Tumor Biology

, Volume 37, Issue 2, pp 2729–2735 | Cite as

MiR-204-5p/Six1 feedback loop promotes epithelial–mesenchymal transition in breast cancer

Original Article


Epithelial–mesenchymal transition (EMT) is a vital process in epithelial cancer invasion and metastasis. The induction of EMT by Six1 has been described as a common mode of cancer progression, which could promote breast cancer migration and invasion. In the study, we found that miR-204-5p could suppress the migration and invasion of breast cancer cell lines. Since overexpression of Six1 promote EMT, we identified a mechanism by which miR-204-5p inhibited the EMT by downregulating the Six1, which was mediated by a conserved miR-204-5p seed-matching sequence in the 3′-UTR of Six1 mRNA. We also identified that upregulation of Six1 could downregulate miR-204-5p expression, affecting the migration and invasion of breast cancer cell lines. In conclusion, the frequent upregulation of Six1 and/or downregulation of miR-204-5p in breast cancer may shift the equilibrium of these reciprocal regulations and lock breast cancer cells in the mesenchymal state.


miR-204-5p Six1 EMT Breast cancer 


Authors’ contributions

JZ and MW designed all the experiments. JZ, MW, and RS performed clinical data acquisition, statistical analysis, and drafted the manuscript. CXC and XRL performed experiment studies. YBS and WLZ performed critical revision. WLM designed and directed the study. All authors read and approved the final manuscript.


  1. 1.
    DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin. 2014;64:52–62.CrossRefPubMedGoogle Scholar
  2. 2.
    Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene. 2005;24:7443–54.CrossRefPubMedGoogle Scholar
  3. 3.
    Behbakht K, Qamar L, Aldridge CS, Coletta RD, Davidson SA, Thorburn A. Six1 overexpression in ovarian carcinoma causes resistance to trail-mediated apoptosis and is associated with poor survival. Cancer Res. 2007;67:3036–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Micalizzi DS, Christensen KL, Jedlicka P, Coletta RD, Baron AE, Harrell JC, et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest. 2009;119:2678–90.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Coletta RD, Christensen K, Reichenberger KJ, Lamb J, Micomonaco D, Huang L, et al. The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin a1. Proc Natl Acad Sci U S A. 2004;101:6478–83.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ford HL, Kabingu EN, Bump EA, Mutter GL, Pardee AB. Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis. Proc Natl Acad Sci U S A. 1998;95:12608–13.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wang CA, Jedlicka P, Patrick AN, Micalizzi DS, Lemmer KC, Deitsch E, et al. SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer. J Clin Invest. 2012;122:1895–906.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yu Y, Davicioni E, Triche TJ, Merlino G. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res. 2006;66:1982–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Bartel DP. Micrornas: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  10. 10.
    Kong KL, Kwong DL, Chan TH, Law SY, Chen L, Li Y, et al. MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor. Gut. 2012;61:33–42.CrossRefPubMedGoogle Scholar
  11. 11.
    Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, Zepeniuk M, et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol. 2008;26:462–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Song Q, Xu Y, Yang C, Chen Z, Jia C, Chen J, et al. MiR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM. Cancer Res. 2014;74:3031–42.CrossRefPubMedGoogle Scholar
  13. 13.
    Imam JS, Plyler JR, Bansal H, Prajapati S, Bansal S, Rebeles J, et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLoS One. 2012;7:e52397.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Li W, Jin X, Zhang Q, Zhang G, Deng X, Ma L. Decreased expression of miR-204 is associated with poor prognosis in patients with breast cancer. Int J Clin Exp Pathol. 2014;7:3287–92.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Ma L, Deng X, Wu M, Zhang G, Huang J. Down-regulation of miRNA-204 by LMP-1 enhances CDC42 activity and facilitates invasion of EBV-associated nasopharyngeal carcinoma cells. FEBS Lett. 2014;588:1562–70.CrossRefPubMedGoogle Scholar
  16. 16.
    Bao W, Wang HH, Tian FJ, He XY, Qiu MT, Wang JY, et al. A TrkB-STAT3-miR-204-5p regulatory circuitry controls proliferation and invasion of endometrial carcinoma cells. Mol Cancer. 2013;12:155.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Camp RL, Rimm EB, Rimm DL. Met expression is associated with poor outcome in patients with axillary lymph node negative breast carcinoma. Cancer. 1999;86:2259–65.CrossRefPubMedGoogle Scholar
  18. 18.
    Thomas PA, Kirschmann DA, Cerhan JR, Folberg R, Seftor EA, Sellers TA, et al. Association between keratin and vimentin expression, malignant phenotype, and survival in postmenopausal breast cancer patients. Clin Cancer Res. 1999;5:2698–703.PubMedGoogle Scholar
  19. 19.
    Kumar JP. The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease. Cell Mol Life Sci. 2009;66:565–83.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wan F, Miao X, Quraishi I, Kennedy V, Creek KE, Pirisi L. Gene expression changes during HPV-mediated carcinogenesis: a comparison between an in vitro cell model and cervical cancer. Int J Cancer. 2008;123:32–40.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Coletta RD, Christensen KL, Micalizzi DS, Jedlicka P, Varella-Garcia M, Ford HL. Six1 overexpression in mammary cells induces genomic instability and is sufficient for malignant transformation. Cancer Res. 2008;68:2204–13.CrossRefPubMedGoogle Scholar
  22. 22.
    McCoy EL, Iwanaga R, Jedlicka P, Abbey NS, Chodosh LA, Heichman KA, et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. J Clin Invest. 2009;119:2663–77.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ono H, Imoto I, Kozaki K, Tsuda H, Matsui T, Kurasawa Y, et al. SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation. Oncogene. 2012;31:4923–34.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Institute of Genetic EngineeringSouthern Medical UniversityGuangzhouPeople’s Republic of China
  2. 2.Sleep Center, Nanfang HospitalSouthern Medical UniversityGuangzhouPeople’s Republic of China

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