Tumor Biology

, Volume 37, Issue 12, pp 15601–15606 | Cite as

Role of miR-138 in the regulation of larynx carcinoma cell metastases

  • Shang Gao
  • Jie Wang
  • Jin Xie
  • Tianzhen Zhang
  • Pin Dong
Original Article


The cases of larynx carcinoma (LC) with poor prognosis largely result from the distal metastases of the primary tumor. Since microRNAs (miRNAs) play critical roles during cancer metastases, determination of the involved miRNAs in the regulation of the LC metastases may provide novel therapeutic targets for LC treatment. Here, we studied the LC specimens from the patients and found that the levels of miR-138 were significantly decreased and the levels of ZEB2, a critical factor that regulates cancer cell invasiveness, were significantly increased in LC, compared to the paired normal larynx tissue. Metastatic LC appeared to contained lower levels of miR-138. Moreover, miR-138 and ZEB2 inversely correlated in LC specimens. Bioinformatics analyses showed that miR-138 targeted the 3′-untranslated region (3′-UTR) of ZEB2 mRNA to inhibit its translation, which was confirmed in a luciferase reporter assay. Further, miR-138 overexpression inhibited ZEB2-mediated cell invasiveness, while miR-138 depletion increased ZEB2-mediated cell invasiveness in LC cells. Together, our data suggest that miR-138 suppression in LC cells may promote ZEB2-mediated cancer metastases. Thus, miR-138 appears to be an intriguing therapeutic target to prevent metastases of LC.


Larynx carcinoma (LC) ZEB2 miR-138 Cancer metastases 


Compliance with ethical standards

For the use of the clinical materials for research purposes, approval from the Institutional Research Ethics Committee was obtained.

Conflicts of interest


Informed consent

Patient’s consents were obtained.


  1. 1.
    Mojica-Manosa P, Reidy J, Wilson K, Douglas W. Larynx squamous cell carcinoma: concepts and future directions. Surg Oncol Clin N Am. 2004;13:99–112.CrossRefPubMedGoogle Scholar
  2. 2.
    Hu Q, Tong S, Zhao X, Ding W, Gou Y, Xu K, et al. Periostin mediates TGF-beta-induced epithelial mesenchymal transition in prostate cancer cells. Cell Physiol Biochem. 2015;36:799–809.CrossRefPubMedGoogle Scholar
  3. 3.
    Sa Y, Li C, Li H, Guo H. TIMP-1 induces alpha-smooth muscle actin in fibroblasts to promote urethral scar formation. Cell Physiol Biochem. 2015;35:2233–43.CrossRefPubMedGoogle Scholar
  4. 4.
    Lan A, Qi Y, Du J. Akt2 mediates TGF-beta1-induced epithelial to mesenchymal transition by deactivating GSK3beta/snail signaling pathway in renal tubular epithelial cells. Cell Physiol Biochem. 2014;34:368–82.CrossRefPubMedGoogle Scholar
  5. 5.
    Teng Y, Zhao L, Zhang Y, Chen W, Li X. Id-1, a protein repressed by miR-29b, facilitates the TGFbeta1-induced epithelial-mesenchymal transition in human ovarian cancer cells. Cell Physiol Biochem. 2014;33:717–30.CrossRefPubMedGoogle Scholar
  6. 6.
    Guo Y, Lang X, Lu Z, Wang J, Li T, Liao Y, et al. MiR-10b directly targets ZEB1 and PIK3CA to curb adenomyotic epithelial cell invasiveness via upregulation of E-cadherin and inhibition of Akt phosphorylation. Cell Physiol Biochem. 2015;35:2169–80.CrossRefPubMedGoogle Scholar
  7. 7.
    Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 2009;28:151–66.CrossRefPubMedGoogle Scholar
  8. 8.
    Di Leva G, Croce CM. MiRNA profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Mei Q, Li F, Quan H, Liu Y, Xu H. Busulfan inhibits growth of human osteosarcoma through miR-200 family microRNAs in vitro and in vivo. Cancer Sci. 2014;105:755–62.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wang F, Xiao W, Sun J, Han D, Zhu Y. MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol. 2014;35:8653–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Liu G, Jiang C, Li D, Wang R, Wang W. MiRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer. Tumour Biol. 2014;35:9801–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Mitomo S, Maesawa C, Ogasawara S, Iwaya T, Shibazaki M, Yashima-Abo A, et al. Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines. Cancer Sci. 2008;99:280–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhao X, Yang L, Hu J, Ruan J. MiR-138 might reverse multidrug resistance of leukemia cells. Leuk Res. 2010;34:1078–82.CrossRefPubMedGoogle Scholar
  15. 15.
    Liu X, Lv XB, Wang XP, Sang Y, Xu S, Hu K, et al. MiR-138 suppressed nasopharyngeal carcinoma growth and tumorigenesis by targeting the CCND1 oncogene. Cell Cycle. 2012;11:2495–506.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang W, Zhao LJ, Tan YX, Ren H, Qi ZT. MiR-138 induces cell cycle arrest by targeting cyclin D3 in hepatocellular carcinoma. Carcinogenesis. 2012;33:1113–20.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zhou X, Qi Y. PLGF inhibition impairs metastasis of larynx carcinoma through MMP3 downregulation. Tumour Biol. 2014;35:9381–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhou X, Qi Y. Larynx carcinoma regulates tumor-associated macrophages through PLGF signaling. Sci Rep. 2015;5:10071.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2:329–33.CrossRefPubMedGoogle Scholar
  20. 20.
    Xu C, Fu H, Gao L, Wang L, Wang W, Li J, et al. BCR-ABl/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia. Oncogene. 2014;33:44–54.CrossRefPubMedGoogle Scholar
  21. 21.
    Long L, Huang G, Zhu H, Guo Y, Liu Y, Huo J. Down-regulation of miR-138 promotes colorectal cancer metastasis via directly targeting TWIST2. J Transl Med. 2013;11:275.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhang H, Zhang H, Zhao M, Lv Z, Zhang X, Qin X, et al. MiR-138 inhibits tumor growth through repression of EZH2 in non-small cell lung cancer. Cell Physiol Biochem. 2013;31:56–65.CrossRefPubMedGoogle Scholar
  23. 23.
    Gao Y, Fan X, Li W, Ping W, Deng Y, Fu X. MiR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124. Biochem Biophys Res Commun. 2014;446:179–86.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shang Gao
    • 1
  • Jie Wang
    • 1
  • Jin Xie
    • 1
  • Tianzhen Zhang
    • 1
  • Pin Dong
    • 1
  1. 1.Department of Otolaryngology-Head and Neck Surgery, Shanghai First People’s HospitalShanghai Jiaotong UniversityShanghaiChina

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