Abstract
Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting the proliferation while promoting the differentiation of keratinocytes, the major cell in the epidermis from which NMSC are derived, is well known. However, recent findings that mice lacking the VDR are predisposed to skin cancer has brought to the fore the question of how the VDR is protective. In this review we will look first at the role of vitamin D signaling in regulating the proliferation and differentiation of keratinocytes. We will examine two pathways, β-catenin (CTNNB) and hedgehog (HH), that are regulated by vitamin D signaling and may contribute to the dysregulated proliferation and differentiation in the absence of VDR. We will then examine the failure of VDR deficient keratinocytes to repair DNA damaged by UVB. Finally we will examine the change in long non-coding RNA (LncRNA) expression in VDR null keratinocytes that in other cells is associated with malignant transformation, a potential newly appreciated mechanism by which vitamin D signaling is protective against NMSC.
Highlights
Skin cancer is by far the most common cancer afflicting humankind
For other types of tumors epidemiologic evidence linking adequate vitamin D levels from diet and/or sun exposure to cancer prevention, especially colon cancer prevention, is strong [2,3,4,5,6]. Such epidemiologic evidence is lacking for skin cancers [7,8,9], and some studies have even demonstrated a positive correlation between 25OHD levels and basal cell carcinomas (BCC) [10]
We have found that knockdown of vitamin D receptor (VDR) in keratinocytes reduces E-cadherin expression and formation of the CTNNB/E-cadherin membrane complex resulting in increased CTNNB transcriptional activity, whereas 1,25(OH)2D administration has the opposite effect [30]
Summary
Skin cancer is by far the most common cancer afflicting humankind. Over 1 million skin cancers occur annually in the United States, 80% of which are basal cell carcinomas (BCC), 16% squamous cell carcinomas (SCC), and 4% melanomas [1]. For other types of tumors epidemiologic evidence linking adequate vitamin D levels from diet and/or sun exposure to cancer prevention, especially colon cancer prevention, is strong [2,3,4,5,6] Such epidemiologic evidence is lacking for skin cancers [7,8,9], and some studies have even demonstrated a positive correlation between 25OHD levels (the marker of vitamin D status) and BCC [10]. When Zinser et al [15] treated VDR null mice orally with the carcinogen 7,12-dimethylbenzanthracene (DMBA), they observed that most the VDR null mice developed skin tumors, mostly papillomas, whereas none of the wildtype controls did These results have been confirmed by other groups including ourselves using topical administration of DMBA/phorbol esters [16] or UVB [17,18]. We will review new data from our laboratory that keratinocytes lacking VDR have altered expression of long non-coding RNAs (LncRNA) in a pattern associated with malignant transformation in other tissues [23]
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