1. Veterans Affairs Palo Alto Healthcare System and the Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA
2. These authors contributed equally to this work

Correspondence to: Paul A. Khavari Correspondence and requests for materials should be addressed to P.A.K. (e-mail: Email: khavari@CMGM.stanford.edu).

Abstract

The nuclear factor NF-B and oncogenic Ras can alter proliferation in epidermis, the most common site of human cancer^{1, 2}. These proteins are implicated in epidermal squamous cell carcinoma in mice^{3, 4, 5}, however, the potential effects of altering their function are uncertain. Whereas inhibition of NF-B enhances apoptosis in certain tumours⁶, blockade of NF-B predisposes murine skin to squamous cell carcinoma^{5, 7}. Because therapeutics inhibiting Ras and NF-B pathways are being developed to treat human cancer^{8, 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-B and oncogenic Ras trigger cell-cycle arrest. Growth arrest triggered by oncogenic Ras can be bypassed by IB-mediated blockade of NF-B, generating malignant human epidermal tissue resembling squamous cell carcinoma. Human cell tumorigenesis is dependent on laminin 5 and 64 integrin. Thus, IB circumvents restraints on growth promotion induced by oncogenic Ras and can act with Ras to induce invasive human tissue neoplasia.