Skip to main content

Advertisement

SpringerLink
Log in

miRNA-204 suppresses human non-small cell lung cancer by targeting ATF2

  • Original Article
  • Published:
Tumor Biology

Abstract

MicroRNAs (miRNAs) play a critical role in cancer development and progression. Deregulated expression of miR-204 has been reported in several cancers, but the mechanism through which miR-204 modulates human non-small cell lung cancer (NSCLC) is largely unknown. In this study, we investigate the expression and functional role of miR-204 in human NSCLC tissues and cell lines. RNA isolation, qRT-PCR, MTT, colony formation assay, cell cycle assay, cell apoptosis assay, cell migration assay, and Western blot were performed. Statistical analysis was performed using SPSS 18.0 software and statistical significance was accepted at p value <0.05. miR-204 level was significantly reduced in NSCLC tissues as compared to that of non-neoplastic tissues. Transient over-expression of miR-204 by transfecting with miR-204 mimics suppressed NSCLC cell proliferation, migration, and induced apoptosis and G1 arrest, whereas inhibition of miR-204 showed the converse effects. Additionally, activating transcription factor 2 (ATF2), an important transcription factor, was demonstrated as a potential target gene of miR-204. Subsequent investigations found a negative correlation between miR-204 level and ATF2 expression in NSCLC tissue samples. Moreover, we observed that miR-204 expression inversely affected endogenous ATF2 expression at both mRNA and protein levels in vitro. Taken together, miR-204 may act as a tumor suppressor by directly targeting ATF2 in NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi:10.3322/caac.21262.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. doi:10.3322/caac.21254.

    Article  PubMed  Google Scholar 

  3. She J, Yang P, Hong Q, Bai C. Lung cancer in China: challenges and interventions. Chest. 2013;143(4):1117–26. doi:10.1378/chest.11-2948.

    Article  PubMed  Google Scholar 

  4. Rivera MP. Multimodality therapy in the treatment of lung cancer. Semin Respir Crit Care Med. 2004;25 Suppl 1:3–10. doi:10.1055/s-2004-829639.

    Article  PubMed  Google Scholar 

  5. Palanichamy JK, Rao DS. miRNA dysregulation in cancer: towards a mechanistic understanding. Front Genet. 2014;5:54. doi:10.3389/fgene.2014.00054.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Romero-Cordoba SL, Salido-Guadarrama I, Rodriguez-Dorantes M, Hidalgo-Miranda A. miRNA biogenesis: biological impact in the development of cancer. Cancer Biol Ther. 2014;15(11):1444–55. doi:10.4161/15384047.2014.955442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li J, Wang Q, Wen R, Liang J, Zhong X, Yang W, et al. MiR-138 inhibits cell proliferation and reverses epithelial-mesenchymal transition in non-small cell lung cancer cells by targeting GIT1 and SEMA4C. J Cell Mol Med. 2015. doi:10.1111/jcmm.12666.

    Google Scholar 

  8. Sun JB, Ji JH, Huo GX, Song QL, Zhang X. miR-182 induces cervical cancer cell apoptosis through inhibiting the expression of DNMT3a. Int J Clin Exp Pathol. 2015;8(5):4755–63.

    PubMed  PubMed Central  Google Scholar 

  9. Ho CS, Yap SH, Phuah NH, In LL, Hasima N. MicroRNAs associated with tumour migration, invasion and angiogenic properties in A549 and SK-Lu1 human lung adenocarcinoma cells. Lung Cancer. 2014;83(2):154–62. doi:10.1016/j.lungcan.2013.11.024.

    Article  PubMed  Google Scholar 

  10. Yoo JK, Jung HY, Lee JM, Yi H, Oh SH, Ko HY, et al. The novel miR-9500 regulates the proliferation and migration of human lung cancer cells by targeting Akt1. Cell Death Differ. 2014;21(7):1150–9. doi:10.1038/cdd.2014.33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Madison BB, Jeganathan AN, Mizuno R, Winslow MM, Castells A, Cuatrecasas M, et al. Let-7 represses carcinogenesis and a stem cell phenotype in the intestine via regulation of Hmga2. PLoS Genet. 2015;11(8):e1005408. doi:10.1371/journal.pgen.1005408.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wang XL, Qiu WX, Zhang GQ, Xu SJ, Gao Q, Yang ZL. MicroRNA-204 targets JAK2 in breast cancer and induces cell apoptosis through the STAT3/BCl-2/survivin pathway. Int J Clin Exp Pathol. 2015;8(5):5017–25.

