NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma

Maria Carmela Speranza, Véronique Frattini, Federica Pisati, Dimos Kapetis, Paola Porrati, Marica Eoli, Serena Pellegatta, Gaetano Finocchiaro

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

miR-145 is an important repressor of pluripotency in embryonic stem cells and a tumor suppressor in different cancers. Here, we found that miR-145 is strongly down-regulated in glioblastoma (GB) specimens and corresponding glioblastoma-neurospheres (GB-NS, containing GB stem-like cells) compared to normal brain (NB) and to low-grade gliomas (LGG). We observed a direct correlation between miR-145 expression and the progression-free survival (PFS) in LGG patients and overall survival (OS) in GB patients. Using microarray analysis, we identified relevant differences in gene expression profiles between GB-NS over-expressing miR-145 (miRover-NS) and GB-NS Empty (Empty-NS). We focused our attention on HEF1/Cas-L/NEDD9, a scaffold protein involved in invasion in several types of cancer. We confirmed a significant down-regulation of NEDD9 in miRover-NS and we found a higher expression in GB and GB-NS compared to NB. Approximately 50% of LGG patients expressed higher levels of NEDD9 than NB, and the PFS of such patients was shorter than in patients expressing lower levels of NEDD9. We observed that intracranial injection of GB-NS over-expressing miR-145 delays significantly tumor development :deriving tumors showed a significant down-regulation of NEDD9. In addition, we demonstrated a significant inhibition of invasion in silencing experiments with GB-NS shNEDD9 (shNEDD9), and an up-regulation of miR-145 in shNEDD9, suggesting a double-negative feedback loop between miR-145 and NEDD9. Our results demonstrate the critical role of miR-145 and NEDD9 in regulating glioblastoma invasion and suggest a potential role of NEDD9 as a biomarker for glioma progression.

Original languageEnglish
Pages (from-to)723-734
Number of pages12
JournalOncotarget
Volume3
Issue number7
Publication statusPublished - Jul 2012

Fingerprint

Glioblastoma
Glioma
Neoplasms
Disease-Free Survival
Brain
Down-Regulation
Microarray Analysis
Embryonic Stem Cells
Transcriptome
Up-Regulation
Stem Cells
Biomarkers

Keywords

  • Glioblastoma
  • Glioma
  • Invasion
  • MiR-145
  • NEDD9
  • Progression

ASJC Scopus subject areas

  • Oncology

Cite this

Speranza, M. C., Frattini, V., Pisati, F., Kapetis, D., Porrati, P., Eoli, M., ... Finocchiaro, G. (2012). NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget, 3(7), 723-734.

NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. / Speranza, Maria Carmela; Frattini, Véronique; Pisati, Federica; Kapetis, Dimos; Porrati, Paola; Eoli, Marica; Pellegatta, Serena; Finocchiaro, Gaetano.

In: Oncotarget, Vol. 3, No. 7, 07.2012, p. 723-734.

Research output: Contribution to journalArticle

Speranza, MC, Frattini, V, Pisati, F, Kapetis, D, Porrati, P, Eoli, M, Pellegatta, S & Finocchiaro, G 2012, 'NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma', Oncotarget, vol. 3, no. 7, pp. 723-734.
Speranza MC, Frattini V, Pisati F, Kapetis D, Porrati P, Eoli M et al. NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget. 2012 Jul;3(7):723-734.
Speranza, Maria Carmela ; Frattini, Véronique ; Pisati, Federica ; Kapetis, Dimos ; Porrati, Paola ; Eoli, Marica ; Pellegatta, Serena ; Finocchiaro, Gaetano. / NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. In: Oncotarget. 2012 ; Vol. 3, No. 7. pp. 723-734.
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AU - Kapetis, Dimos

AU - Porrati, Paola

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AU - Pellegatta, Serena

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AB - miR-145 is an important repressor of pluripotency in embryonic stem cells and a tumor suppressor in different cancers. Here, we found that miR-145 is strongly down-regulated in glioblastoma (GB) specimens and corresponding glioblastoma-neurospheres (GB-NS, containing GB stem-like cells) compared to normal brain (NB) and to low-grade gliomas (LGG). We observed a direct correlation between miR-145 expression and the progression-free survival (PFS) in LGG patients and overall survival (OS) in GB patients. Using microarray analysis, we identified relevant differences in gene expression profiles between GB-NS over-expressing miR-145 (miRover-NS) and GB-NS Empty (Empty-NS). We focused our attention on HEF1/Cas-L/NEDD9, a scaffold protein involved in invasion in several types of cancer. We confirmed a significant down-regulation of NEDD9 in miRover-NS and we found a higher expression in GB and GB-NS compared to NB. Approximately 50% of LGG patients expressed higher levels of NEDD9 than NB, and the PFS of such patients was shorter than in patients expressing lower levels of NEDD9. We observed that intracranial injection of GB-NS over-expressing miR-145 delays significantly tumor development :deriving tumors showed a significant down-regulation of NEDD9. In addition, we demonstrated a significant inhibition of invasion in silencing experiments with GB-NS shNEDD9 (shNEDD9), and an up-regulation of miR-145 in shNEDD9, suggesting a double-negative feedback loop between miR-145 and NEDD9. Our results demonstrate the critical role of miR-145 and NEDD9 in regulating glioblastoma invasion and suggest a potential role of NEDD9 as a biomarker for glioma progression.

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