Page 217 - Vitamin D and Cancer

204 F.S.G. Cheung and J.K.V. Reichardt

Understanding the functional effects of the VDR variants can aid us in

understanding the action of vitamin D in the presence of a particular VDR variant.
Genotyping patients for the VDR gene can help us predict the action of vitamin D for
each individual. This in turn may be useful in advising high risk individuals to take
precautions for preventing skin cancer development. Furthermore, patients carrying
different VDR variants may also cause them to respond differently to therapies and
knowledge on the functional effects of VDR variants should allow the development
of drugs that will act most efficiently on the patient with minimal side effects.
Taken together, the epidemiological data from these studies show that there is a
link between sun exposure and skin cancer. More importantly, these evidences sug-
gest a possible link between the role of vitamin D and skin cancer.

9.5 Vitamin D and Skin Cancer

9.5.1 The Role and Expression of 1,25-Dihydroxyvitamin D
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in Extra Renal Sites

Apart from the classical role of 1,25(OH) D in maintaining mineral homeostasis via
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the intestine, parathyroid, bone and kidney. 1,25(OH) D also has non classical func-
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tions in extra-renal tissues. The idea of extra-renal synthesis of 1,25(OH) D started
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when it was observed that the administration of vitamin D in anephric patients led
to an significant increase of serum 1,25(OH) D levels compared to controls and this
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increase of 1,25(OH) D had significant correlation with the precursor 25OHD levels
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[90]. This observation was confirmed in another study by the oral administration of
25OHD to uremic mongrel dogs and anephric patients which also found a similar
significant correlation between serum levels of 25OHD and 1,25(OH) D [42]. The
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enzyme expressed in extra-renal tissues acts locally in an autocrine/paracrine man-
ner (Fig. 9.1b) which serves to complement the endocrine circulating 1,25(OH) D
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produced by the kidneys [80]. This locally elevated concentration of 1,25(OH) D
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can alter gene expression in a tissue specific manner that eventually limit prolifera-
tion and induces differentiation. These effects of proliferation and differentiation
regulation by 1,25(OH) D has been described in various tissues including the cells
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of the immune system [53, 65], prostate, breast [160], colon, bone as well as the skin
[124] (Table 9.1). In fact, the CYP27B1 gene has recently been expressed in the
transgenic mouse and it has been shown that the 5¢ flanking region itself provides
sufficient information for directing cell and tissue specific expression [2]. This is in
agreement with the idea mentioned earlier in Sect. 9.3.2, that the presence of differ-
ent transcription factors in different tissues and cell differentiation state allows
nuclear receptors to regulate gene transcription in a tissue and time specific manner.
These exciting findings of tissue specific proliferation and differentiation regulation
by 1,25(OH) D in extra-renal sites provide an important and direct link on the
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actions of 1,25(OH) D in various cancers including skin cancer.
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