    PubMed  PubMed Central  Google Scholar 

  13. Juzenas S, Salteniene V, Kupcinskas J, Link A, Kiudelis G, Jonaitis L, et al. Analysis of deregulated microRNAs and their target genes in gastric cancer. PLoS ONE. 2015;10(7):e0132327. doi:10.1371/journal.pone.0132327.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pignot G, Cizeron-Clairac G, Vacher S, Susini A, Tozlu S, Vieillefond A, et al. microRNA expression profile in a large series of bladder tumors: identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer. Int J Cancer J Int Cancer. 2013;132(11):2479–91. doi:10.1002/ijc.27949.

    Article  CAS  Google Scholar 

  15. Ding M, Lin BY, Li T, Liu YY, Li YH, Zhou XY, et al. A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells. Oncotarget. 2015;6(10):7686–700.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V. The role of ATF-2 in oncogenesis. BioEssays : News Rev Mol Cel Dev Biol. 2008;30(4):314–27. doi:10.1002/bies.20734.

    Article  CAS  Google Scholar 

  17. Gozdecka M, Breitwieser W. The roles of ATF2 (activating transcription factor 2) in tumorigenesis. Biochem Soc Trans. 2012;40:230–4. doi:10.1042/Bst20110630.

    Article  CAS  PubMed  Google Scholar 

  18. Bhoumik A, Ivanov V, Ronai Z. Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment. Clin Cancer Res Off J Am Assoc Cancer Res. 2001;7(2):331–42.

    CAS  Google Scholar 

  19. Hu CD, Choo R, Huang J. Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure. Front Oncol. 2015;5:90. doi:10.3389/fonc.2015.00090.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Xiao JJ, Liang DD, Zhang H, Liu Y, Zhang DS, Liu Y, et al. MicroRNA-204 is required for differentiation of human-derived cardiomyocyte progenitor cells. J Mol Cell Cardiol. 2012;53(6):751–9. doi:10.1016/j.yjmcc.2012.08.024.

    Article  CAS  PubMed  Google Scholar 

  21. Cho WCS. MicroRNAs as therapeutic targets and their potential applications in cancer therapy. Exp Opin Ther Targets. 2012;16(8):747–59. doi:10.1517/14728222.2012.696102.

    Article  CAS  Google Scholar 

  22. Li WD, Jin XJ, Zhang QB, Zhang G, Deng XB, Ma L. Decreased expression of miR-204 is associated with poor prognosis in patients with breast cancer. Int J Clin Exp Pathol. 2014;7(6):3287–92.

    PubMed  PubMed Central  Google Scholar 

  23. Butrym A, Rybka J, Baczynska D, Tukiendorf A, Kuliczkowski K, Mazur G. Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients. J Exp Clin Canc Res. 2015;34:68. doi:10.1186/s13046-015-0184-z.

    Article  Google Scholar 

  24. Sumbul AT, Gogebakan B, Ergun S, Yengil E, Batmaci CY, Tonyali O, et al. miR-204-5p expression in colorectal cancer: an autophagy-associated gene. Tumour Biol. 2014;35(12):12713–9. doi:10.1007/s13277-014-2596-3.

    Article  CAS  PubMed  Google Scholar 

  25. Ryan J, Tivnan A, Fay J, Bryan K, Meehan M, Creevey L, et al. MicroRNA-204 increases sensitivity of neuroblastoma cells to cisplatin and is associated with a favourable clinical outcome (vol 107, pg 967, 2012). Br J Cancer. 2012;107(7):1203. doi:10.1038/bjc.2012.425.

    Article  PubMed Central  Google Scholar 

  26. Cortinovis D, Monica V, Pietrantonio F, Ceresoli GL, La Spina CM, Wannesson L. MicroRNAs in non-small cell lung cancer: current status and future therapeutic promises. Curr Pharm Des. 2014;20(24):3982–90.

    Article  CAS  PubMed  Google Scholar 

  27. Kang SM, Lee HJ. MicroRNAs in human lung cancer. Exp Biol Med. 2014;239(11):1505–13. doi:10.1177/1535370214533887.

    Article  Google Scholar 

  28. Xia Y, Zhu Y, Ma T, Pan CF, Wang J, He ZC, et al. miR-204 functions as a tumor suppressor by regulating SIX1 in NSCLC. FEBS Lett. 2014;588(20):3703–12. doi:10.1016/j.febslet.2014.08.016.

    Article  CAS  PubMed  Google Scholar 

  29. Shi L, Zhang B, Sun X, Lu S, Liu Z, Liu Y, et al. MiR-204 inhibits human NSCLC metastasis through suppression of NUAK1. Br J Cancer. 2014;111(12):2316–27. doi:10.1038/bjc.2014.580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Desai S, Kumar A, Laskar S, Pandey BN. Differential roles of ATF-2 in survival and DNA repair contributing to radioresistance induced by autocrine soluble factors in A549 lung cancer cells. Cell Signal. 2014;26(11):2424–35. doi:10.1016/j.cellsig.2014.07.021.

