De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures
All-trans retinoic acid is a potent promoter of cellular differentiation processes, which is used in cancer therapy. Glioblastoma spheroid cultures are enriched in tumor-initiating cells, and provide a model to test new treatment options in vitro. We investigated the molecular mechanisms of response...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
22 March 2010
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| In: |
Oncogene
Year: 2010, Volume: 29, Issue: 23, Pages: 3411-3422 |
| ISSN: | 1476-5594 |
| DOI: | 10.1038/onc.2010.83 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/onc.2010.83 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/onc201083 
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| Author Notes: | A. Ernst, B. Campos, J. Meier, F. Devens, F. Liesenberg, M. Wolter, G. Reifenberger, C. Herold-Mende, P. Lichter and B. Radlwimmer |
| Summary: | All-trans retinoic acid is a potent promoter of cellular differentiation processes, which is used in cancer therapy. Glioblastoma spheroid cultures are enriched in tumor-initiating cells, and provide a model to test new treatment options in vitro. We investigated the molecular mechanisms of response to exposure to differentiation-promoting conditions in such cultures. Microarray analyses of five independent cultures showed that after induction of differentiation, inhibitors of transforming growth factor-β/bone morphogenetic protein, Wnt/β-catenin and IGF signaling were upregulated, whereas expression of several microRNAs decreased, particularly that of the miR-17-92 cluster. In primary astrocytic gliomas (n=82), expression of several members of miR-17-92 was significantly higher relative to those of normal brain (n=8) and significantly increased with tumor grade progression (P<0.05). A high-level amplification of the miR-17-92 locus was detected in one glioblastoma specimen. Transfection of inhibitors of miR-17-92 induced increased apoptosis and decreased cell proliferation in glioblastoma spheroids. Mir-17-92 inhibition was also associated with increased messenger RNA (mRNA) and/or protein expression of CDKN1A, E2F1, PTEN and CTGF. The CTGF gene was shown to be a target of miR-17-92 in glioblastoma spheroids by luciferase reporter assays. Our results suggest that miR-17-92 and its target CTGF mediate effects of differentiation-promoting treatment on glioblastoma cells through multiple regulatory pathways. |
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| Item Description: | Gesehen am 27.03.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1476-5594 |
| DOI: | 10.1038/onc.2010.83 |