Tumor Biology

, Volume 37, Issue 2, pp 1581–1590 | Cite as

MicroRNA-148a inhibits migration of breast cancer cells by targeting MMP-13

  • Jinqi Xue
  • Zhiguang Chen
  • Xi Gu
  • Yang Zhang
  • Wenhai Zhang
Original Article


Breast cancer is a threat to the health of women, and metastasis of breast cancer cells plays an important role in the deterioration of breast cancer. MicroRNAs play a critical role in the tumorigenesis and development of breast cancer. MicroRNA-148a (miR-148a) is associated with the growth and metastasis of tumor cells. In the present study, we investigated the role of miR-148a in migration of breast cancer cells as well as the underlying mechanism. MiR-148a was found to inhibit the proliferation and migration of breast cancer cells. To further explore the mechanism through which miR-148a plays its antitumor role, matrix metalloproteinase-13 (MMP-13) was identified as a target of miR-148a by western blot and luciferase reporter assay. Moreover, silence of MMP-13 mimicked the effect of miR-148a, whereas overexpression of MMP-13 rescued the impaired migration caused by miR-148a. Our study demonstrates that miR-148a inhibits the migration of breast cancer cells by targeting MMP-13 and also lays theoretical foundation for further exploration for the function of miR-148a.


MiR-148a MMP-13 Migration Breast cancer cells 


Conflicts of interest



  1. 1.
    Zielinska HA, Bahl A, Holly JM, Perks CM. Epithelial-to-mesenchymal transition in breast cancer: a role for insulin-like growth factor i and insulin-like growth factor-binding protein 3? Breast Cancer (Dove Med Press). 2015;7:9–19.Google Scholar
  2. 2.
    Foshay KM, Gallicano GI. Small RNAs, big potential: the role of microRNAs in stem cell function. Curr Stem Cell Res Ther. 2007;2:264–71.CrossRefPubMedGoogle Scholar
  3. 3.
    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294:853–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Meltzer PS. Cancer genomics: Small RNAs with big impacts. Nature. 2005;435:745–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–79.CrossRefPubMedGoogle Scholar
  6. 6.
    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.CrossRefPubMedGoogle Scholar
  7. 7.
    Pan L, Huang S, He R, Rong M, Dang Y, Chen G. Decreased expression and clinical significance of miR-148a in hepatocellular carcinoma tissues. Eur J Med Res. 2014;19:68.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Xia J, Guo X, Yan J, Deng K. The role of miR-148a in gastric cancer. J Cancer Res Clin Oncol. 2014;140:1451–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang SL, Liu L. MicroRNA-148a inhibits hepatocellular carcinoma cell invasion by targeting sphingosine-1-phosphate receptor 1. Exp Ther Med. 2015;9:579–84.PubMedGoogle Scholar
  10. 10.
    Zheng B, Liang L, Wang C, Huang S, Cao X, Zha R, et al. MicroRNA-148a suppresses tumor cell invasion and metastasis by downregulating ROCK1 in gastric cancer. Clin Cancer Res. 2011;17:7574–83.CrossRefPubMedGoogle Scholar
  11. 11.
    Aydogdu E, Katchy A, Tsouko E, Lin CY, Haldosen LA, Helguero L, et al. MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer. Carcinogenesis. 2012;33:1502–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Liffers ST, Munding JB, Vogt M, Kuhlmann JD, Verdoodt B, Nambiar S, et al. MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25b. Lab Invest. 2011;91:1472–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhang H, Li Y, Huang Q, Ren X, Hu H, Sheng H, et al. MiR-148a promotes apoptosis by targeting Bcl-2 in colorectal cancer. Cell Death Differ. 2011;18:1702–10.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Xu Q, Jiang Y, Yin Y, Li Q, He J, Jing Y, et al. A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1. J Mol Cell Biol. 2013;5:3–13.CrossRefPubMedGoogle Scholar
  15. 15.
    Stetler-Stevenson WG, Hewitt R, Corcoran M. Matrix metalloproteinases and tumor invasion: From correlation and causality to the clinic. Semin Cancer Biol. 1996;7:147–54.CrossRefPubMedGoogle Scholar
  16. 16.
    Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000;18:1135–49.CrossRefPubMedGoogle Scholar
  17. 17.
    Balbin M, Pendas AM, Uria JA, Jimenez MG, Freije JP, Lopez-Otin C. Expression and regulation of collagenase-3 (MMP-13) in human malignant tumors. APMIS. 1999;107:45–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Corte MD, Gonzalez LO, Corte MG, Quintela I, Pidal I, Bongera M, et al. Collagenase-3 (MMP-13) expression in cutaneous malignant melanoma. Int J Biol Markers. 2005;20:242–8.PubMedGoogle Scholar
  19. 19.
    Leeman MF, McKay JA, Murray GI. Matrix metalloproteinase 13 activity is associated with poor prognosis in colorectal cancer. J Clin Pathol. 2002;55:758–62.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yang B, Gao J, Rao Z, Shen Q. Clinicopathological significance and prognostic value of MMP-13 expression in colorectal cancer. Scand J Clin Lab Invest. 2012;72:501–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang B, Cao X, Liu Y, Cao W, Zhang F, Zhang S, et al. Tumor-derived matrix metalloproteinase-13 (MMP-13) correlates with poor prognoses of invasive breast cancer. BMC Cancer. 2008;8:83.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yeh WL, Lu DY, Lee MJ, Fu WM. Leptin induces migration and invasion of glioma cells through MMP-13 production. Glia. 2009;57:454–64.CrossRefPubMedGoogle Scholar
