Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

MicroRNA-145 functions as a tumor suppressor by targeting matrix metalloproteinase 11 and Rab GTPase family 27a in triple-negative breast cancer

Cancer Gene Therapy volume 23, pages 258–265 (2016)Cite this article

Subjects

Abstract

Although increasing evidence has documented that microRNA-145 (miR-145) acts as a tumor suppressor in breast cancer, its exact role in triple-negative breast cancer (TNBC) remains poorly defined. In this study, the expression of miR-145 in human TNBC cells and samples from 30 patients was analyzed by stem-loop real-time PCR. We found that miR-145 was significantly downregulated in TNBC tissues and cells. Upregulating miR-145 in HCC1937 cells dramatically suppressed cell proliferation and induced G1-phase arrest, whereas MDA-MB-231 cells did not show growth inhibition. MiR-145 exhibited an inhibitory role in cell invasion through the post-transcriptional regulation of the novel targets MMP11 and Rab27a in TNBC cells. Additionally, miR-145 silencing could be reversed by 5-aza-2′-deoxycytidine (DAC). These results demonstrated that miR-145 has an inhibitory role in TNBC malignancy by targeting MMP11 and Rab27a, which might be potential therapeutic and diagnostic targets for TNBC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Zhu X, Ying J, Wang F, Wang J, Yang H . Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status in invasive breast cancer: a 3,198 cases study at National Cancer Center, China. Breast Cancer Res Treat 2014; 147: 551–555.

    Article  CAS  Google Scholar 

  2. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007; 13: 2329–2334.

    Article  CAS  Google Scholar 

  3. Eades G, Wolfson B, Zhang Y, Li Q, Yao Y, Zhou Q . LincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res 2015; 13: 330–338.

    Article  CAS  Google Scholar 

  4. Pekow J, Meckel K, Dougherty U, Butun F, Mustafi R, Lim J et al. Tumor suppressors miRNA-143 and miR-145 and predicted target proteins API5, ERK5, KRAS, and IRS1 are differentially expressed in proximal and distal colon. Am J Physiol Gastrointest Liver Physiol 2015; 308: G179–G187.

    Article  CAS  Google Scholar 

  5. Noh JH, Chang YG, Kim MG, Jung KH, Kim JK, Bae HJ et al. MiR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer. Cancer Lett 2013; 335: 455–462.

    Article  CAS  Google Scholar 

  6. Kim SJ, Oh JS, Shin JY, Lee KD, Sung KW, Nam SJ et al. Development of microRNA-145 for therapeutic application in breast cancer. J Control Release 2011; 155: 427–434.

    Article  CAS  Google Scholar 

  7. Shi B, Sepp-Lorenzino L, Prisco M, Linsley P, deAngelis T, Baserga R, Micro RNA . 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. J Biol Chem 2007; 282: 32582–32590.

    Article  CAS  Google Scholar 

  8. Shen WF, Hu YL, Uttarwar L, Passegue E, Largman C . MicroRNA-126 regulates HOXA9 by binding to the homeobox. Mol Cell Biol 2008; 28: 4609–4619.

    Article  CAS  Google Scholar 

  9. Rani SB, Rathod SS, Karthik S, Kaur N, Muzumdar D, Shiras AS . MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. Neuro Oncol 2013; 15: 1302–1316.

    Article  CAS  Google Scholar 

  10. Yu CC, Tsai LL, Wang ML, Yu CH, Lo WL, Chang YC et al. MiR-145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer. Cancer Res 2013; 73: 3425–3240.

    Article  CAS  Google Scholar 

  11. Cioce M, Ganci F, Canu V, Sacconi A, Mori F, Canino C et al. Protumorigenic effects of miR-145 loss in malignant pleural mesothelioma. Oncogene 2014; 33: 5319–5331.

    Article  CAS  Google Scholar 

  12. Liu H, Lin H, Zhang L, Sun Q, Yuan G, Zhang L . MiR-145 and miR-143 regulate odontoblast differentiation through targeting Klf4 and Osx genes in a feedback loop. J Biol Chem 2012; 88: 9261–9271.

    Google Scholar 

  13. Xu Q, Liu LZ, Qian X, Chen Q, Jiang Y, Li D et al. MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res 2012; 40: 761–774.

    Article  CAS  Google Scholar 

  14. Shao Y, Qu Y, Dang S, Yao B, Ji M . MiR-145 inhibits oral squamous cell carcinoma (OSCC) cell growth by targeting c-Myc and Cdk6. Cancer Cell Int 2013; 13: 51.

