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Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells

Sandrine Valsesia-Wittmann1, Maud Magdeleine, Sébastien Dupasquier

  • 1INSERM U590, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon F-69008 France.

Cancer Cell
|December 21, 2004
PubMed

Insights

N-Myc amplification in neuroblastoma drives cancer growth. Overexpressed Twist inhibits the ARF/p53 pathway, cooperating with N-Myc to promote cell transformation and malignant outgrowth, bypassing apoptosis safeguards.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • N-Myc oncogene amplification is common in neuroblastoma, correlating with poor prognosis.
  • N-Myc activation promotes cell proliferation and apoptosis, but p53 mutations are rare in neuroblastoma.
  • This suggests an alternative mechanism circumvents p53-mediated apoptosis in N-Myc-driven neuroblastoma.

Purpose of the Study:

  • To investigate cooperating genetic events in N-Myc-amplified neuroblastomas.
  • To identify factors that circumvent the ARF/p53 pathway in this cancer.
  • To understand the oncogenic cooperation between N-Myc and other regulatory genes.

Main Methods:

  • Pangenomic cDNA microarray analysis was performed on neuroblastoma samples.
  • Expression levels of human Twist (H-Twist) were assessed in relation to N-Myc amplification.
  • The impact of H-Twist overexpression on the ARF/p53 pathway was investigated.

Main Results:

  • Human Twist (H-Twist) is consistently overexpressed in N-Myc-amplified neuroblastomas.
  • H-Twist overexpression inhibits the ARF/p53 pathway.
  • This inhibition bypasses the apoptotic response typically triggered by Myc activation.

Conclusions:

  • Overexpression of Twist cooperates with N-Myc in neuroblastoma pathogenesis.
  • The Twist/ARF/p53 axis is a critical pathway in N-Myc-driven oncogenesis.
  • This oncogenic cooperation between N-Myc and Twist leads to cell transformation and tumor growth.

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