Tumor Biology

, Volume 37, Issue 4, pp 5001–5011 | Cite as

MicroRNA-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/β-catenin signaling pathway

  • Qian Jiang
  • Miao He
  • Shu Guan
  • Mengtao Ma
  • Huizhe Wu
  • Zhaojin Yu
  • Longyang Jiang
  • Yan Wang
  • Xingyue Zong
  • Feng Jin
  • Minjie Wei
Original Article


Wnt/β-catenin signaling pathway plays a major role in the cancer metastasis. Several microRNAs (miRNAs) are contributed to the inhibition of breast cancer metastasis. Here, we attempted to find novel targets and mechanisms of microRNA-100 (miR-100) in regulating the migration and invasion of breast cancer cells. In this study, we found that miR-100 expression was downregulated in human breast cancer tissues and cell lines. The overexpression of miR-100 inhibited the migration and invasion of MDA-MB-231 breast cancer cells. Inversely, the downregulation of miR-100 increased the migration and invasion of MCF-7 breast cancer cells. Furthermore, FZD-8, a receptor of Wnt/β-catenin signaling pathway, was demonstrated a direct target of miR-100. The overexpression of miR-100 decreased the expression levels not only FZD-8 but also the key components of Wnt/β-catenin pathway, including β-catenin, metalloproteniase-7 (MMP-7), T-cell factor-4 (TCF-4), and lymphoid enhancing factor-1 (LEF-1), and increased the protein expression levels of GSK-3β and p-GSK-3β in MDA-MB-231 cells, and the transfection of miR-100 inhibitor in MCF-7 cells showed the opposite effects. In addition, the expression of miR-100 was negatively correlated with the FZD-8 expression in human breast cancer tissues. Overall, these findings suggest that miR-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/β-catenin signaling pathway and manipulation of miR-100 may provide a promoting therapeutic strategy for cancer breast treatment.


MiR-100 FZD-8 Breast cancer Wnt/β-catenin signaling pathway Migration Invasion 



This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81373427), Program for Liaoning Innovative Research Team in University, LNIRT, China (Grant No. LT2014016), the Liaoning Provincial Science and Technology Program, China (Grant No. 2013225079), Program for Liaoning Excellent Talents in University, China (Grant No. LJQ2014084), and the S&T Projects in Shenyang, China (Grant No. F14-232-6-05).

Authors’ contributions

Minjie Wei and Miao He designed the experiments. Qian Jiang, Huizhe Wu, Zhaojin Yu, Longyang Jiang, Yan Wang, and Xingyue Zong performed the experiments. Qian Jiang, Mengtao Ma, and Miao He analyzed the data. Shu Guan and Feng Jin gave technical and material support. Miao He, Qian Jiang, and Minjie Wei wrote and reviewed the manuscript.

