Overexpression of Hedgehog Signaling Is Associated with Epidermal Tumor Formation in Vitamin D Receptor–Null Mice

Abstract

The vitamin D receptor (VDR) ligand, 1,25(OH)2D3, reduces proliferation and enhances differentiation and thus has been investigated for a role in preventing or treating cancer. Mice deficient for the VDR display a hyperproliferative response in the hair follicle and epidermis and decreased epidermal differentiation. Unlike their wild type littermates, when treated with 7,12 dimethylbenzanthracene (DMBA) or UVB, they develop skin tumors, including some characteristic of over-expression of the hedgehog (Hh) pathway. Both the epidermis and utricles of the VDR null animals over-express elements of the Hh pathway [Sonic Hedgehog (Shh, 2.02 fold), Patched1 1.58 fold, Smoothened 3.54 fold, Gli1 1.17 fold, and Gli2 1.66 fold]. This over-expression occurs at an age (11 weeks) where epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA or UVB induced tumors in the VDR null mice also over-express elements of this pathway. Moreover, 1,25(OH)2D3 down-regulates the expression of some members of the Hh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)2D3. Our results suggest that increased expression of Shh in the keratinocytes of the VDR null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms.

A Humanized Mouse Model of Hereditary 1,25-Dihydroxyvitamin D–Resistant Rickets Without Alopecia

“…It is important to note that not all VDR actions in the skin are ligand independent, because it has been shown that the VDR is able to induce in a 1,25(OH) 2 D 3 -sensitive manner the expression of numerous genes in the epidermis that appear to play a role in keratinocyte differentiation and barrier function (51)(52)(53)(54). A similar likelihood exists in the ability of the VDR to control the development of tumors in the skin and perhaps elsewhere (55)(56)(57). Indeed, analogous to the phenotype of alopecia, although tumors develop in the skin in response to UV irradiation or to 7,12-dimethylbenzanthracene treatment in the absence of the VDR, genetic inactivation of Cyp27b1 and the accompanying loss of circulating 1,25(OH) 2 D 3 in these animals does not lead to an increase in tumor formation (56,57).…”

“…A similar likelihood exists in the ability of the VDR to control the development of tumors in the skin and perhaps elsewhere (55)(56)(57). Indeed, analogous to the phenotype of alopecia, although tumors develop in the skin in response to UV irradiation or to 7,12-dimethylbenzanthracene treatment in the absence of the VDR, genetic inactivation of Cyp27b1 and the accompanying loss of circulating 1,25(OH) 2 D 3 in these animals does not lead to an increase in tumor formation (56,57). Given this dual role of the VDR in both 1,25(OH) 2 D 3 -independent and -sensitive functions, the question arises as to how these two functionally distinct activities of the VDR may be coordinated.…”

CYP11A1 in skin: An alternative route to photoprotection by vitamin D compounds

“…As noted earlier, increased susceptibility to photocarcinogenesis has been observed in mice deprived of VDR [11], and conversely, this predisposition was not found in mice without the 1a-hydroxylase enzyme [12,13]. Ellison et al (2008) proposed that it is the 1,25D-independent action of the VDR, not the 1,25D ligand, which may be mediating the pathway for skin carcinogenesis protection [11].…”

“…In that study, cyclobutane pyrimidine dimer repair was found to be decreased in the VDR knockout mice exposed to UVR [11]. Recently, a study in CYP27B1 knockout mice, which are unable to produce 1a-hydroxylated metabolites, reported that after chronic exposure to UVR, skin tumor development was not different to wild-type mice [12,13]. These 1a-hydroxylase knockout mice showed no increased susceptibility to photocarcinogenesis.…”

A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells

“…Vitamin D3 (VD3) bound VDR is responsible for clearing cyclobutane pyrimidine dimers (CPDs) and pyrimidone photoproducts (6,4 PP) in mice that were exposed to UVB. 49 Moreover, topically applied VD3 protected skin from UV induced photodamage. 50 We first compared the sensitization achieved with VDR knockdown to that of Chk1 knockdown, a well known chemosensitization target that overrides the DNA damage checkpoint and promotes mitotic catastrophe.…”