The majority of all human cancers originate in the skin and these malignancies exceed all others combined. Approximately one million new non-melanoma skin cancers (NSMC) including basal cell carcinomas (BCCs) and squamous cell carcinoma (SCCs) are diagnosed in the United States annually. Solar UVB radiation is the major known cause of NMSCs. The carcinogenic effects of UVB are the result of direct structural changes in DNA such as cyclobutane pyrimidine dimers and 6-4 photoproducts leading to mutations in the form of C to T and CC to TT transitions (UVB signature mutations). NMSCs harbor different and distinct mutations (p53 in the case of SCCs and ptc & p53 in the case of BCCs), which culminate in the growth of these neoplasms. Insight into the genetic basis of sporadic skin cancers has come from the identification of special genes or genetic loci that relate to inherited skin tumor syndromes. Although UVB is directly involved in the induction of both types of NMSCs, it is intriguing that an identical carcinogen yields unique types of tumors. Among known human cyclin genes, only cyclin D1 has been convincingly implicated in oncogenesis. Cyclin D1 is amplified or overexpressed in a variety of human epithelial cancers including human NMSCs. In addition, targeted overexpression of cyclin D1 in skin enhances murine chemical carcinogenesis. We have previously shown that progressive accumulation of cyclin D1 occurs during UVB induction of SCCs in SKH-1 hairless and BCCs in ptc+/- knockout mice. Taken together, it is likely that cyclin D 1 overexpression in cells carrying p53 mutations is critical for induction of SCCs whereas its overexpression in cells carrying ptc mutations is important for BCCs. One of the mechanisms by which cyclin D1 is overexpressed involves activation of p38 MAP kinase. UVB induces p38 MAP kinase and its downstream pathway in skin. In this proposal we will test the hypothesis that alterations in cell signaling (p38 MAP kinase) following skin exposure to UVB either have unique effects for each tumor-type and/or converge on shared downstream gene (cyclin D1) expression pathways that coordinate the consequences of specific mutations (p53 and ptch) that contribute to the molecular pathogenesis of UVB-induced NMSCs, both SCCs and BCCs. We will determine UVB-induced shared signaling pathways leading to overexpression of cyclin D1 via p38 MAP kinase in p53+/-, p53-/- and ptc+/- mice; define the relationship between cyclin D1 overexpression and p53 loss in the pathogenesis of NMSCs; define the mechanism whereby cyclin D1 accumulates during NMSCs tumorigenesis and assess the effect of genetically overexpressed cyclin D1 on NMSCs development in p53-/- and ptc+/- mice. Our animal models offer an innovative approach for assessing the molecular pathogenesis of UVB-induced SCCs and BCCs and could help create novel approaches to the prevention/treatment of human NMSCs.
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