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.