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Suppression of Type I Interferon Signaling Proteins Is an Early Event in Squamous Skin Carcinogenesis¹

Departments of Clinical Cancer Prevention [J. L. C., E. W., X. Y., X. X., G. L. C., S. M. L.], Pathology [A. K. E-N.], Head and Neck Surgery [G. L. C.], and Thoracic/Head and Neck Medical Oncology [R. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Medicine and Pharmacology, Arizona Cancer Center, [D. S. A.] Tucson, Arizona 85724

Purpose: IFN-based therapy has been shown to be active in the treatmentof squamous cell carcinoma (SCC) of the skin, the most aggressive form of non-melanoma skin cancer. Based largely on this activity, we began programmatically examining the expression of IFN-stimulated gene factor 3 (ISGF-3) proteins (signal transducers and activators of transcription 1/ß, signal transducers and activators of transcription 2, and p48), which are important mediators of IFN- signaling, in skin premalignancy and SCC. Our previous preliminary studies suggested suppression of some or all of the ISGF-3 proteins in skin SCC.

Experimental Design: To determine the timing of the suppression of IFN- signaling proteins in squamous skin carcinogenesis, we have now compared ISGF-3 expression by immunohistochemical staining in biopsies of actinic keratosis, a form of skin premalignancy, and matched normal skin.

Results: We observed a significant decrease in expression of one or more ISGF-3 proteins in 76% of patients with actinic keratosis (19 of 25 patients). In addition, we found a suppression of one or more ISGF-3 proteins in 67% of skin SCC patients tested (12 of 18 patients), confirming our previous observations.

Conclusions: These data have led to the hypothesis that the suppressed expression of ISGF-3 proteins and consequent reduction in responsiveness to endogenous IFN likely are an early event in skin carcinogenesis.

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