Artikel
miR-328 promotes glioma cell invasion via SFRP1-dependent WNT-signaling activation
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Autoren
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Sabit Delic
- Regensburg University Hospital, Department of Neuropathology, Regensburg, Germany
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Nadine Lottmann
- Regensburg University Hospital, Department of Neuropathology, Regensburg, Germany
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Franziska Liesenberg
- Heinrich-Heine-University, Department of Neuropathology, Düsseldorf, Germany
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Marietta Wolter
- Heinrich-Heine-University, Department of Neuropathology, Düsseldorf, Germany
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Silke Götze
- Max Planck Institute of Molecular Physiology, Department of Structural Biology, Dortmund, Germany
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Marc Zapatka
- German Cancer Research Center (DKFZ), Division of Molecular Genetics, Heidelberg, Germany
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Guido Reifenberger
- Heinrich-Heine-University, Department of Neuropathology, Düsseldorf, Germany
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Markus J. Riemenschneider
- Regensburg University Hospital, Department of Neuropathology, Regensburg, Germany
| Veröffentlicht: | 11. September 2012 |
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Gliederung
Text
Diffusely infiltrative growth of human astrocytic gliomas is one of the major obstacles to successful tumor therapy. Thorough insights into the molecules and pathways signaling glioma cell invasion thus appear of major relevance for the development of targeted and individualized therapies. By miRNA expression profiling of microdissected human tumor biopsy specimens we identified miR-328 as one of the main miRNAs upregulated in invading glioblastoma cells in vivo. Employing miRNA mimics and inhibitors in vitro we corroborated the invasion-promoting role of miR-328 in A172 and TP365MG glioma cells. In subsequent 3`UTR luciferase assays we pinpointed SFRP1, an inhibitor of WNT signaling, as a miR-328 target. SFRP1 is a gene of prognostic relevance in gliomas and its downregulation is associated with significantly lower overall patient survival in both the Rembrandt and TCGA datasets. In vitro manipulation of miR-328 expression in glioma cells efficiently affected both SFRP1 protein expression levels and WNT signaling pathway activity as assessed by TCF/LEF reporter assays. Interestingly, molecular analysis in a larger panel of gliomas suggests that miR-328 expression accounts for the downregulation of SFRP1 preferentially in lower-grade astrocytic gliomas and is inversely related to SFRP1 promoter hypermethylation. Taken together, we report on a novel molecular miR-328-dependent mechanism that via SFRP1 inhibition and WNT activation contributes to the infiltrative glioma phenotype already at early stages of glioma progression, with unfavorable prognostic implications for the final outcome of the disease.
