Micro-RNA (miR) 199b-5p targets Hes1 in medulloblastoma, one of the downstream effectors of both the canonical Notch and noncanonical Sonic Hedgehog pathways. In medulloblastoma patients, expression of miR-199b-5p is significantly decreased in metastatic cases, thus suggesting a downregulation mechanism. We studied this mechanism, which is mediated mostly by Hes1 and epigenetic promoter modifications. The miR-199b-5p promoter region was characterized, which identified a Hes1 binding site, thus demonstrating a negative feedback loop of regulation. MiR-199b-5p was shown to be downregulated in several medulloblastoma cell lines and in tumors by epigenetic methylation of a cytosine-phosphate-guanine island upstream of the miR-199b-5p promoter. Furthermore, the cluster of differention (CD) carbohydrate antigen CD15, a marker of medulloblastoma tumor-propagating cells, is an additional direct target of miR-199b-5p. Most importantly, regulation of miR-199b-5p expression in these CD15+/CD133+ tumor-propagating cells was influenced by only Hes1 expression and not by any epigenetic mechanism of regulation. Moreover, reverse-phase protein array analysis showed both the Akt and extracellular-signal-regulated kinase pathways as being mainly negatively regulated by miR-199b-5p expression in several medulloblastoma cell lines and in primary cell cultures. We present here the finely tuned regulation of miR-199b-5p in medulloblastoma, underlining its crucial role by its additional targeting of CD15.

The micro-RNA 199b-5p regulatory circuit involves Hes1, CD15, and epigenetic modifications in medulloblastoma / Andolfo, Immacolata; Liguori, Lucia; De Antonellis, Pasqualino; Cusanelli, Emilio; Marinaro, Federica; Pistollato, Francesca; Garzia, Livia; De Vita, Gennaro; Petrosino, Giuseppe; Accordi, Benedetta; Migliorati, Roberta; Basso, Giuseppe; Iolascon, Achille; Cinalli, Giuseppe; Zollo, Massimo. - In: NEURO-ONCOLOGY. - ISSN 1522-8517. - 14:5(2012), pp. 596-612. [10.1093/neuonc/nos002]

The micro-RNA 199b-5p regulatory circuit involves Hes1, CD15, and epigenetic modifications in medulloblastoma

Cusanelli, Emilio;
2012-01-01

Abstract

Micro-RNA (miR) 199b-5p targets Hes1 in medulloblastoma, one of the downstream effectors of both the canonical Notch and noncanonical Sonic Hedgehog pathways. In medulloblastoma patients, expression of miR-199b-5p is significantly decreased in metastatic cases, thus suggesting a downregulation mechanism. We studied this mechanism, which is mediated mostly by Hes1 and epigenetic promoter modifications. The miR-199b-5p promoter region was characterized, which identified a Hes1 binding site, thus demonstrating a negative feedback loop of regulation. MiR-199b-5p was shown to be downregulated in several medulloblastoma cell lines and in tumors by epigenetic methylation of a cytosine-phosphate-guanine island upstream of the miR-199b-5p promoter. Furthermore, the cluster of differention (CD) carbohydrate antigen CD15, a marker of medulloblastoma tumor-propagating cells, is an additional direct target of miR-199b-5p. Most importantly, regulation of miR-199b-5p expression in these CD15+/CD133+ tumor-propagating cells was influenced by only Hes1 expression and not by any epigenetic mechanism of regulation. Moreover, reverse-phase protein array analysis showed both the Akt and extracellular-signal-regulated kinase pathways as being mainly negatively regulated by miR-199b-5p expression in several medulloblastoma cell lines and in primary cell cultures. We present here the finely tuned regulation of miR-199b-5p in medulloblastoma, underlining its crucial role by its additional targeting of CD15.
2012
5
Andolfo, Immacolata; Liguori, Lucia; De Antonellis, Pasqualino; Cusanelli, Emilio; Marinaro, Federica; Pistollato, Francesca; Garzia, Livia; De Vita, Gennaro; Petrosino, Giuseppe; Accordi, Benedetta; Migliorati, Roberta; Basso, Giuseppe; Iolascon, Achille; Cinalli, Giuseppe; Zollo, Massimo
The micro-RNA 199b-5p regulatory circuit involves Hes1, CD15, and epigenetic modifications in medulloblastoma / Andolfo, Immacolata; Liguori, Lucia; De Antonellis, Pasqualino; Cusanelli, Emilio; Marinaro, Federica; Pistollato, Francesca; Garzia, Livia; De Vita, Gennaro; Petrosino, Giuseppe; Accordi, Benedetta; Migliorati, Roberta; Basso, Giuseppe; Iolascon, Achille; Cinalli, Giuseppe; Zollo, Massimo. - In: NEURO-ONCOLOGY. - ISSN 1522-8517. - 14:5(2012), pp. 596-612. [10.1093/neuonc/nos002]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/154267
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