Tumor Biology

, Volume 35, Issue 9, pp 8653–8658 | Cite as

RETRACTED ARTICLE: MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma

  • Fei Wang
  • Weizhong Xiao
  • Jiyong Sun
  • Donghua Han
  • Youhou Zhu
Research Article


As the most aggressive malignant primary human brain tumor, glioblastoma is noted with extremely poor patient survival. Previous studies have demonstrated that expression of matrix metalloproteinase-9 (MMP9) in glioblastoma cells is critical for cancer metastasis. However, the molecular signaling pathways that control MMP9 activation remain undefined. Here, we reported a strong negative correlation of microRNA (miRNA)-181c levels with either MMP9 levels or activation of epidermal growth factor receptor (EGFR) signaling in glioblastoma patients. EGF-induced activation of EGFR in a human glioblastoma line, A-172 cells, increased MMP9 expression through activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway, without affecting expression of miRNA-181c. On the other hand, overexpression of miRNA-181c in A-172 cells inhibited MMP9 expression by inhibiting Akt phosphorylation, but not phosphorylation of EGFR receptor. Taken together, these findings suggest that EGFR signaling activates downstream PI3K/Akt to increase MMP9 expression in glioblastoma, while phosphorylation of Akt is a control point by miRNA-181c. Our work thus provides new insights into the molecular basis underlying the metastasis of glioblastoma.


Glioblastoma,miRNA-181c Epidermal growth factor receptor Phosphatidylinositol 3-kinase Akt MMP9 


Conflicts of interest



  1. 1.
    Schonberg DL, Bao S, Rich JN. Genomics informs glioblastoma biology. Nat Genet. 2013;45:1105–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Chen J, Huang Q, Wang F: Inhibition of foxo1 nuclear exclusion prevents metastasis of glioblastoma. Tumour Biol 2014.Google Scholar
  3. 3.
    Li S, Gao Y, Ma W, Guo W, Zhou G, Cheng T, Liu Y: EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2. Tumour Biol 2014.Google Scholar
  4. 4.
    Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Cho S, et al. EGF-induced MMP-9 expression is mediated by the JAK3/ERK pathway, but not by the JAK3/STAT-3 pathway in a SKBR3 breast cancer cell line. Cell Signal. 2009;21:892–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol. 2009;218:460–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Lee CC, Lai JH, Hueng DY, Ma HI, Chung Y, Sun YY, et al. Disrupting the CXCL12/CXCR4 axis disturbs the characteristics of glioblastoma stem-like cells of rat RG2 glioblastoma. Cancer Cell Int. 2013;13:85.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Liu Q, Li G, Li R, Shen J, He Q, Deng L, et al. IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines. J Neurooncol. 2010;100:165–76.CrossRefPubMedGoogle Scholar
  8. 8.
    Papi A, Bartolini G, Ammar K, Guerra F, Ferreri AM, Rocchi P, et al. Inhibitory effects of retinoic acid and IIF on growth, migration and invasiveness in the U87MG human glioblastoma cell line. Oncol Rep. 2007;18:1015–21.PubMedGoogle Scholar
  9. 9.
    Feng X, Miao G, Han Y, Xu Y. CARMA3 is overexpressed in human glioma and promotes cell invasion through MMP9 regulation in A172 cell line. Tumour Biol. 2014;35:149–54.CrossRefPubMedGoogle Scholar
  10. 10.
    Yan Y, Liang H, Li T, Li M, Li R, Qin X, Li S: The MMP-1, MMP-2, and MMP-9 gene polymorphisms and susceptibility to bladder cancer: a meta-analysis. Tumour Biol 2014.Google Scholar
  11. 11.
    Sun GG, Lu YF, Zhang J, Hu WN: Filamin a regulates MMP-9 expression and suppresses prostate cancer cell migration and invasion. Tumour Biol 2014.Google Scholar
  12. 12.
    Tang ZP, Cui QZ, Dong QZ, Xu K, Wang EH. Ataxia-telangiectasia group d complementing gene (ATDC) upregulates matrix metalloproteinase 9 (MMP-9) to promote lung cancer cell invasion by activating ERK and JNK pathways. Tumour Biol. 2013;34:2835–42.CrossRefPubMedGoogle Scholar
  13. 13.
    Sutnar A, Pesta M, Liska V, Treska V, Skalicky T, Kormunda S, et al. Clinical relevance of the expression of mRNA of MMP-7, MMP-9, TIMP-1, TIMP-2 and CEA tissue samples from colorectal liver metastases. Tumour Biol. 2007;28:247–52.CrossRefPubMedGoogle Scholar
  14. 14.
    Schutz A, Schneidenbach D, Aust G, Tannapfel A, Steinert M, Wittekind C. Differential expression and activity status of MMP-1, MMP-2 and MMP-9 in tumor and stromal cells of squamous cell carcinomas of the lung. Tumour Biol. 2002;23:179–84.CrossRefPubMedGoogle Scholar
  15. 15.
    Di Leva G, Croce CM. MiRNA profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Slaby O, Lakomy R, Fadrus P, Hrstka R, Kren L, Lzicarova E, et al. MicroRNA-181 family predicts response to concomitant chemoradiotherapy with temozolomide in glioblastoma patients. Neoplasma. 2010;57:264–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Xuan Nguyen TL, Choi JW, Lee SB, Ye K, Woo SD, Lee KH, et al. Akt phosphorylation is essential for nuclear translocation and retention in NGF-stimulated PC12 cells. Biochem Biophys Res Commun. 2006;349:789–98.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of Neurosurgery, Tongji HospitalTongji UniversityShanghaiChina
  2. 2.Department of Neurology, Shanghai Pudong HospitalFudan UniversityShanghaiChina
  3. 3.Department of NeurosurgeryWuxi Second Hospital Affiliated to Nanjing Medical UniversityWuxiChina

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