? Exposure to ultraviolet (UV) light is the major etiologic event for cutaneous squamous and basal cell carcinomas in humans and is also a risk factor for melanoma. The molecular pathways responsible for UV irradiation-induced tumors involve genetic and epigenetic events. While initiation events are generally irreversible, at least some of the processes associated with promotion and progression can be effectively inhibited or reversed, leading to a reduction in tumor incidence and severity. The goal of the proposed study is to determine the relative importance of each of three processes and pathways, i.e., proliferation, survival and/or inflammation/angiogenesis on the development of squamous cell carcinoma. We propose to identify the key signaling molecules and pathways that control each of these processes and determine which is more important, through use of genetic manipulation of the UV-sensitive SKH-1 hairless mouse. Available evidence indicates that cell cycle processes and cell survival can be regulated by the NFkB pathway, the Akt pathway, the stat3 pathway, and the Rb-E2F1 pathway while inflammation is regulated by the NFkB pathway, thus these pathways may control critical processes in cancer development. The goal of this study will be approached through answering the following questions: 1) How important is cell survival to skin cancer? 2) How important is inflammation and angiogenesis to skin cancer? 3) How important are alterations in the expression of cell cycle genes to skin cancer? These questions will be addressed through the use of existing mouse models, or where needed, through the development of new models. These models will also be made available to other investigators for their studies of pathways and UV carcinogenesis.
The specific aims of this comprehensive Project are: (1) Transfer existing genetic modifications relating to proliferation, apoptosis and inflammation/angiogenesis onto the SKH-1 hairless background, the most useful strain for UV carcinogenesis studies. This includes transgenes for stat3, Akt, VEGF and Cre, and deficiencies (knockout) for cyclin D1, cdk4, E2F1, Rb, stat3, Bcl-xL, VEGF and IL-1R1. This will be done using the speed congenic approach. (2) Create needed new SKH-1 hairless models using inducible systems. Targeted inducible transgenics (Bcl2, Bcl-xL, FasL, NFkB(p50), IL-la and inducible conditional transgenics (Akt, FasL, Bcl2 and NFkB(p50), will made using gene switch approaches. (3) Where indicated, models with multiple genetic alterations will be developed. ? ? ?
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