Page 206 - Vitamin D and Cancer

9 Molecular Biology of Vitamin D Metabolism and Skin Cancer 193

UVC Ultraviolet C
UVR UV radiation
VDIR VDR-interacting repressor
VDR Vitamin D receptor
VDRE Vitamin D response element

9.1 Introduction

Incidence and mortality rates of skin cancer in most developed countries have expe-
rienced a steady increase over the past 25 years [57]. In the past few decades, the
5 year survival has improved to over 90% in some developed countries including
the United States, Sweden and Australia [57], but survival rates in many nations
remain low [36]. Therefore, it is important to understand the cellular and molecular
events involved in skin cancer pathogenesis to provide new approaches to reduce
the incidence and mortality of skin cancer.
It is long known that ultraviolet B (UVB) (280–315 nm) irradiation is a major
cause of skin cancer. Cyclobutane pyrimidine dimers (CPDs) constitute the major
DNA photoproducts upon exposure to UVB light [140]. If not repaired, these can
become initiating mutations in skin cancer [140] or if the DNA damage is irrepa-
rable, the cell may undergo apoptosis [144]. Skin chronically exposed to UV radia-
tion (UVR) may also suffer irreversible suppression of cell-mediated immunity
promoting skin cancer outgrowth [45].
UVR is also essential in the synthesis of pre-vitamin D from 7-dehydrocholes-
terol (7-DHC) in the skin. Pre-vitamin D then undergoes further hydroxylation
3
reactions in the liver and kidneys to form 25-hydroxyvitamin D (25OHD ) and
3 3
1,25-dihydroxyvitamin D (1,25(OH) D ) respectively [69]. The 1,25(OH) D
3 2 3 2 3
formed from the kidney is essential in maintaining mineral and bone homeostasis
(Fig. 9.1a). Vitamin D deficiency can arise in older individuals as a result of age
related factors including reduced capacity to produce vitamin D, reduced sunlight
exposure, lower vitamin D intake and decline in renal function [116].
Interestingly, epidemiologic studies have shown seasonal melanoma fatality pat-
terns, with fatality rates lower during summer than in winter [17]. In addition, fatal-
ity from melanoma is lower in people with a history of higher sun exposure than in
people with low sun exposure [9]. Together with the knowledge that UV exposure
is important for vitamin D synthesis, this raised the idea of a possible relationship
between melanoma and vitamin D. The effect of sun exposure on vitamin D status
appears to be important in protecting against a number of non-cutaneous cancers,
including cancers of the breast, colon and prostate and non-Hodgkin lymphoma
[17, 55, 56, 87, 101].
Much of the knowledge of the connection between vitamin D and the epidemio-
logical data on cancer have been contributed by investigations into the role of
vitamin D in extra-renal tissues, initiated by the discovery of the vitamin D receptor
(VDR) in breast cancer cells [44]. Other experiments have also demonstrated the