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Gangadhara S, Barrett-Lee P, Nicholson RI, Hiscox S. Pro-metastatic tumor-stroma interactions in breast cancer. Future Oncol. 2012;8(11):1427–42. doi: 10.2217/fon.12.134.CrossRefPubMedGoogle Scholar
  2. 2.
    Klemm F, Bleckmann A, Siam L, Chuang HN, Rietkotter E, Behme D, et al. beta-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis. Carcinogenesis. 2011;32(3):434–42. doi: 10.1093/carcin/bgq269.CrossRefPubMedGoogle Scholar
  3. 3.
    Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, et al. TGF-beta switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest. 2003;112(7):1116–24. doi: 10.1172/JCI18899.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hu YY, Zheng MH, Zhang R, Liang YM, Han H. Notch signaling pathway and cancer metastasis. Adv Exp Med Biol. 2012;727:186–98. doi: 10.1007/978-1-4614-0899-4_14.CrossRefPubMedGoogle Scholar
  5. 5.
    Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127(3):469–80. doi: 10.1016/j.cell.2006.10.018.CrossRefPubMedGoogle Scholar
  6. 6.
    MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26. doi: 10.1016/j.devcel.2009.06.016.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Khramtsov AI, Khramtsova GF, Tretiakova M, Huo DZ, Olopade OI, Goss KH. Wnt/beta-Catenin Pathway Activation Is Enriched in Basal-Like Breast Cancers and Predicts Poor Outcome. Am J Pathol. 2010;176(6):2911–20. doi: 10.2353/ajpath.2010.091125.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Arend RC, Londono-Joshi AI, Straughn Jr JM, Buchsbaum DJ. The Wnt/beta-catenin pathway in ovarian cancer: a review. Gynecol Oncol. 2013;131(3):772–9. doi: 10.1016/j.ygyno.2013.09.034.CrossRefPubMedGoogle Scholar
  9. 9.
    Serafino A, Moroni N, Zonfrillo M, Andreola F, Mercuri L, Nicotera G, et al. WNT-pathway components as predictive markers useful for diagnosis, prevention and therapy in inflammatory bowel disease and sporadic colorectal cancer. Oncotarget. 2014;5(4):978–92.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMedGoogle Scholar
  11. 11.
    Liu P, Tang H, Chen B, He Z, Deng M, Wu M, et al. miR-26a suppresses tumour proliferation and metastasis by targeting metadherin in triple negative breast cancer. Cancer Lett. 2015;357(1):384–92. doi: 10.1016/j.canlet.2014.11.050.CrossRefPubMedGoogle Scholar
  12. 12.
    Chan SH, Huang WC, Chang JW, Chang KJ, Kuo WH, Wang MY, et al. MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis. Oncogene. 2014;33(36):4496–507. doi: 10.1038/onc.2014.10.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Christodoulou F, Raible F, Tomer R, Simakov O, Trachana K, Klaus S, et al. Ancient animal microRNAs and the evolution of tissue identity. Nature. 2010;463(7284):1084–8. doi: 10.1038/nature08744.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zheng YS, Zhang H, Zhang XJ, Feng DD, Luo XQ, Zeng CW, et al. MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia. Oncogene. 2012;31(1):80–92. doi: 10.1038/onc.2011.208.CrossRefPubMedGoogle Scholar
  15. 15.
    Li ZP, Li X, Yu C, Wang M, Peng F, Xiao J, et al. MicroRNA-100 regulates pancreatic cancer cells growth and sensitivity to chemotherapy through targeting FGFR3. Tumor Biol. 2014;35(12):11751–9. doi: 10.1007/s13277-014-2271-8.CrossRefGoogle Scholar
  16. 16.
    Gebeshuber CA, Martinez J. miR-100 suppresses IGF2 and inhibits breast tumorigenesis by interfering with proliferation and survival signaling. Oncogene. 2013;32(27):3306–10. doi: 10.1038/onc.2012.372.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen D, Sun Y, Yuan Y, Han Z, Zhang P, Zhang J, et al. miR-100 induces epithelial-mesenchymal transition but suppresses tumorigenesis, migration and invasion. PLoS Genet. 2014;10(2):e1004177. doi: 10.1371/journal.pgen.1004177.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ma MT, He M, Wang Y, Jiao XY, Zhao L, Bai XF, et al. MiR-487a resensitizes mitoxantrone (MX)-resistant breast cancer cells (MCF-7/MX) to MX by targeting breast cancer resistance protein (BCRP/ABCG2). Cancer Lett. 2013;339(1):107–15. doi: 10.1016/j.canlet.2013.07.016.CrossRefPubMedGoogle Scholar
