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Endocrine Research Unit, VA Medical Center, University of California, San Francisco, CA 94121
3To whom correspondence should be addressed. E-mail: doctor{at}itsa.ucsf.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • keratinocytes • squamous-cell carcinoma • vitamin D • calcium • differentiation
1,25 Dihydroxyvitamin D3 [1,25(OH)2D3]4 has been evaluated for it potential anticancer activity for 
25 y, since the initial observations of the vitamin D receptor (VDR) in breast cancer cells (1). The list of malignant cells that contain VDR is now quite extensive and, for the purposes of this review, includes basal- and squamous-cell carcinomas (2,3) as well as melanomas (4). The basis for the promise of 1,25(OH)2D3 in the prevention and the treatment of malignancy includes its antiproliferative, prodifferentiating effects on most cells. As will be discussed, malignant transformation may cause a resistance to these actions of 1,25(OH)2D3 for a variety of reasons, including loss of VDRs, although it is equally clear that loss of VDRs is not the sole reason for failure of cells to respond to 1,25(OH)2D3. This resistance may have made clinical efforts to use 1,25(OH)2D3 and its analogs to treat malignancies so difficult.
Epidemiologic evidence supporting the importance of adequate vitamin D nutrition (including sunlight exposure) has been obtained for colon, breast, and prostate cancer (5–9). However, several large epidemiologic surveys have not shown such a correlation with skin cancers (10–12). One potential complication is that UV light exposure has the dual effect of promoting vitamin D-3 (cholecalciferol) synthesis in the skin and of increasing the risk of skin cancer.
This review will focus on the mechanisms by which 1,25(OH)2D3 regulates the proliferation and differentiation of the normal keratinocyte and, where known, will compare these actions in the normal cell to those in the transformed cell. The story in melanocytes has parallels with that in keratinocytes but is not as well developed and will not be discussed further here.
Anatomic considerations
The epidermis is the largest organ in the body and is critical for life. It keeps what we need inside and keeps what we do not need outside—the barrier function. The primary cell in the epidermis responsible for this barrier function is the keratinocyte. One environmental insult to which the epidermis is constantly exposed is UV radiation. UV radiation in excess is harmful—it causes DNA damage that can result in cancer. However, UV is also beneficial in that the epidermis uses the energy in UV to convert 7-dehydrocholesterol (7-DHC) to previtamin D-3, which then isomerizes to vitamin D-3. The epidermis is self-renewing (Fig. 1). Proliferating keratinocytes are found only in the base of the epidermis, in the layer known as the stratum basale. Daughter cells leave the stratum basale and differentiate on their journey to the surface, where, as the enucleated cells of stratum corneum, they form the permeability barrier. Along the way genes are sequentially turned on and off to produce proteins that contribute to the fully differentiated keratinocyte. For example, basal keratinocytes produce keratins 5 and 14. As they enter the stratum spinosum, the production of keratins 1 and 10 replaces that of keratins 5 and 14. Involucrin, an important component of the cornified envelope, and transglutaminase-K, the enzyme that cross-links involucrin and other substrates to form the cornified envelope, are also made in the keratinocytes of the stratum spinosum. The next higher level, the stratum granulosum, is marked by the presence of keratohyalin granules. These granules contain loricrin, a major component of the cornified envelope, and profilaggrin, a precursor of filaggrin that serves as a bundling protein for the keratin filaments. The stratum granulosum also contains lamellar bodies whose contents of lipids and lipid-processing enzymes are secreted into the junction between the stratum granulosum and stratum corneum to provide the mortar between the bricks that are the corneocytes of the stratum corneum.
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Epidermal production of 1,25(OH)2D3
As previously mentioned, keratinocytes not only produce vitamin D-3 but metabolize it via the vitamin D-25 hydroxylase (25OHase) and the 25hydroxyvitamin D3-1
-hydroxylase (1OHase) to form the active metabolite 1,25(OH)2D3 (13–16) (Fig. 2). The 25OHase in keratinocytes is the same mitochondrial enzyme (P450c27 or CYP27) that converts vitamin D-3 to 25OHD3 in the liver (18,19). Its expression is increased by vitamin D and UVB irradiation (18,19). Similarly, 1OHase in the epidermis is the same enzyme (P450c27B1 or CYP27B1) as that found in the kidney (20). 25-Hydroxyvitamin D-24 hydroxylase (24OHase) in the keratinocyte is presumed to be identical to the 24OHase in other tissues (P450c24 or CYP24). 24OHase initiates the degradative pathway for both 25OHD3 and 1,25(OH)2D3. 24OHase is readily induced by 1,25(OH)2D3 and as such may protect the cells from excessive 1,25(OH)2D3 production. The expression and enzymatic activities of 1OHase and 24OHase are tightly regulated and coupled to the differentiation of these cells (21). 1OHase activity is greatest in the undifferentiated cells. Growing the cells in calcium at 0.1 mmol/L, which retards differentiation, permits the cells to maintain higher 1OHase activity than when they are grown in calcium at 1.2 mmol/L (22), although acute changes in calcium have little effect on 1,25(OH)2D3 production. These observations in vitro are consistent with the finding that 1OHase expression is highest in the stratum basale of the epidermis in vivo (23).
