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Action in Skin Squamous Cell Carcinoma Cells1
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
2 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, Box 236, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-0627; Fax: (713) 792-0628; E-mail: jclifford{at}mdanderson.org
We have demonstrated previously that suppression of some or all of the IFN-stimulated gene factor 3 (ISGF-3) proteins in skin squamous cell carcinomas is an early event in squamous skin carcinogenesis. This finding led to the hypothesis that suppressed expression of ISGF-3 proteins may lead to reduced IFN responsiveness, which in turn may contribute to skin malignancy by conferring a growth and/or survival advantage. To test this hypothesis, we have developed a skin cell-based model for inhibiting the IFN-
signaling pathway through the forced expression of a dominant negative-acting signal transducer and activator of transcription 2 (dnSTAT2) protein. Expression of dnSTAT2 suppressed cell growth inhibition with a pharmacologically achievable concentration (100 IU/ml) of IFN- in the IFN--sensitive skin squamous cell carcinoma cell line SRB12-p9. dnSTAT2 also suppressed the IFN--induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT2, which are early events following IFN- treatment, but did not suppress the IFN-
-induced phosphorylation of STAT1. Finally, the dnSTAT2 protein suppressed the up-regulation of several IFN--inducible genes that were identified in this system by cDNA microarray screening. We conclude that the cell growth-inhibitory effect of IFN- in skin cells requires an intact STAT2 protein and is therefore mediated by the ISGF-3 complex. These results support STAT2 as an important molecular target for skin cancer chemoprevention. Furthermore, we propose that these dnSTAT2-expressing cells provide a novel in vitro model for the study of type I IFN action in human skin cells.
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