Tumor Biology

, Volume 37, Issue 4, pp 5551–5560 | Cite as

miR-411 contributes the cell proliferation of lung cancer by targeting FOXO1

  • Zhiju ZhaoEmail author
  • Limei Qin
  • Shu Li
Original Article


Lung cancer is the leading cause of cancer deaths worldwide; the study of microRNAs gives new hope for lung cancer treatment. miR-411 has been demonstrated to be an independent prognostic factor for lung adenocarcinoma, but the role and regulatory mechanism are largely unknown. In the present study, we found miR-411 was overexpressed in the lung cancer cells; overexpression of miR-411 promoted anchorage-dependent and anchorage-independent growths of lung cancer, while miR-411 knockdown reduced this effect. Further study showed forkhead box O1 (FOXO1) was a target of miR-411. Overexpression of miR-411 suppressed the expression of FOXO1; the effect of suppression was abrogated when the mutation occurred in the 3′UTR of FOXO1. Knockdown of FOXO1 in cells which miR-411 was inhibited recapitulated the phenotype of miR-411 overexpression. Taken together, our study revealed miR-411 promoted cell proliferation of lung cancer by targeting tumor suppressor gene FOXO1 and miR-411 might be a potential target for lung cancer therapy.


Lung cancer Cell proliferation miR-411 FOXO1 



This work was supported by grants from the Science and technology project of Guangdong Province grant (No.2014A020212640, LM Qin).

Compliance with ethical standards

Conflicts of interest


Supplementary material

13277_2015_4425_Fig7_ESM.gif (4.7 mb)
Supplemental Figure 1

miR-411 regulates cell proliferation of BEAS-2B. (A). MTT assay determined the effect on the proliferation after miR-411 was downregulated in BEAS-2B. (B). Colony formation assay determined the effect on the proliferation after miR-411 was downregulated in BEAS-2B. (C). Real-time quantitative PCR analysis determined the expression of cell cycle regulator, p21, p27 and Cyclin D1 transfected miR-411 inhibitor. *p < 0.05, Error bars represent mean ± STDEV . (GIF 4.67 mb)

13277_2015_4425_MOESM1_ESM.tif (465 kb)
High Resolution Image (TIF 464 kb)


