# Identification of Novel Markers of Prostate Cancer Progression, Potentially Modulated by Vitamin D
## 1 Introduction  
Vitamin D is synthesized in the body through a complex series of steps beginning in the skin, under the influence of ultraviolet light, where a cholesterol precursor molecule (7-dehydrocholesterol) is transformed into the Vitamin D hormone precursor, _cholesterol_ (also known as Vitamin D3). Vitamin D3 is subsequently hydroxylated in the liver by the 25-hydroxycholecalcfirol and transformed in _calcidiol_ or _calcifediol_ (25(OH)D\({}_{3}\) or 25D\({}_{3}\)), and this latter is subjected, in the kidney, to an hydroxylation, to yield the most active hormone form of these compounds, _calcitriol_ (1,25-dihydroxycholecalciferol or 1,25(OH)\({}_{2}\)D\({}_{3}\) or 1,25D\({}_{3}\)) [1]. The three main stages in Vitamin D metabolism, 25-hydroxylation, 1\(\alpha\)-hydroxylation and 24-hydroxylation, are all performed by cytochrome P450 mixed-function oxidases (CYPs). These enzymes are distributed either in the endoplasmic reticulum (ER) (CYP2R1) or in the mitochondria (CYP27A1, CYP27B1 and CYP24A1). The 24-hydroxylase (CYP24A1) and 1-hydroxylase(CYP27B1) enzymes are considered to be pivotal determinants of the local concentration of active vitamin D. When Vitamin D3 is transferred to the liver, it is hydroxylated (by CYP27A1) and then converted to 25-hydroxyvitamin D3, which is the major form of vitamin D present in the blood. In this form it is also hydroxylated in other tissues, predominantly the kidney, through 1-\(\alpha\) hydroxylase (CYP27B1), which is then converted to 1,25-dihydroxyvitamin D3. This form is able to bind to vitamin D-binding proteins (VBP) in the bloodstream and modulate the transcription of its target gene through binding to the vitamin D receptor (VDR) in tissues. The last steps of Vitamin D3 catabolism are played by the catalytic enzyme, 24-hydroxylase, encoded by CYP24A1 and responsible for vitamin D catabolism, which is then metabolized to calcitroic acid, a bile secretion [2]. Serum 25(OH)D3 is the barometer for Vitamin D status. Serum calcitriol provides no information about Vitamin D status, and it is often at physiological or even elevated due to secondary hyperparathyroidismyroidism associated with Vitamin D deficiency. The Vitamin D plays a relevant role in bone formation, activates the immune cells [3; 4; 5], regulates the host defense against microbial and virus infections [6; 7; 8], inhibits several tumor pathways, such as the proliferation and angiogenesis [9] and it has been hypothesized that it is able to reduce prostate cancer (PCa) risk [10]. In this regard, it has been shown that a 'U' shaped relationship may exist between Vitamin D status (_cholesterol_, _calcidiol_, _calcitriol_ and _calcitroic acid_) and PCa, and that the optimal range of circulating 25(OH)D3 for PCa prevention may be narrow [11]. Prostate cancer (PCa) is one of the most common causes of morbidity and mortality in men. Several factors have been linked to the incidence of PCa and its aggressiveness. Among these, age, race and family history are some of the strongest [12]. The incidence rate is high in men 65-74 years of age with a median age at diagnosis of 66. The percent of PCa deaths is highest among men between 75 to 84 years old with a median age at death of 80 [13] Epidemiologic studies regarding PCa showed that there are significant differences in geographical distribution and race. The African-American race, for example, experiences an incidence rate of 60% compared to Caucasian men, other than more aggressive forms and worse treatment management, leading to increased mortality [14]. Interestingly, one of the major correlations between Vitamin D levels and PCa is based on studies on African-American men. In these individuals, 25(OH)D3 levels are often low (probably for the effect of skin pigmentation on the synthesis of Vitamin D), and PCa risks are clearly higher than those of Caucasian men. Nowadays, the mechanisms for this association are still unclear. There are a large number of epidemiologic studies linking Vitamin D and prostate cancer risk and outcomes.