Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis

Maurizio Martini, Tonia Cenci, Giorgio Quintino D'Alessandris, Valeriana Cesarini, Alessandra Cocomazzi, Lucia Ricci-Vitiani, Ruggero De Maria, Roberto Pallini, Luigi Maria Larocca

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Inhibitors of DNA binding/differentiation (Id1 to Id4) are a family of helix-loop-helix transcription factors, which are highly expressed during embryogenesis and at lower levels in mature tissues. Id4 plays an important role in neuronal stem cell differentiation, and its deregulation has been implicated in glial neoplasia. METHODS: The methylation status of Id4 was analyzed by methylation-specific polymerase chain reaction (PCR) in 62 glioblastoma (GBM) cases and in 20 normal brain tissues. Methylation status of Id4 was confirmed by sequencing after subcloning and messenger RNA (mRNA) and protein expression. We also evaluated the mRNA expression of MGP (matrix GLA protein), TGF-β1 (transforming growth factor beta 1), and VEGF (vascular endothelial growth factor) by real-time PCR analysis. Clinical and histological assessment of tumor angiogenesis was performed by evaluating the relative enhancing tumor ratio on magnetic resonance imaging and microvessel density on von Willebrand factor-stained sections, respectively. RESULTS: The promoter of Id4 was methylated in 23 of 62 (37%) GBMs. In methylated GBMs, Id4 mRNA was significantly reduced, compared with unmethylated GBMs (P =.0002). A significant reduction of protein expression was detected in all hypermethylated cases. GBMs with methylated Id4 showed a significant reduction of MGP, TGF-β1, and VEGF mRNA expression and had significantly lower relative enhancing tumor ratio (P =.0108) and microvessel density (P =.0241) values with respect to unmethylated GBMs. Finally, Id4 methylation was significantly associated with a favorable clinical outcome (P =.0006). CONCLUSIONS: These data suggest that methylation of Id4 may be involved in the pathogenesis of GBM and in the resistance of this neoplasm to conventional treatment throughout MGP-mediated neoangiogenesis. Cancer 2013.

Original languageEnglish
Pages (from-to)1004-1012
Number of pages9
JournalCancer
Volume119
Issue number5
DOIs
Publication statusPublished - Mar 1 2013

Fingerprint

Glioblastoma
Epigenomics
Methylation
Neoplasms
Messenger RNA
Microvessels
Transforming Growth Factor beta
Vascular Endothelial Growth Factor A
von Willebrand Factor
Neuroglia
Embryonic Development
Real-Time Polymerase Chain Reaction
Cell Differentiation
Proteins
Transcription Factors
Stem Cells
Magnetic Resonance Imaging
Polymerase Chain Reaction
DNA
Brain

Keywords

  • adjuvant radiotherapy
  • glioblastoma
  • Id4
  • temozolomide.
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Martini, M., Cenci, T., D'Alessandris, G. Q., Cesarini, V., Cocomazzi, A., Ricci-Vitiani, L., ... Larocca, L. M. (2013). Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis. Cancer, 119(5), 1004-1012. https://doi.org/10.1002/cncr.27821

Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis. / Martini, Maurizio; Cenci, Tonia; D'Alessandris, Giorgio Quintino; Cesarini, Valeriana; Cocomazzi, Alessandra; Ricci-Vitiani, Lucia; De Maria, Ruggero; Pallini, Roberto; Larocca, Luigi Maria.

In: Cancer, Vol. 119, No. 5, 01.03.2013, p. 1004-1012.

