Tumor Biology

, Volume 36, Issue 8, pp 5913–5923 | Cite as

DYRK2 regulates epithelial-mesenchymal-transition and chemosensitivity through Snail degradation in ovarian serous adenocarcinoma

  • Noriko Yamaguchi
  • Rei Mimoto
  • Nozomu Yanaihara
  • Yoshimi Imawari
  • Shinichi Hirooka
  • Aikou Okamoto
  • Kiyotsugu Yoshida
Research Article


Epithelial-mesenchymal-transition (EMT) plays essential roles in ovarian cancer invasion, metastasis, and drug resistance. A hallmark of EMT is the loss of E-cadherin, which is regulated by Snail. Recently, it was shown that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls Snail degradation in breast cancer. The aim of this study is to clarify whether DYRK2 regulates EMT through Snail degradation in ovarian serous adenocarcinoma (SA). Expression of DYRK2 and Snail in two pairs of cisplatin-resistant and the original cisplatin-sensitive ovarian cancer cell line were analyzed by immunoblotting and real-time RT-PCR analysis. Morphological change, invasion ability, and chemosensitivity were evaluated by using DYRK2 stable knockdown cell line in 2008 (2008 shDYRK2). Immunohistochemical analyses for DYRK2 and Snail were performed with surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including prognosis, were determined. Moreover, we conducted a hypodermic administration test in nude mice and examined reproductive and cisplatin response activities. DYRK2 protein expression was posttranslationally reduced in cisplatin-resistant SA cell lines. 2008 shDYRK2 showed mesenchymal phenotype and resistant to cisplatin. Immunohistochemistry demonstrated that DYRK2 expression inversely correlated with Snail expression, and reduced expression of DYRK2 was associated with shorter overall survival in SA. DYRK2 may regulate EMT through Snail degradation in ovarian SA and might be a predictive marker for a favorable prognosis in the treatment of this cancer.

Key words

Ovarian cancer DYRK2 Snail EMT Cisplatin Chemosensitivity 





Ovarian serous adenocarcinoma


Dual-specificity tyrosine-regulated kinase 2


Matrix metalloproteinase


Extracellular matrix






Glycogen synthase kinase-3β


Lymph node


The International Federation of Gynecology and Obstetrics



This work was supported by grants from the Japan Society for the Promotion of Science, the Jikei University Graduate Research Fund, the Jikei University Research Fund, Takeda Science Foundation, the Naito Foundation, Project Mirai Cancer Research Grants, and the Vehicle Racing Commemorative Foundation.

