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NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia

Maya Dajee1, Mirella Lazarov, Jennifer Y Zhang

  • 1Veterans Affairs Palo Alto Healthcare System and the Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.

Nature
|February 7, 2003
PubMed

Insights

Nuclear factor kappa B (NF-kappaB) and oncogenic Ras normally arrest cell-cycle in human epidermal cells. Blocking NF-kappaB with oncogenic Ras can lead to squamous cell carcinoma.

Area of Science:

  • Oncology
  • Cell Biology
  • Dermatology

Background:

  • The nuclear factor NF-kappaB and oncogenic Ras regulate cell proliferation in the epidermis, a common site for human cancers.
  • While implicated in murine squamous cell carcinoma, their precise roles in human epidermal cells remain unclear.
  • Therapeutics targeting Ras and NF-kappaB pathways are under development for human cancer treatment.

Purpose of the Study:

  • To investigate the effects of altering NF-kappaB and oncogenic Ras function in normal human epidermal cells.
  • To determine the mechanisms by which these factors influence cell-cycle arrest and tumorigenesis.
  • To assess the potential for NF-kappaB blockade to promote Ras-induced malignant transformation.

Main Methods:

  • Utilized normal human epidermal cells.
  • Investigated the impact of NF-kappaB and oncogenic Ras on cell-cycle arrest.
  • Examined the role of IkappaBalpha in modulating Ras-induced growth arrest.
  • Assessed the dependence of human cell tumorigenesis on laminin 5 and alpha6beta4 integrin.

Main Results:

  • Both NF-kappaB and oncogenic Ras were found to trigger cell-cycle arrest in normal human epidermal cells.
  • Oncogenic Ras-induced growth arrest could be overcome by IkappaBalpha-mediated NF-kappaB blockade.
  • This blockade, in conjunction with oncogenic Ras, generated malignant human epidermal tissue resembling squamous cell carcinoma.
  • Human cell tumorigenesis in this context was dependent on laminin 5 and alpha6beta4 integrin.

Conclusions:

  • NF-kappaB and oncogenic Ras act as crucial regulators of cell-cycle control in human epidermis.
  • IkappaBalpha can circumvent growth-inhibitory signals from oncogenic Ras.
  • Combined action of Ras and NF-kappaB blockade can induce invasive human neoplasia, highlighting potential therapeutic vulnerabilities.

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