Abstract
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.
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References
Schonberg DL, Bao S, Rich JN. Genomics informs glioblastoma biology. Nat Genet. 2013;45:1105–7.
Chen J, Huang Q, Wang F: Inhibition of foxo1 nuclear exclusion prevents metastasis of glioblastoma. Tumour Biol 2014.
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.
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.
Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol. 2009;218:460–6.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Di Leva G, Croce CM. MiRNA profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.
Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282–9.
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.
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.
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Fei Wang and Weizhong **ao equally contributed to this work.
The Publisher and Editor retract this article in accordance with the recommendations of the Committee on Publication Ethics (COPE). After a thorough investigation we have strong reason to believe that the peer review process was compromised.
An erratum to this article can be found online at http://dx.doi.org/10.1007/s13277-017-5487-6.
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Wang, F., **ao, W., Sun, J. et al. RETRACTED ARTICLE: MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumor Biol. 35, 8653–8658 (2014). https://doi.org/10.1007/s13277-014-2131-6
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DOI: https://doi.org/10.1007/s13277-014-2131-6