De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures
2010; Springer Nature; Volume: 29; Issue: 23 Linguagem: Inglês
10.1038/onc.2010.83
ISSN1476-5594
AutoresAurélie Ernst, Benito Campos, Jan Meier, Frauke Devens, Franziska Liesenberg, Marietta Wolter, Guido Reifenberger, Christel Herold‐Mende, Peter Lichter, Bernhard Radlwimmer,
Tópico(s)MicroRNA in disease regulation
ResumoAll-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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