Tumor Biology

, Volume 35, Issue 11, pp 10897–10904 | Cite as

MicroRNA-124 inhibits cellular proliferation and invasion by targeting Ets-1 in breast cancer

  • Wentao Li
  • Wenqiao Zang
  • Pei Liu
  • Yuanyuan Wang
  • Yuwen Du
  • Xiaonan Chen
  • Meng Deng
  • Wencong Sun
  • Lei Wang
  • Guoqiang Zhao
  • Baoping Zhai
Research Article


MicroRNAs (miRNAs) are small non-coding RNAs that, by targeting certain messenger RNAs (mRNAs) for translational repression or cleavage, can regulate the expression of these genes. In addition, miRNAs may also function as oncogenes and tumor-suppressor genes, as the abnormal expression of miRNAs is associated with various human tumors. However, the effects of the expression of miR-124 in breast cancer remain unclear. The present study was conducted to study the expression of miR-124 in breast cancer, paying particular attention to miR-124’s relation to the proliferation, invasion, and apoptosis in breast cancer cell MCF-7 and MDA-MB-231. Real-time quantitative RT-PCR (qRT-PCR) was performed to identify miR-124 that was down-regulated in breast cancer tissues. We also showed E26 transformation specific-1 (Ets-1) and miR-124 expression levels in breast cancer tissues that were associated with lymph node metastases. With transfected synthetic miR-124 agomir into MCF-7 and MDA-MB-231, a significant reduction (P < 0.05) in MCF-7 and MDA-MB-231 cell proliferation and colony forming potential was observed after treatment with miR-124. Apoptosis and migration rates were found to be significantly higher in two breast-derived cell lines transfected with a miR-124 agomir (P < 0.05). Luciferase reporter assay and Western blot were used to verify Ets-1 as a potential major target gene of miR-124, and the result showed that miR-124 can bind to putative binding sites within the Ets-1 mRNA 3′ untranslated region (UTR) to reduce its expression. Based on these findings, we propose that miR-124 and Ets-1 may serve as a therapeutic agent in breast cancer.


Breast cancer miR-124 Ets-1 Proliferation Apoptosis Invasion 



This study was supported in part by Henan key programs for science and technology development (112101310500, 132102310093) and medical science and technology research programs in Henan Province (201201016).