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Role of 1,25(OH)2D3 in epidermal proliferation
Like proliferation in many other cells, keratinocyte proliferation is inhibited by high doses of 1,25(OH)2D3 (24,25). Of interest is that lower doses of 1,25(OH)2D3 have a proproliferative effect (26,27), and topical application of 1,25(OH)2D3 to mouse skin stimulates epidermal proliferation (28). This biphasic action of 1,25(OH)2D3 may underlie an apparent paradox in the effect of 1,25(OH)2D3 and its analogs on skin tumor induction. Topical application of 1,25(OH)2D3 and its analogs prevents papilloma formation by a 2-step carcinogenesis model in which a single application of dimethylbenzanthracene (DMBA) is followed by biweekly applications of phorbol ester. 1,25(OH)2D3 or an analogue is then applied 30–60 min before each phorbol ester administration (29–31). However, 1,25(OH)2D3 promoted tumor development when only DMBA was used both to initiate and to promote tumor development (32).
Although the proliferative actions of 1,25(OH)2D3 are not understood, the antiproliferative actions can be attributed to several mechanisms. 1,25(OH)2D3 administration blocks cells at the Go/G1 to S transition (25). Although this has not received extensive study in keratinocytes, this block is presumed to occur because of an upregulation of the cell-cycle inhibitors p21 and p27, as occurs in other cell types (33,34). The p21 promoter has a functional vitamin D response element (VDRE), indicating that the regulation of at least this cell-cycle inhibitor is at the transcriptional level (35). However, 1,25(OH)2D3 also increases transforming growth factor-ß1 and ß2 production by keratinocytes (36,37), which indirectly could mediate the antiproliferative actions of 1,25(OH)2D3. Transformed keratinocytes are less responsive to the antiproliferative actions of 1,25(OH)2D3 than are normal keratinocytes (24,25). This is not because of a loss of the VDR or a change in VDR binding to 1,25(OH)2D3 (2,24,25). One potential mechanism for this resistance involves increased serine phosphorylation of the retinoid X receptor (RXR) . RXR is the preferred partner for VDR with respect to transcriptional activation. In transformed cells, RXR is phosphorylated via the activated ras/MAPK pathway (38). This phosphorylation apparently makes RXR a less stable partner for VDR in VDR-RXR complexes binding to the VDRE in promoters of genes regulated by 1,25(OH)2D3 (38). A second mechanism involves coactivator recruitment. As will be discussed subsequently, we (39) have observed overexpression of the DRIP complex in transformed cells. This coactivator complex may prevent VDR interaction with the SRC family of coactivators that appears to be critical for induction by 1,25(OH)2D3 for differentiation (Fig. 3). Either or both mechanisms could result in the resistance to 1,25(OH)2D3 found in transformed keratinocytes.
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As mentioned above, calcium is a potent means for inducing keratinocyte differentiation in vitro (40) (Fig. 4). The effects of calcium can be seen within minutes, as the rapid development of cell-to-cell contact, desmosome formation, and realignment of actin and keratin bundles near the cell membrane at the point of intercellular contacts. Desmoplakin (a component of desmosomes), fodrin (an actin- and calmodulin-binding spectrin-like protein), and calmodulin are redistributed to the membrane shortly after the calcium switch by a mechanism that is blocked by cytochalasin, an agent that disrupts microfilament reorganization (41–43). Within hours of the calcium switch, the cells begin to make involucrin (44–46), loricrin (47), transglutaminase (44–46), keratins K1 and K10 (48), and filaggrin (48), and they start to form cornified envelopes (44,48). The mRNA levels for these proteins increase after the calcium switch (45,47,48), indicating that these effects of calcium represent genomic actions, a conclusion confirmed by nuclear run-on and promoter-construct experiments for many of these genes. Calcium response regions have been identified in the promoters of the involucrin (49) and Kl (50) genes.
