Tumor Biology

, Volume 35, Issue 4, pp 3487–3494 | Cite as

MiR-495 regulates proliferation and migration in NSCLC by targeting MTA3

  • Heying Chu
  • Xudong Chen
  • Huaqi Wang
  • Yuwen Du
  • Yuanyuan Wang
  • Wenqiao Zang
  • Ping Li
  • Juan Li
  • Jingxia Chang
  • Guoqiang Zhao
  • Guojun Zhang
Research Article


Our previous studies have showed that metastasis-associated protein 3 (MTA 3) is overexpressed in non-small cell lung cancer (NSCLC) tissue, and increased MTA3 mRNA levels is a risk factor of lymph node metastasis. Using bioinformatics analyses, we found that MTA3 was a potential target of miR-495. However, the pathophysiological role of miR-495 and its relevance to the growth and development of NSCLC have yet to be investigated. The purpose of this study was to elucidate the molecular mechanisms by which miR-495 acts as a tumor suppressor in NSCLC. qRT-PCR data showed significant downregulation of miR-495 in 56 NSCLC tissue samples and 5 lung cancer cell lines, compared with their adjacent normal tissue; furthermore, western blotting analysis revealed MTA3 protein was overexpressed in the tumor samples compared with the matched adjacent normal tissue. MiR-495 was shown to not only inhibit the proliferation of lung cancer cells (A549 and Calu-3) but also to inhibit cell migration in vitro. Using western blotting and luciferase assays, MTA3 was identified as a target of miR-495. These findings suggest the importance of miR-495 targeting of MTA3 in the regulation of lung cancer growth and migration.


miR-495 MTA3 NSCLC Proliferation Migration 



This study was supported by Science and Technology Commission of Henan Province of China (no. 122102310552).