Conflicts of interest



  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol. 2006;20:207–25.CrossRefPubMedGoogle Scholar
  3. 3.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  4. 4.
    Moore RG, Maclaughlan S. Current clinical use of biomarkers for epithelial ovarian cancer. Curr Opin Oncol. 2010;22:492–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Cho KR, Shih Ie M. Ovarian cancer. Annu Rev Pathol. 2009;4:287–313.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch. 2012;460:237–49.CrossRefPubMedGoogle Scholar
  7. 7.
    Hoskins WJ. Epithelial ovarian carcinoma: principles of primary surgery. Gynecol Oncol. 1994;55:S91–6.CrossRefPubMedGoogle Scholar
  8. 8.
    du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M, et al. Consensus statements on the management of ovarian cancer: final document of the 3rd international gynecologic cancer intergroup ovarian cancer consensus conference (gcig occc 2004). Ann Oncol. 2005;16 Suppl 8:viii7–12.PubMedGoogle Scholar
  9. 9.
    Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundqvist E, Brady M, et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer. 2011;21:771–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Colombo N, Gore M. Treatment of recurrent ovarian cancer relapsing 6–12 months post platinum-based chemotherapy. Crit Rev Oncol Hematol. 2007;64:129–38.CrossRefPubMedGoogle Scholar
  11. 11.
    Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K. Dyrk2 is targeted to the nucleus and controls p53 via ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell. 2007;25:725–38.CrossRefPubMedGoogle Scholar
  12. 12.
    Becker W. Emerging role of dyrk family protein kinases as regulators of protein stability in cell cycle control. Cell Cycle. 2012;11:3389–94.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Maddika S, Chen J. Protein kinase dyrk2 is a scaffold that facilitates assembly of an e3 ligase. Nat Cell Biol. 2009;11:409–19.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Matsuo R, Ochiai W, Nakashima K, Taga T. A new expression cloning strategy for isolation of substrate-specific kinases by using phosphorylation site-specific antibody. J Immunol Methods. 2001;247:141–51.CrossRefPubMedGoogle Scholar
  15. 15.
    Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, et al. The kinase dyrk phosphorylates protein-synthesis initiation factor eif2bepsilon at ser539 and the microtubule-associated protein tau at thr212: potential role for dyrk as a glycogen synthase kinase 3-priming kinase. Biochem J. 2001;355:609–15.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, et al. A genome-wide drosophila rnai screen identifies dyrk-family kinases as regulators of nfat. Nature. 2006;441:646–50.CrossRefPubMedGoogle Scholar
  17. 17.
    Varjosalo M, Bjorklund M, Cheng F, Syvanen H, Kivioja T, Kilpinen S, et al. Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell. 2008;133:537–48.CrossRefPubMedGoogle Scholar
  18. 18.
    Taira N, Mimoto R, Kurata M, Yamaguchi T, Kitagawa M, Miki Y, et al. Dyrk2 priming phosphorylation of c-jun and c-myc modulates cell cycle progression in human cancer cells. J Clin Invest. 2012;122:859–72.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mimoto R, Taira N, Takahashi H, Yamaguchi T, Okabe M, Uchida K, et al. Dyrk2 controls the epithelial-mesenchymal transition in breast cancer by degrading snail. Cancer Lett. 2013;339:214–25.CrossRefPubMedGoogle Scholar
  20. 20.
    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.CrossRefPubMedGoogle Scholar
  21. 21.
    Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and ig-cams in cancer. Nat Rev Cancer. 2004;4:118–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Barrallo-Gimeno A, Nieto MA. The snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132:3151–61.CrossRefPubMedGoogle Scholar
  23. 23.
    Fishman DA, Bozorgi K. The scientific basis of early detection of epithelial ovarian cancer: the national ovarian cancer early detection program (nocedp). Cancer Treat Res. 2002;107:3–28.PubMedGoogle Scholar
  24. 24.
    Liu CM. Cancer of the ovary. N Engl J Med. 2005;352:1268–9. author reply 1268–1269.CrossRefPubMedGoogle Scholar
  25. 25.
    Jia L, Jin H, Zhou J, Chen L, Lu Y, Ming Y, et al. A potential anti-tumor herbal medicine, corilagin, inhibits ovarian cancer cell growth through blocking the tgf-beta signaling pathways. BMC Complement Altern Med. 2013;13:33.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Fraser M, Bai T, Tsang BK. Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 2008;122:534–46.CrossRefPubMedGoogle Scholar
  27. 27.
    Colomiere M, Ward AC, Riley C, Trenerry MK, Cameron-Smith D, Findlay J, et al. Cross talk of signals between egfr and il-6r through jak2/stat3 mediate epithelial-mesenchymal transition in ovarian carcinomas. Br J Cancer. 2009;100:134–44.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of snail by gsk-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004;6:931–40.CrossRefPubMedGoogle Scholar
  29. 29.
    Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of e-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009;27:2059–68.CrossRefPubMedGoogle Scholar
  31. 31.
    Haslehurst AM, Koti M, Dharsee M, Nuin P, Evans K, Geraci J, et al. Emt transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer. 2012;12:91.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Iseri OD, Kars MD, Arpaci F, Gunduz U. Gene expression analysis of drug-resistant mcf-7 cells: implications for relation to extracellular matrix proteins. Cancer Chemother Pharmacol. 2010;65:447–55.CrossRefPubMedGoogle Scholar
  33. 33.
    Yamashita S, Chujo M, Moroga T, Anami K, Tokuishi K, Miyawaki M, et al. Dyrk2 expression may be a predictive marker for chemotherapy in non-small cell lung cancer. Anticancer Res. 2009;29:2753–7.PubMedGoogle Scholar
  34. 34.
    Darai E, Scoazec JY, Walker-Combrouze F, Mlika-Cabanne N, Feldmann G, Madelenat P, et al. Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopathologic study of 60 cases. Hum Pathol. 1997;28:922–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Cho EY, Choi Y, Chae SW, Sohn JH, Ahn GH. Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms. Pathol Int. 2006;56:62–70.CrossRefPubMedGoogle Scholar
  36. 36.
    Helleman J, Smid M, Jansen MP, van der Burg ME, Berns EM. Pathway analysis of gene lists associated with platinum-based chemotherapy resistance in ovarian cancer: the big picture. Gynecol Oncol. 2010;117:170–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Zha YH, He JF, Mei YW, Yin T, Mao L. Zinc-finger transcription factor snail accelerates survival, migration and expression of matrix metalloproteinase-2 in human bone mesenchymal stem cells. Cell Biol Int. 2007;31:1089–96.CrossRefPubMedGoogle Scholar
  38. 38.
    Dyall S, Gayther SA, Dafou D. Cancer stem cells and epithelial ovarian cancer. J Oncol. 2010;2010:105269.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Noriko Yamaguchi
    • 1
    • 2
  • Rei Mimoto
    • 1
    • 3
  • Nozomu Yanaihara
    • 2
  • Yoshimi Imawari
    • 1
    • 3
  • Shinichi Hirooka
    • 4
  • Aikou Okamoto
    • 2
  • Kiyotsugu Yoshida
    • 1
  1. 1.Department of BiochemistryThe Jikei University School of MedicineTokyoJapan
  2. 2.Department of Obstetrics and GynecologyThe Jikei University School of MedicineTokyoJapan
  3. 3.Department of SurgeryThe Jikei University School of MedicineTokyoJapan
  4. 4.Department of PathologyThe Jikei University School of MedicineTokyoJapan

Personalised recommendations