    Article  CAS  PubMed  Google Scholar 

  31. Li S, Ezhevsky S, Dewing A, Cato MH, Scortegagna M, Bhoumik A, et al. Radiation sensitivity and tumor susceptibility in ATM phospho-mutant ATF2 mice. Genes Cancer. 2010;1(4):316–30. doi:10.1177/1947601910370700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bhoumik A, Fichtman B, DeRossi C, Breitwieser W, Kluger HM, Davis S, et al. Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proc Natl Acad Sci U S A. 2008;105(5):1674–9. doi:10.1073/pnas.0706057105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Berger AJ, Kluger HM, Li N, Kielhorn E, Halaban R, Ronai Z, et al. Subcellular localization of activating transcription factor 2 in melanoma specimens predicts patient survival. Cancer Res. 2003;63(23):8103–7.

    CAS  PubMed  Google Scholar 

  34. Maekawa T, Shinagawa T, Sano Y, Sakuma T, Nomura S, Nagasaki K, et al. Reduced levels of ATF-2 predispose mice to mammary tumors. Mol Cell Biol. 2007;27(5):1730–44. doi:10.1128/Mcb.01579-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nagase T, Sudo T, Maekawa T, Yoshimura T, Fujisawa J, Yoshida M, et al. Promoter region of the human Cre-Bp1 gene encoding the transcriptional regulator binding to the cyclic-Amp response element. J Biol Chem. 1990;265(28):17300–6.

    CAS  PubMed  Google Scholar 

  36. Ricote M, Garcia-Tunon I, Bethencourt F, Fraile B, Onsurbe P, Paniagua R, et al. The p38 transduction pathway in prostatic neoplasia. J Pathol. 2006;208(3):401–7. doi:10.1002/path.1910.

    Article  CAS  PubMed  Google Scholar 

  37. Beier F, Lee RJ, Taylor AC, Pestell RG, LuValle P. Identification of the cyclin D1 gene as a target of activating transcription factor 2 in chondrocytes. Proc Natl Acad Sci U S A. 1999;96(4):1433–8. doi:10.1073/pnas.96.4.1433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Laferriere J, Houle F, Taher MM, Valerie K, Huot J. Transendothelial migration of colon carcinoma cells requires expression of E-selectin by endothelial cells and activation of stress-activated protein kinase-2 (SAPK2/p38) in the tumor cells. J Biol Chem. 2001;276(36):33762–72. doi:10.1074/jbc.M008564200.

    Article  CAS  PubMed  Google Scholar 

  39. Ma Q, Li X, Vale-Cruz D, Brown ML, Beier F, LuValle P. Activating transcription factor 2 controls Bcl-2 promoter activity in growth plate chondrocytes. J Cell Biochem. 2007;101(2):477–87. doi:10.1002/jcb.21198.

    Article  CAS  PubMed  Google Scholar 

  40. Decesare D, Vallone D, Caracciolo A, Sassonecorsi P, Nerlov C, Verde P. Heterodimerization of C-Jun with Atf-2 and C-Fos is required for positive and negative regulation of the human urokinase enhancer. Oncogene. 1995;11(2):365–76.

    CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant from the National Natural Science Foundation of P. R. China (no. 81302029), Natural Science Foundation of Shaanxi Province of P. R. China (no. 2014JQ4149), Fundamental Research Funds for the Central Universities in Xi’an Jiaotong University (no. xjj2015086), and China Postdoctoral Science Foundation (no. 2015M570841).

Author information

Author notes

    Authors and Affiliations

    1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, 710061, China

      Shuo Zhang, Lei Gao, Asmitananda Thakur, Puyu Shi, Feng Liu, Jing Feng, Ting Wang, Yiqian Liang, Mingwei Chen & Hui Ren

    2. Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi’an, Shaanxi, China

      Shuo Zhang, Lei Gao, Asmitananda Thakur, Puyu Shi, Feng Liu, Jing Feng, Ting Wang, Yiqian Liang, Mingwei Chen & Hui Ren

    3. Department of Internal Medicine, Life Guard Hospital, Biratnagar, Nepal

      Asmitananda Thakur

    4. S. R. Laboratory and Diagnostic Center, Biratnagar, Nepal

      Asmitananda Thakur

    5. Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia

      Johnson J. Liu

    Authors
    1. Shuo Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Lei Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Asmitananda Thakur
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Puyu Shi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Feng Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Jing Feng
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Ting Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Yiqian Liang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Johnson J. Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Mingwei Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Hui Ren
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Mingwei Chen or Hui Ren.

    Ethics declarations

    Conflicts of interest

    None

    Additional information

    Shuo Zhang and Lei Gao contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhang, S., Gao, L., Thakur, A. et al. miRNA-204 suppresses human non-small cell lung cancer by targeting ATF2. Tumor Biol. 37, 11177–11186 (2016). https://doi.org/10.1007/s13277-016-4906-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13277-016-4906-4

    Keywords

    Search

    Navigation