  19. 19.
    Bai X, Song Z, Fu Y, Yu Z, Zhao L, Zhao H, et al. Clinicopathological significance and prognostic value of DNA methyltransferase 1, 3a, and 3b expressions in sporadic epithelial ovarian cancer. PLoS One. 2012;7(6):e40024. doi: 10.1371/journal.pone.0040024.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Han HS, Son SM, Yun J, Jo YN, Lee OJ. MicroRNA-29a suppresses the growth, migration, and invasion of lung adenocarcinoma cells by targeting carcinoembryonic antigen-related cell adhesion molecule 6. FEBS Lett. 2014;588(20):3744–50. doi: 10.1016/j.febslet.2014.08.023.CrossRefPubMedGoogle Scholar
  21. 21.
    Nishikawa R, Goto Y, Kojima S, Enokida H, Chiyomaru T, Kinoshita T, et al. Tumor-suppressive microRNA-29s inhibit cancer cell migration and invasion via targeting LAMC1 in prostate cancer. Int J Oncol. 2014;45(1):401–10. doi: 10.3892/ijo.2014.2437.PubMedGoogle Scholar
  22. 22.
    Chen P, Zhao X, Ma L. Downregulation of microRNA-100 correlates with tumor progression and poor prognosis in hepatocellular carcinoma. Mol Cell Biochem. 2013;383(1-2):49–58. doi: 10.1007/s11010-013-1753-0.CrossRefPubMedGoogle Scholar
  23. 23.
    Peng DX, Luo M, Qiu LW, He YL, Wang XF. Prognostic implications of microRNA-100 and its functional roles in human epithelial ovarian cancer. Oncol Rep. 2012;27(4):1238–44. doi: 10.3892/or.2012.1625.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Petrelli A, Carollo R, Cargnelutti M, Iovino F, Callari M, Cimino D, et al. By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy. Oncotarget. 2015;6(4):2315–30.CrossRefPubMedGoogle Scholar
  25. 25.
    Tang J, Tao ZH, Wen D, Wan JL, Liu DL, Zhang S, et al. MiR-612 suppresses the stemness of liver cancer via Wnt/beta-catenin signaling. Biochem Biophys Res Commun. 2014;447(1):210–5. doi: 10.1016/j.bbrc.2014.03.135.CrossRefPubMedGoogle Scholar
  26. 26.
    Subramanian M, Rao SR, Thacker P, Chatterjee S, Karunagaran D. MiR-29b downregulates canonical Wnt signaling by suppressing coactivators of beta-catenin in human colorectal cancer cells. J Cell Biochem. 2014;115(11):1974–84. doi: 10.1002/jcb.24869.PubMedGoogle Scholar
  27. 27.
    Zhao JJ, Lin JH, Zhu D, Wang XJ, Brooks D, Chen M, et al. miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic wnt/beta-catenin/bcl9 pathway. Cancer Res. 2014;74(6):1801–13. doi: 10.1158/0008-5472.CAN-13-3311-T.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang HQ, Xu ML, Ma J, Zhang Y, Xie CH. Frizzled-8 as a putative therapeutic target in human lung cancer. Biochem Biophys Res Commun. 2012;417(1):62–6. doi: 10.1016/j.bbrc.2011.11.055.CrossRefPubMedGoogle Scholar
  29. 29.
    Yin S, Xu L, Bonfil RD, Banerjee S, Sarkar FH, Sethi S, et al. Tumor-initiating cells and FZD8 play a major role in drug resistance in triple-negative breast cancer. Mol Cancer Ther. 2013;12(4):491–8. doi: 10.1158/1535-7163.MCT-12-1090.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Qian Jiang
    • 1
  • Miao He
    • 1
  • Shu Guan
    • 2
  • Mengtao Ma
    • 1
  • Huizhe Wu
    • 1
  • Zhaojin Yu
    • 1
  • Longyang Jiang
    • 1
  • Yan Wang
    • 1
  • Xingyue Zong
    • 1
  • Feng Jin
    • 2
  • Minjie Wei
    • 1
  1. 1.Department of Pharmacology, School of PharmacyChina Medical UniversityShenyangChina
  2. 2.Department of Surgical OncologyThe First Affiliated Hospital of China Medical UniversityShenyangChina

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