  23. 23.
    Inoue A, Takahashi H, Harada H, Kohno S, Ohue S, Kobayashi K, et al. Cancer stem-like cells of glioblastoma characteristically express MMP-13 and display highly invasive activity. Int J Oncol. 2010;37:1121–31.PubMedGoogle Scholar
  24. 24.
    Wang J, Li Y, Li C, Yu K, Wang Q. Increased expression of matrix metalloproteinase-13 in glioma is associated with poor overall survival of patients. Med Oncol. 2012;29:2432–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Chang HJ, Yang MJ, Yang YH, Hou MF, Hsueh EJ, Lin SR. MMP13 is potentially a new tumor marker for breast cancer diagnosis. Oncol Rep. 2009;22:1119–27.PubMedGoogle Scholar
  26. 26.
    Fujita Y, Kojima K, Ohhashi R, Hamada N, Nozawa Y, Kitamoto A, et al. MiR-148a attenuates paclitaxel resistance of hormone-refractory, drug-resistant prostate cancer PC3 cells by regulating MSK1 expression. J Biol Chem. 2010;285:19076–84.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ma W, Zhang X, Chai J, Chen P, Ren P, Gong M. Circulating miR-148a is a significant diagnostic and prognostic biomarker for patients with osteosarcoma. Tumour Biol. 2014;35:12467–72.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhao S, Wen Z, Liu S, Liu Y, Li X, Ge Y, et al. MicroRNA-148a inhibits the proliferation and promotes the paclitaxel-induced apoptosis of ovarian cancer cells by targeting PDIA3. Mol Med Rep. 2015;12:3923–9.PubMedGoogle Scholar
  29. 29.
    Chang Y, Zhao Y, Gu W, Cao Y, Wang S, Pang J, et al. Bufalin inhibits the differentiation and proliferation of cancer stem cells derived from primary osteosarcoma cells through miR-148a. Cell Physiol Biochem. 2015;36:1186–96.CrossRefPubMedGoogle Scholar
  30. 30.
    Kim J, Zhang Y, Skalski M, Hayes J, Kefas B, Schiff D, et al. MicroRNA-148a is a prognostic oncomiR that targets Mig6 and Bim to regulate EGFR and apoptosis in glioblastoma. Cancer Res. 2014;74:1541–53.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Guo SL, Peng Z, Yang X, Fan KJ, Ye H, Li ZH, et al. MiR-148a promoted cell proliferation by targeting p27 in gastric cancer cells. Int J Biol Sci. 2011;7:567–74.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zhang R, Li M, Zang W, Chen X, Wang Y, Li P, et al. MiR-148a regulates the growth and apoptosis in pancreatic cancer by targeting CCKBR and Bcl-2. Tumour Biol. 2014;35:837–44.CrossRefPubMedGoogle Scholar
  33. 33.
    Wen Z, Zhao S, Liu S, Liu Y, Li X, Li S. MicroRNA-148a inhibits migration and invasion of ovarian cancer cells via targeting sphingosine-1-phosphate receptor 1. Mol Med Rep. 2015;12:3775–80.PubMedGoogle Scholar
  34. 34.
    Wang SH, Li X, Zhou LS, Cao ZW, Shi C, Zhou CZ, et al. MicroRNA-148a suppresses human gastric cancer cell metastasis by reversing epithelial-to-mesenchymal transition. Tumour Biol. 2013;34:3705–12.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang JP, Zeng C, Xu L, Gong J, Fang JH, Zhuang SM. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene. 2014;33:4069–76.CrossRefPubMedGoogle Scholar
  36. 36.
    Yan H, Dong X, Zhong X, Ye J, Zhou Y, Yang X, et al. Inhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in miR-148a-mediated anti-metastasis of hepatocellular carcinoma. Mol Carcinog. 2014;53:960–9.PubMedGoogle Scholar
  37. 37.
    Li J, Song Y, Wang Y, Luo J, Yu W. MicroRNA-148a suppresses epithelial-to-mesenchymal transition by targeting ROCK1 in non-small cell lung cancer cells. Mol Cell Biochem. 2013;380:277–82.CrossRefPubMedGoogle Scholar
  38. 38.
    Hellman NE, Spector J, Robinson J, Zuo X, Saunier S, Antignac C, et al. Matrix metalloproteinase 13 (MMP13) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1), regulated by the MAPK pathway, are both necessary for Madin-Darby canine kidney tubulogenesis. J Biol Chem. 2008;283:4272–82.CrossRefPubMedGoogle Scholar
  39. 39.
    Xu N, Zhang L, Meisgen F, Harada M, Heilborn J, Homey B, et al. MicroRNA-125b down-regulates matrix metallopeptidase 13 and inhibits cutaneous squamous cell carcinoma cell proliferation, migration, and invasion. J Biol Chem. 2012;287:29899–908.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Osaki M, Takeshita F, Sugimoto Y, Kosaka N, Yamamoto Y, Yoshioka Y, et al. MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Mol Ther. 2011;19:1123–30.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jinqi Xue
    • 1
  • Zhiguang Chen
    • 2
  • Xi Gu
    • 1
  • Yang Zhang
    • 1
  • Wenhai Zhang
    • 1
  1. 1.The Seventh Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Spine and Joint SurgeryShengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China

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