  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: Cancer J Clin. 2013;63(1):11–30. doi: 10.3322/caac.21166.Google Scholar
  2. 2.
    McDoniels-Silvers AL, Nimri CF, Stoner GD, Lubet RA, You M. Differential gene expression in human lung adenocarcinomas and squamous cell carcinomas. Clin Cancer Res: Off J Am Assoc Cancer Res. 2002;8(4):1127–38.Google Scholar
  3. 3.
    Jacks DATT. Modeling human lung cancer in mice: similarities and shortcomings. Oncogene. 1999;18:5318–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell. 2006;9(6):485–95. doi: 10.1016/j.ccr.2006.04.022.CrossRefPubMedGoogle Scholar
  5. 5.
    Mahoney CL, Choudhury B, Davies H, Edkins S, Greenman C, Haaften G, et al. LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer. 2009;100(2):370–5. doi: 10.1038/sj.bjc.6604886.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    To MD, Wong CE, Karnezis AN, Del Rosario R, Di Lauro R, Balmain A. Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nat Genet. 2008;40(10):1240–4. doi: 10.1038/ng.211.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6. doi: 10.1038/nature05945.CrossRefPubMedGoogle Scholar
  8. 8.
    Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500. doi: 10.1126/science.1099314.CrossRefPubMedGoogle Scholar
  9. 9.
    Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350(4):351–60. doi: 10.1056/NEJMoa031644.CrossRefPubMedGoogle Scholar
  10. 10.
    Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8. doi: 10.1016/S1470-2045(09)70364-X.CrossRefPubMedGoogle Scholar
  11. 11.
    Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011;12(11):1004–12. doi: 10.1016/S1470-2045(11)70232-7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lam EWF, Brosens JJ, Gomes AR, Koo CY. Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer. 2013;13(7):482–95. doi: 10.1038/Nrc3539.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhang X, Yalcin S, Lee DF, Yeh TYJ, Lee SM, Su J, et al. FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol. 2011;13(9):1092–U1118. doi: 10.1038/Ncb2293.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM, et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci U S A. 2005;102(5):1649–54. doi: 10.1073/pnas.0406789102.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, et al. Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell. 2008;32(2):221–31. doi: 10.1016/j.molcel.2008.09.013.CrossRefPubMedGoogle Scholar
  16. 16.
    Wu L, Li H, Jia CY, Cheng W, Yu M, Peng M, et al. MicroRNA-223 regulates FOXO1 expression and cell proliferation. FEBS Lett. 2012;586(7):1038–43. doi: 10.1016/j.febslet.2012.02.050.CrossRefPubMedGoogle Scholar
  17. 17.
    Wu Z, Sun H, Zeng W, He J, Mao X. Upregulation of MircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1. PLoS ONE. 2012;7(9), e45825. doi: 10.1371/journal.pone.0045825.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zhang L, Quan H, Wang S, Li X, Che X. MiR-183 promotes growth of non-small cell lung cancer cells through FoxO1 inhibition. Tumour Biol: J Int Soc Oncodev Biol Med. 2015. doi: 10.1007/s13277-015-3550-8.Google Scholar
  19. 19.
    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33. doi: 10.1016/j.cell.2009.01.002.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ke J, Zhao Z, Hong SH, Bai S, He Z, Malik F, et al. Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells. Oncotarget. 2015;6(6):3709–21.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9(3):189–98. doi: 10.1016/j.ccr.2006.01.025.CrossRefPubMedGoogle Scholar
  22. 22.
    Nadal E, Zhong J, Lin J, Reddy RM, Ramnath N, Orringer MB, et al. A microRNA cluster at 14q32 drives aggressive lung adenocarcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2014;20(12):3107–17. doi: 10.1158/1078-0432.CCR-13-3348.CrossRefGoogle Scholar
  23. 23.
    Harafuji N, Schneiderat P, Walter M, Chen YW. miR-411 is up-regulated in FSHD myoblasts and suppresses myogenic factors. Orapant Journal of Rare Diseases. 2013;8:55.Google Scholar
  24. 24.
    van Schooneveld E, Wouters MC, Van der Auwera I, Peeters DJ, Wildiers H, Van Dam PA, et al. Expression profiling of cancerous and normal breast tissues identifies microRNAs that are differentially expressed in serum from patients with (metastatic) breast cancer and healthy volunteers. Breast Cancer Res :BCR. 2012;14(1):R34. doi: 10.1186/bcr3127.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gao Y, Xiao Q, Ma H, Li L, Liu J, Feng Y, et al. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci U S A. 2010;107(44):18892–7. doi: 10.1073/pnas.1004952107.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shen G, Jia H, Tai Q, Li Y, Chen D. miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis. 2013;34(1):211–9. doi: 10.1093/carcin/bgs320.CrossRefPubMedGoogle Scholar
  27. 27.
    Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9(3):153–66. doi: 10.1038/nrc2602.CrossRefPubMedGoogle Scholar
  28. 28.
    van der Horst A, Burgering BMT. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol. 2007;8(6):440–50. doi: 10.1038/Nrm2190.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011;1813(11):1978–86. doi: 10.1016/j.bbamcr.2011.03.010.CrossRefPubMedGoogle Scholar
  30. 30.
    Massagué J. G1 cell-cycle control and cancer. Nature. 2004;432:9.CrossRefGoogle Scholar
  31. 31.
    Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol. 2000;20(23):8969–82.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Seoane J, Le HV, Shen L, Anderson SA, Massague J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004;117(2):211–23.CrossRefPubMedGoogle Scholar
  33. 33.
    Abukhdeir AM, Park BH. P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med. 2008;10, e19. doi: 10.1017/S1462399408000744.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ramaswamy S, Nakamura N, Sansal I, Bergeron L, Sellers WR. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell. 2002;2(1):81–91.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang WC, Liu J, Xu X, Wang G. The role of microRNAs in lung cancer progression. Med Oncol. 2013;30(3):675. doi: 10.1007/s12032-013-0675-8.CrossRefPubMedGoogle Scholar
  36. 36.
    Gao Y, Gao F, Ma JL, Sun WZ, Song LP. The potential clinical applications and prospects of microRNAs in lung cancer. OncoTargets Ther. 2014;7:901–6. doi: 10.2147/OTT.S62227.CrossRefGoogle Scholar
  37. 37.
    Marshall AD, Lagutina I, Grosveld GC. PAX3-FOXO1 induces cannabinoid receptor 1 to enhance cell invasion and metastasis. Cancer Res. 2011;71(24):7471–80. doi: 10.1158/0008-5472.CAN-11-0924.CrossRefPubMedGoogle Scholar
  38. 38.
    Ailles LE, Weissman IL. Cancer stem cells in solid tumors. Curr Opin Biotechnol. 2007;18(5):460–6. doi: 10.1016/j.copbio.2007.10.007.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Innovation Center for Cell Biology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical CenterUniversity of Science and Technology of ChinaHefeiChina
  2. 2.Laboratory of Pathogen Biology, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouChina
  3. 3.Department of PathophysiologyWannan Medical CollegeWuhuChina
  4. 4.School of Life SciencesUniversity of Science and Technology of ChinaHefeiChina

Personalised recommendations