Conflicts of interest



  1. 1.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics 2010. CA Cancer J Clin. 2010;60(5):277–300.PubMedCrossRefGoogle Scholar
  2. 2.
    Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367–80.PubMedCrossRefGoogle Scholar
  3. 3.
    Brundage MD, Davies D, Mackillop WJ. Prognostic factors in non-small cell lung cancer: a decade of progress. Chest. 2002;122(3):1037–57.PubMedCrossRefGoogle Scholar
  4. 4.
    Humphrey GW, Wang Y, Russanova VR, Hirai T, Qin J, Nakatani Y, et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J Biol Chem. 2001;276(9):6817–24.PubMedCrossRefGoogle Scholar
  5. 5.
    Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell. 2003;113(2):207–19.PubMedCrossRefGoogle Scholar
  6. 6.
    Toh Y, Nicolson GL. The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications. Clin Exp Metastasis. 2009;26(3):215–27.PubMedCrossRefGoogle Scholar
  7. 7.
    Bowen NJ, Fujita N, Kajita M, Wade PA. Mi-2/NuRD: multiple complexes for many purposes. Biochim Biophys Acta. 2004;1677(1–3):52–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Li H, Sun L, Xu Y, Li Z, Luo W, Tang Z, et al. Overexpression of MTA3 correlates with tumor progression in non-small cell lung cancer. Plos One. 2013;8(6):1–8.Google Scholar
  9. 9.
    Brüning A, Makovitzky J, Gingelmaier A, Friese K, Mylonas I. The metastasis-associated genes MTA1 and MTA3 are abundantly expressed in human placenta and chorionic carcinoma cells. Histochem Cell Biol. 2009;132(1):33–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Bruning A, Juckstock J, Blankenstein T, Makovitzky J, Kunze S, Mylonas I. The metastasis-associated gene MTA3 is downregulated in advanced endometrioid adenocarcinomas. Histol Histopathol. 2010;25(11):1447–56.PubMedGoogle Scholar
  11. 11.
    Zhang H, Stephens LC, Kumar R. Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer. Clin Cancer Res. 2006;12(5):1479–86.PubMedCrossRefGoogle Scholar
  12. 12.
    Dannenmann C, Shabani N, Friese K, Jeschke U, Mylonas I, Bruning A. The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO. Cancer Biol Ther. 2008;7(9):1460–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Hofer MD, Kuefer R, Varambally S, Li H, Ma J, Shapiro GI, et al. The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Res. 2004;64(3):825–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Iguchi H, Imura G, Toh Y, Ogata Y. Expression of MTA1, a metastasis-associated gene with histone deacetylase activity in pancreatic cancer. Int J Oncol. 2000;16(6):1211–4.PubMedGoogle Scholar
  15. 15.
    Jang KS, Paik SS, Chung H, Oh YH, Kong G. MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancers. Cancer Sci. 2006;97(5):374–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Xia Y, Chen Q, Zhong Z, Caihua X, Chen W, Liu B, et al. Down-regulation of MiR-30c promotes the invasion of non-small cell lung cancer by targeting MTA1. CELL Physiol Biochem. 2013;32(2):476–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Zheng S, Du Y, Chu H, Chen X, Li P, Wang Y, et al. Analysis of MAT3 gene expression in NSCLC. Diagn Pathol. 2013;8:166Google Scholar
  18. 18.
    Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death and tumorigenesis. Br J Cancer. 2006;94(6):776–80.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Wan HY, Guo LM, Liu T, Liu M, Li X, Tang H. Regulation of the transcription factor NF-kappaB1 by microRNA-9 in human gastric adenocarcinoma. Mol Cancer. 2010;9(16):1–10.Google Scholar
  20. 20.
    Zamore PD, Haley B. Ribo-gnome: the big world of small RNAs. Science. 2005;309(5740):1519–24.PubMedCrossRefGoogle Scholar
  21. 21.
    Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet.2006;15(Spec No 1):R17–29Google Scholar
  22. 22.
    Norbury C, Nurse P. Animal cell cycles and their control. Annu Rev Biochem. 1992;61:441–70.PubMedCrossRefGoogle Scholar
  23. 23.
    Manchado E, Guillamot M, Malumbres M. Killing cells by targeting mitosis. Cell Death Differ. 2012;19(3):369–77.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Ouyang W, Ma Q, Li J, Zhang D, Liu ZG, Rustgi AK, et al. Cyclin D1 induction through IkappaB kinase beta/nuclear factor-kappaB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes. Cancer Res. 2005;65(20):9287–93.PubMedCrossRefGoogle Scholar
  25. 25.
    Ouyang W, Li J, Ma Q, Huang C. Essential roles of PI-3K/Akt/IKKbeta/ NFkappaB pathway in cyclinD1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis. 2006;27(4):864–73.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhang H, Singh RR, Talukder AH, Kumar R. Metastatic tumor antigen 3 is a direct corepressor of the Wnt4 pathway. Genes Dev. 2006;20(21):2943–8.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Mishra SK, Talukder AH, Gururaj AE, Yang Z, Singh RR, Mahoney MG, et al. Upstream determinants of estrogen receptor-alpha regulation of metastatic tumor antigen 3 pathway. J Biol Chem. 2004;279(31):32709–15.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Fujita N, Kajita M, Taysavang P, Wade PA. Hormonal regulation of metastasis-associated protein 3 transcription in breast cancer cells. Mol Endocrinol. 2004;18(12):2937–49.PubMedCrossRefGoogle Scholar
  29. 29.
    Chen Y, Miyazaki J, Nishizawa H, Kurahashi H, Leach R, Wang K. MTA3 regulates CGB5 and Snail genes in trophoblast. Biochem Biophys Res Commun. 2013;433(4):379–84.PubMedCrossRefGoogle Scholar
  30. 30.
    Bagheri-Yarmand R, Talukder AH, Wang RA, Vadlamudi RK, Kumar R. Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis. Development. 2004;131(14):3469–79.PubMedCrossRefGoogle Scholar
  31. 31.
    Manavathi B, Singh K, Kumar R. MTA family of coregulators in nuclear receptor biology and pathology. Nucl Recept Signal. 2007;5:e010.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature. 1994;369(6482):669–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Resnitzky D, Reed SI. Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Mol Cell Biol. 1995;15(7):3463–9.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Spruck CH, Won KA, Reed SI. Deregulated cyclin E induces chromosome instability. Nature. 1999;401(6750):297–300.PubMedCrossRefGoogle Scholar
  35. 35.
    Hubalek MM, Widschwendter A, Erdel M, Gschwendtner A, Fiegl HM, Muller HM, et al. Cyclin E dysregulation and chromosomal instability in endometrial cancer. Oncogene. 2004;23(23):4187–92.PubMedCrossRefGoogle Scholar
  36. 36.
    Noren Hooten N, Abdelmohsen K, Gorospe M, Ejiogu N, Zonderman AB, Evans MK. microRNA expression patterns reveal differential expression of target genes with age. PloS One. 2010;5(5):e10724Google Scholar
  37. 37.
    Takahashi Y, Forrest AR, Maeno E, Hashimoto T, Daub CO, Yasuda J. MiR-107 and MiR-185 can induce cell cycle arrest in human non small cell lung cancer cell lines. PloS One. 2009;4(8):e6677.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Qin W, Ren Q, Liu T, Huang Y, Wang J. MicroRNA-155 is a novel suppressor of ovarian cancer-initiating cells that targets CLDN1. FEBS Lett. 2013;587(9):1434–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Miao LJ, Huang SF, Sun ZT, Gao ZY, Zhang RX, Liu Y, et al. Mir-449 targets c-myc and inhibits NSCLC cell progression. FEBS Lett. 2013;587(9):1359–65.PubMedCrossRefGoogle Scholar
  40. 40.
    Li J, Wang Y, Luo J, Fu Z, Ying J, Yu Y, et al. Mir-134 inhibits epithelial to mesenchymal transition by targeting FOXM1 in non-small cell lung cancer cells. FEBS Lett. 2012;586(20):3761–5.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Heying Chu
    • 1
  • Xudong Chen
    • 2
  • Huaqi Wang
    • 1
  • Yuwen Du
    • 3
  • Yuanyuan Wang
    • 3
  • Wenqiao Zang
    • 3
  • Ping Li
    • 1
  • Juan Li
    • 1
  • Jingxia Chang
    • 1
  • Guoqiang Zhao
    • 3
  • Guojun Zhang
    • 1
  1. 1.Department of Respiratory MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  2. 2.Department of Histology and EmbryologyLuohe Medical CollegeLuoheChina
  3. 3.College of Basic Medical SciencesZhengzhou UniversityZhengzhouChina

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