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

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Abstract

The nuclear factor NF-κB and oncogenic Ras can alter proliferation in epidermis, the most common site of human cancer1,2. These proteins are implicated in epidermal squamous cell carcinoma in mice3,4,5, however, the potential effects of altering their function are uncertain. Whereas inhibition of NF-κB enhances apoptosis in certain tumours6, blockade of NF-κB predisposes murine skin to squamous cell carcinoma5,7. Because therapeutics inhibiting Ras and NF-κB pathways are being developed to treat human cancer8,9, it is essential to assess the effects of altering these regulators. The medical relevance of murine studies is limited, however, by differences between mouse and human skin, and by the greater ease of transforming murine cells. Here we show that in normal human epidermal cells both NF-κB and oncogenic Ras trigger cell-cycle arrest. Growth arrest triggered by oncogenic Ras can be bypassed by IκBα-mediated blockade of NF-κB, generating malignant human epidermal tissue resembling squamous cell carcinoma. Human cell tumorigenesis is dependent on laminin 5 and α6β4 integrin. Thus, IκBα circumvents restraints on growth promotion induced by oncogenic Ras and can act with Ras to induce invasive human tissue neoplasia.

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Figure 1: Ras and IκBα human epidermal neoplasia.
Figure 2: IκBα rescues keratinocyte growth arrest triggered by oncogenic Ras.
Figure 3: Effects of Ras, p65 and IκBα on CDK expression, proliferation, telomere length and apoptosis.
Figure 4: Ras–IκBα tumorigenesis.

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Acknowledgements

We thank H. Gladstone, M. Cooper, E. Fincher and Z. Cooper for SCC specimens; A. Anguiano for assistance with SKY-FISH; and N. Griffiths and P. Bernstein for administrative support. This work was supported by the US Veterans Affairs Office of Research and Development and by grants from the NIH to P.A.K. We acknowledge the generous support of the Epidermolysis Bullosa Research Foundation and the Nu Skin Center for Research at Stanford.

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Author notes

  1. Maya Dajee and Mirella Lazarov: These authors contributed equally to this work

  2. Paul A. Khavari: Correspondence and requests for materials should be addressed to P.A.K.

Authors and Affiliations

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

    Maya Dajee, Mirella Lazarov, Jennifer Y. Zhang, Ti Cai, Cheryl L. Green, Alan J. Russell, M. Peter Marinkovich, Shiying Tao, Qun Lin, Yoshiaki Kubo & Paul A. Khavari

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  1. Maya Dajee
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  2. Mirella Lazarov
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  3. Jennifer Y. Zhang
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  7. M. Peter Marinkovich
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  10. Yoshiaki Kubo
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  11. Paul A. Khavari
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Correspondence to Paul A. Khavari.

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Dajee, M., Lazarov, M., Zhang, J. et al. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643 (2003). https://doi.org/10.1038/nature01283

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