Oral squamous cell carcinoma (SCC) is the sixth most frequent cancer worldwide; nearly 380,000 cases were diagnosed in 1980. SCCs are the most frequent malignancy of the oral cavity with an estimates 44,000 new cases and 12,000 deaths reported in the United States in 1991. Early detection and diagnosis has led to increased survival, but the overall 5 year rate is still among the lowest of the major cancers and has not changed in the past two decades. One of the primary diagnostic criteria distinguishing these neoplasms from normal oral mucosa is altered cell morphology in vivo and in vitro. The cytoplasmic cytoskeleton is one the primary determinants of cell shape in eukaryotes. The altered expression of the filamentous cytoskeletal proteins contributes in large part to the bizarre phenotype of oral SCCs. One of the major cytoskeletal components produced specifically by transformed oral epithelia is the keratin intermediate filament K19. Regulation of K19 expression is dramatically different in oral SCCs compared to normal oral mucosa. The vitamin A metabolite retinoic acid (RA) is a powerful mediator of K19 expression in normal and transformed oral epithelia, yet the precise mechanisms of this regulation are largely unknown. The effects of RA are mediated by both cytoplasmic (CRABP) and nuclear (RAR, RXR) proteins. Recent work has identified a novel K19 regulatory pathway in oral SCCs which points to an RA dependent, posttranscriptional, cytoplasmic mechanism for stabilizing K19 mRNA. Using the K19 gene as a model system, this proposal will examine RA mediated mechanisms of gene regulation in oral SCCs and how altered K19 expression contributes to the malignant phenotype. The effect of altered RAR and RXR expression on RA responsive gene expression will be determined. The effect of altered CRABP levels on K19 transcription and mRNA expression will also be examined. The RA dependent factor which stabilizes K19 mRNA will be characterized. These results will be extended to oral SCC lines in which the K19 gene is unresponsive to RA. Understanding how RA produces its dramatic effects on K19 gene expression in oral SCCs will provide important insights into the mechanisms of altered gene regulation underlying the pathogenesis of these tumors.