Research output: Contribution to journalArticle

Martini, M, Cenci, T, D'Alessandris, GQ, Cesarini, V, Cocomazzi, A, Ricci-Vitiani, L, De Maria, R, Pallini, R & Larocca, LM 2013, 'Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis', Cancer, vol. 119, no. 5, pp. 1004-1012. https://doi.org/10.1002/cncr.27821
Martini M, Cenci T, D'Alessandris GQ, Cesarini V, Cocomazzi A, Ricci-Vitiani L et al. Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis. Cancer. 2013 Mar 1;119(5):1004-1012. https://doi.org/10.1002/cncr.27821
Martini, Maurizio ; Cenci, Tonia ; D'Alessandris, Giorgio Quintino ; Cesarini, Valeriana ; Cocomazzi, Alessandra ; Ricci-Vitiani, Lucia ; De Maria, Ruggero ; Pallini, Roberto ; Larocca, Luigi Maria. / Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis. In: Cancer. 2013 ; Vol. 119, No. 5. pp. 1004-1012.
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abstract = "BACKGROUND: Inhibitors of DNA binding/differentiation (Id1 to Id4) are a family of helix-loop-helix transcription factors, which are highly expressed during embryogenesis and at lower levels in mature tissues. Id4 plays an important role in neuronal stem cell differentiation, and its deregulation has been implicated in glial neoplasia. METHODS: The methylation status of Id4 was analyzed by methylation-specific polymerase chain reaction (PCR) in 62 glioblastoma (GBM) cases and in 20 normal brain tissues. Methylation status of Id4 was confirmed by sequencing after subcloning and messenger RNA (mRNA) and protein expression. We also evaluated the mRNA expression of MGP (matrix GLA protein), TGF-β1 (transforming growth factor beta 1), and VEGF (vascular endothelial growth factor) by real-time PCR analysis. Clinical and histological assessment of tumor angiogenesis was performed by evaluating the relative enhancing tumor ratio on magnetic resonance imaging and microvessel density on von Willebrand factor-stained sections, respectively. RESULTS: The promoter of Id4 was methylated in 23 of 62 (37{\%}) GBMs. In methylated GBMs, Id4 mRNA was significantly reduced, compared with unmethylated GBMs (P =.0002). A significant reduction of protein expression was detected in all hypermethylated cases. GBMs with methylated Id4 showed a significant reduction of MGP, TGF-β1, and VEGF mRNA expression and had significantly lower relative enhancing tumor ratio (P =.0108) and microvessel density (P =.0241) values with respect to unmethylated GBMs. Finally, Id4 methylation was significantly associated with a favorable clinical outcome (P =.0006). CONCLUSIONS: These data suggest that methylation of Id4 may be involved in the pathogenesis of GBM and in the resistance of this neoplasm to conventional treatment throughout MGP-mediated neoangiogenesis. Cancer 2013.",
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AU - Cenci, Tonia

AU - D'Alessandris, Giorgio Quintino

AU - Cesarini, Valeriana

AU - Cocomazzi, Alessandra

AU - Ricci-Vitiani, Lucia

AU - De Maria, Ruggero

AU - Pallini, Roberto

AU - Larocca, Luigi Maria

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N2 - BACKGROUND: Inhibitors of DNA binding/differentiation (Id1 to Id4) are a family of helix-loop-helix transcription factors, which are highly expressed during embryogenesis and at lower levels in mature tissues. Id4 plays an important role in neuronal stem cell differentiation, and its deregulation has been implicated in glial neoplasia. METHODS: The methylation status of Id4 was analyzed by methylation-specific polymerase chain reaction (PCR) in 62 glioblastoma (GBM) cases and in 20 normal brain tissues. Methylation status of Id4 was confirmed by sequencing after subcloning and messenger RNA (mRNA) and protein expression. We also evaluated the mRNA expression of MGP (matrix GLA protein), TGF-β1 (transforming growth factor beta 1), and VEGF (vascular endothelial growth factor) by real-time PCR analysis. Clinical and histological assessment of tumor angiogenesis was performed by evaluating the relative enhancing tumor ratio on magnetic resonance imaging and microvessel density on von Willebrand factor-stained sections, respectively. RESULTS: The promoter of Id4 was methylated in 23 of 62 (37%) GBMs. In methylated GBMs, Id4 mRNA was significantly reduced, compared with unmethylated GBMs (P =.0002). A significant reduction of protein expression was detected in all hypermethylated cases. GBMs with methylated Id4 showed a significant reduction of MGP, TGF-β1, and VEGF mRNA expression and had significantly lower relative enhancing tumor ratio (P =.0108) and microvessel density (P =.0241) values with respect to unmethylated GBMs. Finally, Id4 methylation was significantly associated with a favorable clinical outcome (P =.0006). CONCLUSIONS: These data suggest that methylation of Id4 may be involved in the pathogenesis of GBM and in the resistance of this neoplasm to conventional treatment throughout MGP-mediated neoangiogenesis. Cancer 2013.

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