Abstract
ΔNp63α, a proto-oncogene, is up-regulated in non-melanoma skin cancers and directly regulates the expression of both Vitamin D receptor (VDR) and phosphatase and tensin homologue deleted on chromosome ten (PTEN). Since ΔNp63α has been shown to inhibit cell invasion via regulation of VDR, we wanted to determine whether dietary Vitamin D3 protected against UVB induced tumor formation in SKH-1 mice, a model for squamous cell carcinoma development. We examined whether there was a correlation between dietary Vitamin D3 and ΔNp63α, VDR or PTEN expression in vivo in SKH-1 mice chronically exposed to UVB radiation and fed chow containing increasing concentrations of dietary Vitamin D3. Although we observed differential effects of the Vitamin D3 diet on ΔNp63α and VDR expression in chronically irradiated normal mouse skin as well as UVB induced tumors, Vitamin D3 had little effect on PTEN expression in vivo. While low-grade papillomas in mice exposed to UV and fed normal chow displayed increased levels of ΔNp63α, expression of both ΔNp63α and VDR was reduced in invasive tumors. Interestingly, in mice fed high Vitamin D3 chow, elevated levels of ΔNp63α were observed in both local and invasive tumors but not in normal skin suggesting that oral supplementation with Vitamin D3 may increase the proliferative potential of skin tumors by increasing ΔNp63α levels.
Highlights
Effects of dietary Vitamin D3 on epidermal structure To investigate the effect of increasing dietary Vitamin D3 on epidermal biology we first measured the skin thickness in SKH-1 hairless mice exposed to chronic ultraviolet B (UVB) irradiation
We have previously demonstrated that the ratio of DNp63a to PTEN is critical for mediating keratinocyte proliferation and that this ratio is significantly perturbed in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) [15]
To determine if perturbation of the balance between DNp63a and PTEN by dietary Vitamin D3 was contributing to the increase in tumor size and SCC frequency, we calculated the ratio of DNp63a to PTEN fluorescence intensity in normal skin and tumors from UVB irradiated mice fed each of the Vitamin D3 diets
Summary
1a,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been investigated as an adjuvant to anti-cancer therapies. 1 mouse model of squamous cell carcinoma [4], protective effects of dietary Vitamin D3 against the development of skin cancer has not been examined. This is an important study due to recent reports highlighting the frequency of Vitamin D3 deficiency, and its association with a myriad of disease states which has led to an increase in Vitamin D3 supplement intake by the general public [5]. We observed differential effects of Vitamin D3 diet on DNp63a and VDR but not PTEN expression in chronically irradiated, but otherwise normal skin and in UVB induced tumors
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