Journal
NEURO-ONCOLOGY
Volume 16, Issue 11, Pages 1510-1522Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/nou111
Keywords
glioblastoma multiforme; invasion; miR-377; proliferation; Sp1
Categories
Funding
- National Natural Science Foundation of China [81201978, 81172389, 81072078, 81200362, 81170786, 81102078]
- Jiangsu Province Natural Science Foundation [BK2012483, BK2010580]
- Program for Advanced Talents Within Six Industries of Jiangsu Province [2012-WSN-019]
- National High Technology Research and Development Program of China [2012AA02A508]
- International Cooperation Program [2012DFA30470]
- Jiangsu Province Key Provincial Talents Program [RC2011051]
- Jiangsu Province Key Discipline of Medicine [XK201117]
- Jiangsu Provincial Special Program of Medical Science [BL2012028]
- Program for Development of Innovative Research Team in the First Affiliated Hospital of Nanjing Medical University
- Provincial Initiative Program for Excellency Disciplines, Jiangsu Province
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
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Background. Increasing evidence has indicated that microRNAs (miRNAs) are strongly implicated in the initiation and progression of glioblastoma multiforme (GBM). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role and therapeutic effect for GBM. Methods. MiRNA global screening was performed on GBM patient samples and adjacent nontumor brain tissues. The expression of miR-377 was detected by real-time reverse-transcription PCR. The effects of miR-377 on GBM cell proliferation, cell cycle progression, invasion, and orthotopic tumorigenicity were investigated The therapeutic effect of miR-377 mimic was explored in a subcutaneous GBM model. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. Results. MiR-377 was markedly downregulated in human GBM tissues and cell lines. Overexpression of miR-377 dramatically inhibited cell growth both in culture and in orthotopic xenograft tumor models, blocked G1/S transition, and suppressed cell invasion in GBM cells. Importantly, introduction of miR-377 could strongly inhibit tumor growth in a subcutaneous GBM model. Subsequent investigation revealed that specificity protein 1 (Sp1) was a direct and functional target of miR-377 in GBM cells. Silencing of Sp1 recapitulated the antiproliferative and anti-invasive effects of miR-377, whereas restoring the Sp1 expression antagonized the tumor-suppressive function of miR-377. Finally, analysis of miR-377 and Sp1 levels in human GBM tissues revealed that miR-377 is inversely correlated with Sp1 expression. Conclusion. These findings reveal that miR-377/Sp1 signaling that may be required for GBM development and may consequently serve as a therapeutic target for the treatment of GBM.
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