Conflicts of interest



  1. 1.
    Abdelrahim M, Smith 3rd R, Burghardt R. Safe S role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res. 2004;64(18):6740–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Brennecke J, Cohen SM. Towards a complete description of the microRNA complement of animal genomes. Genome Biol. 2003;4(9):228.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66.PubMedCrossRefGoogle Scholar
  4. 4.
    Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029–33.PubMedCrossRefGoogle Scholar
  5. 5.
    Dynan WS, Tjian R. The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter. Cell. 1983;35(1):79–87.PubMedCrossRefGoogle Scholar
  6. 6.
    Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Esteller M. Non coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Gao Y, Chen Z, Zhang L, Zhou F, Shi S, Feng X, et al. Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma. Cancer Res. 2008;68(1):26–33.CrossRefGoogle Scholar
  9. 9.
    Han Y, Chen J, Zhao X, Liang C, Wang Y, Sun L, et al. MicroRNA expression signatures of bladder cancer revealed by deep sequencing. PLoS One. 2011;6(3):e18286.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Christensen LL, Holm A, Rantala J, Kallioniemi O, Rasmussen MH, Ostenfeld MS, et al. Functional screening identifies miRNAs influencing apoptosis and proliferation in colorectal cancer. PLoS One. 2014;9(6):e96767.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Chen WX, Ren LH, Shi RH. Implication of miRNAs for inflammatory bowel disease treatment: systematic review. World J Gastrointest Pathophysiol. 2014;5(2):63–70.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Iorio MV, Visone R, Di LG, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67(18):8699–707.PubMedCrossRefGoogle Scholar
  13. 13.
    Wang T, Zang W-q, Li M, Wang N, Zheng Y-l, Zhao G-q. Effect of miR-451 on the biological behavior of the esophageal carcinoma cell line EC9706. Dig Dis Sci. 2013;58(3):706–14.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim IK, Jung YK, Noh DY, Song YS, Choi CH, Oh BH, et al. Functional screening of genes suppressing TRAIL-induced apoptosis: distinct inhibitory activities of Bcl-XL and Bcl-2. Br J Cancer. 2003;88(6):910–7.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Kong LM, Liao CG, Fei F, Guo X, Xing JL, Chen ZN. Transcription factor Sp1 regulates expression of cancer-associated molecule CD147 in human lung cancer. Cancer Sci. 2010;101(6):1463–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Kozomara A, Griffiths Jones S. miRBase: integrating microRNA annotation and deep sequencing data. Nucleic Acids Res. 2011;39:D152–7.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Benson JR, Jatoi I. The global breast cancer burden. Future Oncol. 2012;8:697–702.PubMedCrossRefGoogle Scholar
  18. 18.
    Honrado E, Benítez J, Palacios J. The molecular pathology of hereditary breast cancer genetic testing and therapeutic implications. Mod Pathol. 2005;18:1305–20.PubMedCrossRefGoogle Scholar
  19. 19.
    Span PN, Manders P, Heuvel JJ, Thomas CM, Bosch RR, Beex LV, et al. Expression of the transcription factor Ets-1 is an independent prognostic marker for relapse-free survival in breast cancer. Oncogene. 2002;21:8506–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Gilles C, Polette M, Birembaut P, Brünner N, Thompson EW. Expression of c-ets-1 mRNA is associated with an invasive, EMT-derived phenotype in breast carcinoma cell lines. Clin Exp Metastasis. 1997;15:519–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Wasylyk B, Hahn SL, Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993;211:7–18.PubMedCrossRefGoogle Scholar
  22. 22.
    Seth A, Watson DK. ETS transcription factors and their emerging roles in human cancer. Eur J Cancer. 2005;41:2462–78.PubMedCrossRefGoogle Scholar
  23. 23.
    Buggy Y, Maguire TM, McGreal G, McDermott E, Hill AD, O'Higgins N, et al. Overexpression of the Ets-1 transcription factor in human breast cancer. Br J Cancer. 2004;91:1308–15.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Li R, Pei H, Watson DK. Regulation of Ets function by protein–protein interactions. Oncogene. 2000;19:6514–23.PubMedCrossRefGoogle Scholar
  25. 25.
    Hsu T, Trojanowska M, Watson DK. Ets proteins in biological control and cancer. J Cell Biochem. 2004;91:896–903.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Violette S, Nikolskaya T, Nikolsky Y, Bauerlein EL, Hahn WC. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell. 2008;13:394–406.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Maroulakou IG, Bowe DB. Expression and function of Ets transcription factors in mammalian development: a regulatory network. Oncogene. 2000;19:6432–42.PubMedCrossRefGoogle Scholar
  28. 28.
    Mattick JS, Makunin IV. Small regulatory RNAs in mammals. Hum Mol Genet. 2005;14(Spec No1):R121–32.PubMedCrossRefGoogle Scholar
  29. 29.
    Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008;14(9):2690–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Nagadia R, Pandit P, Coman WB, Cooper-White J, Punyadeera C. miRNAs in head and neck cancer revisited. Cell Oncol. 2013;36(1):1–7.CrossRefGoogle Scholar
  31. 31.
    Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451(7175):147–52.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Li L, Luo J, Wang B, Wang D, Xie X, Yuan L, et al. Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer. Mol Cancer. 2013;12:163.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Zhang H, Wang Q, Zhao Q, Di W. MiR-124 inhibits the migration and invasion of ovarian cancer cells by targeting SphK1. J Ovarian Res. 2013;6(1):84.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Xie L, Zhang Z, Tan Z, He R, Zeng X, Xie Y, et al. microRNA-124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer. Mol Cell Biochem. 2014;392(1–2):153–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Fafeur V, Tulasne D, Queva C, Vercamer C, Dimster V, Mattot V, et al. The ETS1 transcription factor is expressed during epithelial-mesenchymal transitions in the chick embryo and is activated in scatter factor-stimulated MDCK epithelial cells. Cell Growth Differ. 1997;8:655–65.PubMedGoogle Scholar
  36. 36.
    Delannoy-Courdent A, Fauquette W, Dong-Le Bourhis XF, Boilly B, Vandenbunder B, Desbiens X. Expression of c-ets-1 and uPA genes is associated with mammary epithelial cell tubulogenesis or neoplastic scattering. Int J Dev Biol. 1996;40:1097–108.PubMedGoogle Scholar
  37. 37.
    Behrens P, Rothe M, Wellmann A, Krischler J, Wernert N. The Ets-1 transcription factor is up-regulated together with MMP 1 and MMP 9 in the stroma of pre-invasive breast cancer. J Pathol. 2001;194:43–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Katayama S, Nakayama T, Ito M, Naito S, Sekine I. Expression of the ets-1 proto-oncogene in human breast carcinoma: differential expression with histological grading and growth pattern. Histol Histopathol. 2005;20:119–26.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Wentao Li
    • 1
  • Wenqiao Zang
    • 2
  • Pei Liu
    • 3
  • Yuanyuan Wang
    • 2
  • Yuwen Du
    • 2
  • Xiaonan Chen
    • 2
  • Meng Deng
    • 1
  • Wencong Sun
    • 1
  • Lei Wang
    • 1
  • Guoqiang Zhao
    • 2
  • Baoping Zhai
    • 1
  1. 1.Department of Breast SurgeryThe People’s Hospital of Henan Province (The People’s Hospital of Zhengzhou University)ZhengzhouChina
  2. 2.College of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
  3. 3.School of Clinical MedicineZhengzhou UniversityZhengzhouChina

Personalised recommendations