| dc.description.abstract |
ΔNp63a, a proto-oncogene, has been shown to be upregulated in non-melanoma skin cancers while simultaneously inducing the expression of genes involved in inhibition of invasion. Vitamin D receptor (VDR), a target of ΔNp63a, and receptor of 1a25-(OH)2D3, vitamin D (VD3) inhibits cell invasion. The objective of this study was to determine if dietary VD3 modulates the expression of ΔNp63a and/or VDR in ultraviolet radiation induced tumors in SKH1 mice. Effects of chronic ultraviolet exposure and/or increasing amounts of dietary VD3 on ΔNp63a and VDR expression was measured by immunofluorescence in formalin fixed, paraffin embedded tumor and normal skin samples from SKH1 mice. Mice were fed normal chow or increasing amounts of VD3 enriched chow in the presence or absence of UVB exposure, thrice weekly for 25 weeks. Statistical analysis of mean fluorescent intensities for ΔNp63a and VDR were used to correlate ΔNp63a and VDR expression with diet and tumor severity. Chronic UVB exposure in SKH1 mice increased p63 expression while decreasing VDR expression in normal skin, independent of dietary VD3. Low-grade papillomas in mice exposed to UV and fed normal chow, displayed increased levels of ΔNp63a while more invasive tumors showed reduced expression of both ΔNp63a and VDR. Interestingly, mice fed high VD3 chow did not display elevated levels of ΔNp63a in locally invasive tumors but also had higher tumor burdens and size, suggesting that supra- physiologic levels of VD3 may impair tumor suppression by inhibiting the anti-invasive ΔNp63a during early tumor formation. This study provides mechanistic insight into how the traditionally viewed “apoptotic” VD3 can affect skin cancer development and progression. The dose dependent effects of VD3 on ΔNp63a and VDR in chronically UVB exposed skin highlights the need for better understanding of how diet can affect tumor formation and/or progression. Clarifying the roles of ΔNp63a, VDR/VD3 in the mechanism and progression of non-melanoma skin cancer could lead to better methods of cancer prevention. |
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