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Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers

Hung N Tran1, Hardeep P Singh2,3,4, Wenxuan Guo2,3,5

  • 1Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA, United States.

Frontiers in Oncology
|January 11, 2021
PubMed

Insights

MDM2 protein specifically promotes MYCN expression in several cancers, forming an oncogenic feedback loop. This collaboration is essential for tumor growth and originates in normal neuronal tissue.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • MYC family oncoproteins (MYC, MYCN, MYCL) are frequently deregulated in various cancers.
  • MDM2 (mouse double minute 2 homolog) oncoprotein promotes MYCN translation and proliferation independently of p53 in retinoblastoma and neuroblastoma.
  • The roles of MDM2 in regulating other MYC family members and its involvement in tumorigenesis remain unclear.

Purpose of the Study:

  • To investigate if MDM2 regulates other MYC family members beyond MYCN.
  • To determine if MYC family proteins upregulate MDM2 expression in various cancers and during tumorigenesis.
  • To elucidate the specific collaboration between MDM2 and MYC/MYCN oncoproteins.

Main Methods:

  • Analysis of MDM2 and MYCN expression in retinoblastoma, neuroblastoma, small cell lung cancer, and medulloblastoma cell lines.
  • Overexpression studies of MYC and MYCN in a cultured retinoblastoma genesis model.
  • Assessment of MDM2 dependency for proliferation in induced tumor masses.

Main Results:

  • Intrinsically high MDM2 expression is crucial for high-level MYCN expression, but not MYC, across multiple cancer types.
  • Ectopic MYC and MYCN overexpression induce high-level MDM2 expression.
  • Induced MYC/MYCN overexpression leads to rapid proliferation and MDM2-dependent tumor formation in a retinoblastoma genesis model.

Conclusions:

  • MDM2 and MYCN oncoproteins exhibit a highly specific collaborative relationship.
  • An oncogenic positive feedback circuit between MDM2 and MYCN originates within normal neuronal tissue.
  • This specific interaction is a key driver in certain malignancies, particularly those involving MYCN.
Keywords:
MDM2MYCMYCNmedulloblastomaneuroblastomaretinoblastomasmall cell lung cancer

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