    Article  CAS  Google Scholar 

  15. Sachdeva M, Mo YY . MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res 2010; 70: 378–387.

    Article  CAS  Google Scholar 

  16. Radojicic J, Zaravinos A, Vrekoussis T, Kafousi M, Spandidos DA, Stathopoulos EN . MicroRNA expression analysis in triple-negative (ER, PR and Her2/neu) breast cancer. Cell Cycle 2011; 10: 507–517.

    Article  CAS  Google Scholar 

  17. Eiró N, Fernandez-Garcia B, González LO, Vizoso FJ . Cytokines related to MMP-11 expression by inflammatory cells and breast cancer metastasis. Oncoimmunology 2013; 2: e24010.

    Article  Google Scholar 

  18. Selvey S, Haupt LM, Thompson EW, Matthaei KI, Irving MG, Griffiths LR . Stimulation of MMP-11 (stromelysin-3) expression in mouse fibroblasts by cytokines, collagen and co-culture with human breast cancer cell lines. BMC Cancer 2004; 4: 40.

    Article  Google Scholar 

  19. Kwon YJ, Hurst DR, Steg AD, Yuan K, Vaidya KS, Welch DR et al. Gli1 enhances migration and invasion via up-regulation of MMP-11 and promotes metastasis in ERα negative breast cancer cell lines. Clin Exp Metastasis 2011; 28: 437–449.

    Article  CAS  Google Scholar 

  20. Roscilli G, Cappelletti M, De Vitis C, Ciliberto G, Di Napoli A, Ruco L et al. Circulating MMP11 and specific antibody immune response in breast and prostate cancer patients. J Transl Med 2014; 12: 54.

    Article  Google Scholar 

  21. Kasper G, Reule M, Tschirschmann M, Dankert N, Stout-Weider K, Lauster R et al. Stromelysin-3 over-expression enhances tumourigenesis in MCF-7 and MDA-MB-231 breast cancer cell lines: involvement of the IGF-1 signalling pathway. BMC Cancer 2007; 7: 12.

    Article  Google Scholar 

  22. Wang JS, Wang FB, Zhang QG, Shen ZZ, Shao ZM . Enhanced expression of Rab27a gene by breast cancer cells promoting invasiveness and the metastasis potential by secretion of insulin-like growth factor-II. Mol Cancer Res 2008; 6: 372–382.

    Article  CAS  Google Scholar 

  23. Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res 2012; 72: 4920–4930.

    Article  CAS  Google Scholar 

  24. Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal 2014; 7: ra63.

    Article  Google Scholar 

  25. Falcone G, Felsani A, D’Agnano I . Signaling by exosomal microRNAs in cancer. J Exp Clin Cancer Res 2015; 34: 32.

    Article  Google Scholar 

  26. Taraboletti G, D'Ascenzo S, Borsotti P, Giavazzi R, Pavan A, Dolo V . Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol 2002; 160: 673–680.

    Article  CAS  Google Scholar 

  27. Saito Y, Saito H, Liang G, Friedman JM . Epigenetic alterations and microRNA misexpression in cancer and autoimmune diseases: a critical review. Clin Rev Allergy Immunol 2014; 47: 128–135.

    Article  CAS  Google Scholar 

  28. Cui XS, Zhang DX, Ko YG, Kim NH . Aberrant epigenetic reprogramming of imprinted microRNA-127 and Rtl1 in cloned mouse embryos. Biochem Biophys Res Commun 2009; 379: 390–394.

    Article  CAS  Google Scholar 

  29. Ueda Y, Ando T, Nanjo S, Ushijima T, Sugiyama T . DNA methylation of microRNA-124a is a potential risk marker of colitis-associated cancer in patients with ulcerative colitis. Dig Dis Sci 2014; 59: 2444–2451.

    Article  CAS  Google Scholar 

  30. Asangani IA, Harms PW, Dodson L, Pandhi M, Kunju LP, Maher CA et al. Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. Oncotarget 2012; 3: 1011–1125.

    Article  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (21475063), the Jiangsu Provincial Special Program of Medical Science (BL2013036) and the Grand of Medicine Leading Talents of Jiangsu Health Department (LJ201131).

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, Nanjing Medical University Cancer Hospital, Nanjing, PR China

    L Tang & F Yan

  2. Department of Surgery, Nanjing Medical University Cancer Hospital, Nanjing, PR China

    D Wei

Authors
  1. L Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Yan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, L., Wei, D. & Yan, F. MicroRNA-145 functions as a tumor suppressor by targeting matrix metalloproteinase 11 and Rab GTPase family 27a in triple-negative breast cancer. Cancer Gene Ther 23, 258–265 (2016). https://doi.org/10.1038/cgt.2016.27

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2016.27

This article is cited by

Search

Advanced search

Quick links