Tumor Biology

, Volume 37, Issue 3, pp 4105–4113 | Cite as

microRNA-188 is downregulated in oral squamous cell carcinoma and inhibits proliferation and invasion by targeting SIX1

  • Lili Wang
  • Hongchen Liu
Original Article


microRNA-188 expression is downregulated in several tumors. However, its function and mechanism in human oral squamous cell carcinoma (OSCC) remains obscure. The present study aims to identify the expression pattern, biological roles, and potential mechanism by which miR-188 dysregulation is associated with oral squamous cell carcinoma. Significant downregulation of miR-188 was observed in OSCC tissues compared with paired normal tissues. In vitro, gain-of-function, loss-of-function experiments were performed to examine the impact of miR-188 on cancer cell proliferation, invasion, and cell cycle progression. Transfection of miR-188 mimics suppressed Detroit 562 cell proliferation, cell cycle progression and invasion, with downregulation of cyclin D1, MMP9, and p-ERK. Transfection of miR-188 inhibitor in FaDu cell line with high endogenous expression exhibited the opposite effects. Using fluorescence reporter assays, we confirmed that SIX1 was a direct target of miR-188 in OSCC cells. Transfection of miR-188 mimics downregulated SIX1 expression. SIX1 siRNA treatment abrogated miR-188 inhibitor-induced cyclin D1 and MMP9 upregulation. In addition, we found that SIX1 was overexpressed in 32 of 80 OSCC tissues. In conclusion, this study indicates that miR-188 downregulation might be associated with oral squamous cell carcinoma progression. miR-188 suppresses proliferation and invasion by targeting SIX1 in oral squamous cell carcinoma cells.


Oral squamous cell carcinoma miR-188 SIX1 Proliferation Invasion 



The study was supported by the Natural Science Foundation of Liaoning (No. 2014022003).

Compliance with Ethical Standards

Conflicts of interest



  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Xia X, Du R, Zhao L, Sun W, Wang X. Expression of AEG-1 and microvessel density correlates with metastasis and prognosis of oral squamous cell carcinoma. Hum Pathol. 2014;45:858–65.CrossRefPubMedGoogle Scholar
  3. 3.
    Huang WC, Chan SH, Jang TH, Chang JW, Ko YC, Yen TC, et al. miRNA-491-5p and GIT1 serve as modulators and biomarkers for oral squamous cell carcinoma invasion and metastasis. Cancer Res. 2014;74:751–64.CrossRefPubMedGoogle Scholar
  4. 4.
    Chang KP, Wang CL, Kao HK, Liang Y, Liu SC, Huang LL, et al. Overexpression of caldesmon is associated with lymph node metastasis and poorer prognosis in patients with oral cavity squamous cell carcinoma. Cancer. 2013;119:4003–11.CrossRefPubMedGoogle Scholar
  5. 5.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.CrossRefPubMedGoogle Scholar
  6. 6.
    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;9:189–98.CrossRefPubMedGoogle Scholar
  7. 7.
    Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004;64:3753–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhou X, Ren Y, Liu A, Jin R, Jiang Q, Huang Y, et al. WP1066 sensitizes oral squamous cell carcinoma cells to cisplatin by targeting STAT3/miR-21 axis. Sci Rep. 2014;4:7461.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Peng SC, Liao CT, Peng CH, Cheng AJ, Chen SJ, Huang CG, et al. MicroRNAs MiR-218, MiR-125b, and Let-7g predict prognosis in patients with oral cavity squamous cell carcinoma. PLoS One. 2014;9, e102403.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Fang F, Chang RM, Yu L, Lei X, Xiao S, Yang H, et al. MicroRNA-188-5p suppresses tumor cell proliferation and metastasis by directly targeting FGF5 in hepatocellular carcinoma. J Hepatol. 2015;63:874–85.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang H, Qi S, Zhang T, Wang A, Liu R, Guo J, et al. miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression. Oncotarget. 2015;6:6092–104.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kahlert C, Lerbs T, Pecqueux M, Herpel E, Hoffmeister M, Jansen L, et al. Overexpression of SIX1 is an independent prognostic marker in stage I-III colorectal cancer. Int J Cancer. 2015;137:2104–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Li Z, Tian T, Lv F, Chang Y, Wang X, Zhang L, et al. Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PLoS One. 2013;8, e59203.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ono H, Imoto I, Kozaki K, Tsuda H, Matsui T, Kurasawa Y, et al. SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation. Oncogene. 2012;31:4923–34.CrossRefPubMedGoogle Scholar
  15. 15.
    Zheng XH, Liang PH, Guo JX, Zheng YR, Han J, Yu LL, et al. Expression and clinical implications of homeobox gene Six1 in cervical cancer cell lines and cervical epithelial tissues. Int J Gynecol Cancer. 2010;20:1587–92.CrossRefPubMedGoogle Scholar
  16. 16.
    Dong QZ, Wang Y, Tang ZP, Fu L, Li QC, Wang ED, et al. Derlin-1 is overexpressed in non-small cell lung cancer and promotes cancer cell invasion via EGFR-ERK-mediated up-regulation of MMP-2 and MMP-9. Am J Pathol. 2013;182:954–64.CrossRefPubMedGoogle Scholar
  17. 17.
    Kharman-Biz A, Gao H, Ghiasvand R, Zhao C, Zendehdel K, Dahlman-Wright K. Expression of activator protein-1 (AP-1) family members in breast cancer. BMC Cancer. 2013;13:441.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Coletta RD, Christensen K, Reichenberger KJ, Lamb J, Micomonaco D, Huang L, et al. The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1. Proc Natl Acad Sci U S A. 2004;101:6478–83.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Reichenberger KJ, Coletta RD, Schulte AP, Varella-Garcia M, Ford HL. Gene amplification is a mechanism of Six1 overexpression in breast cancer. Cancer Res. 2005;65:2668–75.CrossRefPubMedGoogle Scholar
  20. 20.
    Behbakht K, Qamar L, Aldridge CS, Coletta RD, Davidson SA, Thorburn A, et al. Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res. 2007;67:3036–42.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Institute of StomatologyChinese PLA General HospitalBeijingChina
  2. 2.Department of Prosthodontics, the Affiliated hospital of Stomatology and The Second Affiliated HospitalLiaoning Medical UniversityJinzhouChina

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