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Malignant Transformation of Immortalized HaCaT Keratinocytes through Deregulated Nuclear Factor B Signaling

Departments of ¹ Radiation Oncology, ² Dermatology and Cutaneous Biology, and ³ Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Ulrich Rodeck, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 South 10th Street, BLSB 409, Philadelphia, PA 19107. Phone: 215-503-5622; Fax: 215-503-5622; E-mail: ulrich.rodeck{at}mail.tju.edu and Adam P. Dicker, Department of Radiation Oncology, Thomas Jefferson University, 111 South 11th Street, Philadelphia, PA 19107. Phone: 215-955-6527; Fax: 215-955-0412; E-mail: adam.dicker{at}mail.tju.edu.

Previous studies addressing functional aspects of nuclear factor B (NF-B) activation in normal and transformed keratinocytes revealed complex and seemingly contradictory roles of this transcription factor in this cell type. In normal skin, NF-B signaling seems to inhibit squamous cell carcinoma development whereas, in squamous cell carcinoma themselves, deregulated NF-B expression and/or signaling is frequently observed. To further investigate this paradox, we focused on NF-B activation as it relates to the transformed phenotype of immortalized but nontumorigenic human keratinocytes (HaCaT cells). We observed that NF-B activity contributed to survival and growth of cultured HaCaT keratinocytes as shown by use of pharmacologic NF-B inhibitors, RNA interference, and inducible overexpression of a dominant interfering IB construct. NF-B activation was largely provided through interaction with extracellular matrix components because preventing cell attachment by forced suspension culture markedly reduced NFB signaling associated with cell death (anoikis); conversely, anoikis was partially reversed by NF-B activation induced either by tumor necrosis factor- treatment or by overexpressing the NF-B p65 subunit in HaCaT cells. Furthermore, overexpression of NF-Bp65 in HaCaT cells induced colony formation in soft agar and tumorigenicity in nude mice. In summary, as opposed to normal keratinocytes, immortalized HaCaT keratinocytes provide a cellular context in which deregulated NF-B signaling supports multiple malignant traits in vitro and in vivo. (Cancer Res 2006; 66(10): 5209-15)

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