T, Ichiyama K, Kohno R, Yonemitsu Y, Minami Y, et al. Sprouty2 and sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling. Biochem Biophys Res Commun. 2007;352:896–902.

    Article  CAS  PubMed  Google Scholar 

  27. Klempner SJ, Myers AP, Mills GB, Westin SN. Clinical investigation of receptor and non-receptor tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer. Expert Opin Pharmacother. 2013;14:2171–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Morotti M, Becker CM, Menada MV, Ferrero S. Targeting tyrosine-kinases in ovarian cancer. Expert Opin Investig Drugs. 2013;22:1265–79.

    Article  CAS  PubMed  Google Scholar 

  29. Tennis MA, Van Scoyk MM, Freeman SV, Vandervest KM, Nemenoff RA, Winn RA. Sprouty-4 inhibits transformed cell growth, migration and invasion, and epithelial-mesenchymal transition, and is regulated by Wnt7A through PPARgamma in non-small cell lung cancer. Mol Cancer Res: MCR. 2010;8:833–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang J, Thompson B, Ren C, Ittmann M, Kwabi-Addo B. Sprouty4, a suppressor of tumor cell motility, is down regulated by DNA methylation in human prostate cancer. Prostate. 2006;66:613–24.

    Article  CAS  PubMed  Google Scholar 

  31. Masoumi-Moghaddam S, Amini A, Ehteda A, Wei AQ, Morris DL. The expression of the sprouty 1 protein inversely correlates with growth, proliferation, migration and invasion of ovarian cancer cells. J Ovarian Res. 2014;7:61.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhang Q, Wei T, Shim K, Wright K, Xu K, Palka-Hamblin HL, Jurkevich A, Khare S: Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial-mesenchymal transition. Oncogene 2015.

Download references

Acknowledgments

We also thank Dr. Graeme R. Guy (The Institute of Molecular and Cell Biology, Singapore) for the generous gifts of pXJ40-FLAG and FLAG-SPRY4 plasmids. This work was supported by an operating grant from the Canadian Institutes of Health Research (#143317) to P.C.K.L. P.C.K.L. is a Scientist Level 3 of the Child and Family Research Institute.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Room 317, 950 west 28th Ave, Vancouver, BC, V5Z 4H4, Canada

    Wai-Kin So, Jung-Chien Cheng, Yingtao Liu, Jianfang Zhao, Vincent T. W. Chang & Peter C. K. Leung

  2. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China, 200011

    Yingtao Liu & Congjian Xu

Authors
  1. Wai-Kin So
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jung-Chien Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yingtao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Congjian Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianfang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vincent T. W. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter C. K. Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter C. K. Leung.

Ethics declarations

Conflicts of interest

None.

Grant support

This work was supported by an operating grant from the Canadian Institutes of Health Research (#143317) to P.C.K.L.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

So, WK., Cheng, JC., Liu, Y. et al. Sprouty4 mediates amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells. Tumor Biol. 37, 9197–9207 (2016). https://doi.org/10.1007/s13277-016-4790-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-4790-y

Keywords

Search

Navigation