Page 218 - Vitamin D and Cancer

9 Molecular Biology of Vitamin D Metabolism and Skin Cancer 205

9.5.2 The Role of 1,25-Dihydroxyvitamin D in Normal Skin
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Before investigating the role of 1,25(OH) D in the skin in healthy and diseased state, it
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is important to know the process of keratinocyte differentiation in the epidermis. The
epidermis is composed of four layers. Directly on top of the basal lamina, the basal layer
of the epidermis is the stratum basale, followed by the stratum spinosum, then the stra-
tum granulosum and finally the most superficial layer, the stratum corneum [134]. As
the cells differentiate, they gradually migrate up from the base layer, stratum basale, to
the stratum spinosum then granulosum to finally become completely differentiated
keratinocytes in the stratum corneum. Proliferating keratinocytes found in the stratum
basale express keratin 5 and 14. Upon entering the stratum spinosum, the cell expresses
keratin 1 and 10 instead of 5 and 14 and the synthesis of involucrin and transglutami-
nase-K, an enzyme cross linking the involucrin with other substrates for the formation
of the cornified envelope is now evident. By the time the cells reach the stratum granu-
losum, granules containing loricrin and the keratin filaments bundling protein precursor,
profilaggrin are present. Lamella bodies in this layer, which secretes fatty acid, cer-
amide, and cholesterol, fill the intercorneocyte space to bind the corneocytes together
in the stratum corneum providing the skin its elasticity and barrier function [10].
The fact that keratinocytes are the only cells that supports the complete vitamin D
metabolic pathway from 7-DHC to 1,25(OH) D [93, 104] and the observation of
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1,25(OH) D induces keratinocyte differentiation [73] together with the fact that the
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expression and levels of VDR and 1,25(OH) D vary with differentiation [72]
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strongly suggest that 1,25(OH) D is an autocrine/paracrine factor for keratinocyte
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differentiation [12]. In experiments with 1aOHase knockout mice [11], it was
observed that there were no gross epidermal phenotype differences between the
knockout and their wild type littermates, however, there is a reduction of the dif-
ferentiation markers involucrin, filaggrin and loricrin. It was also found that
1,25(OH) D and calcium act together in a synergistic manner to elicit prodifferen-
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tiation effects including the activation of involucrin and transglutaminase gene
expression (Table 9.1) [150]. A plausible explanation of the observed synergistic
effect of 1,25(OH) D and calcium arises from the close proximity of the calcium
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and VDR elements in the promoter of the involucrin gene although the mechanism
of this synergistic effect is still unknown for the transglutaminase gene [13].
The calcium signaling pathway for keratinocyte differentiation is very similar to the
rapid non genomic/surface membrane pathway of 1,25(OH) D signaling (described in
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detail in Sect. 9.3.3). The binding of extracellular calcium to the calcium receptor
(CaR) activates the receptor to stimulate PLC activity which leads to the formation of
DAG and IP that eventually causes the release of intracellular calcium stores from the
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endoplasmic reticulum and the golgi. This initial and sustained increase of IP through
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PLCb and g respectively allows the sustained increase of intacellular calcium to induce
genes necessary for differentiation [78, 165]. During the differentiation process, apart
from inducing the expression of involucrin and transglutaminase, 1,25(OH) D also
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induces CaR [131] and PLCg expression [164] (Table 9.1). Thus, the requirement for
1,25(OH) D to induce the proteins needed for differentiation is consistent with
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