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Calcium both induces and activates the phospholipase C family, whose members provide additional second messengers for mediating the effects of calcium on the keratinocyte (63,64). The principal enzymes involved are phospholipase C (PLC) ß and 
1. These enzymes hydrolyze phosphatidylinositol bisphosphate to inositol trisphosphate (IP3) and diacylglycerol (DG). As for the response of [Ca2+]i to [Ca2+]0, the rise in IP3 and DG is both immediate and prolonged after the calcium switch. The prolonged increase in inositol phosphates appears to be due to calcium activation of PLC-1, although the initial increase in IP3 and [Ca2+]i after the calcium switch appears to be mediated by PLC-ß. Activation of PLC-1 is mediated by a calcium-induced increase in SRC family tyrosine kinases (65). Keratinocytes lacking PLC-1 fail to differentiate in response to calcium (64). However, when keratinocytes are induced to overexpress PLC-1, they also fail to differentiate in response to calcium (Z. Xie and D. D. Bikle, University of California, San Francisco, unpublished results, 2004). Transformed keratinocytes overexpress PLC-1 in a manner that cannot be regulated by calcium or 1,25(OH)2D3 (24). This may contribute to their resistance to the prodifferentiating effects of calcium and 1,25(OH)2D3.
The mechanisms by which 1,25(OH)2D3 alters keratinocyte differentiation are multiple and overlap with the mechanisms by which calcium regulates differentiation (Fig. 5). Some studies have shown an acute increase in [Ca2+]i associated with an acute increase in phosphoinositide turnover (producing a rise in both IP3 and DG) after 1,25(OH)2D3 administration (66–69). However, we (70) and others have been unable to reproduce these acute effects. The rise in [Ca2+]i, IP3, and DG is accompanied by translocation of protein kinase C to the membrane (68). Downregulation of protein kinase C and inhibition of its activity have been reported to block the ability of 1,25(OH)2D3 to stimulate cornified envelope formation (68). However, the role of protein kinase C in mediating or interacting with 1,25(OH)2D3 in its effects on keratinocyte differentiation remains virtually unexplored.
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1 gene that is critical for its induction by 1,25(OH)2D3. The regulation of gene expression for involucrin and transglutaminase is more complex. Both calcium [in the absence of 1,25(OH)2D3] and 1,25(OH)2D3 (Ca2+ at 0.03 mmol/L) raise the mRNA levels for involucrin and transglutaminase in a dose-dependent fashion. The stimulation is synergistic at intermediate concentrations of calcium (0.1 mmol/L) and 1,25(OH)2D3 (0.1 nmol/L) but not at higher concentrations. The synergism is more apparent earlier (4 h) than later (24–72 h), after the calcium switch. This result stems from the increased turnover of the transcripts from these genes in the presence of elevated calcium and 1,25(OH)2D3. This provides a protective mechanism by which excess involucrin and transglutaminase production is prevented in the face of increased calcium, 1,25(OH)2D3, or both and may be one mechanism by which the production of such proteins is sequentially turned on and off as the keratinocytes differentiate in vivo. One explanation for the synergism in the induction of involucrin is that the calcium response element and VDRE in the involucrin promoter are quite close spatially (75). Mutations in the AP-1 site within the calcium response element block both calcium and 1,25(OH)2D3 induction of the involucrin gene, but mutations within the VDRE block only its response to 1,25(OH)2D3 (75). The molecular basis for the synergism with respect to transglutaminase induction has not been elucidated.
Transformed keratinocytes (SCCs) are resistant to 1,25(OH)2D3 with respect to differentiation as well as to proliferation (24,25). As discussed previously, this is not due to loss of VDR or its partner RXR. This resistance is also not generalized. 1,25(OH)2D3 is as potent in inducing 24OHase transcription and activity in SCC lines as in normal keratinocytes (24,76), although it cannot induce markers of differentiation such as involucrin and transglutaminase (2), cornified envelope formation (24), or PLC-1 (76). We observed that 1,25(OH)2D3 induction of 24OHase prefers the DRIP coactivator complex, which is well expressed in proliferating keratinocytes and SCC lines (77). Differentiation markers such as keratin 1 prefer a complex of the VDR with the SRC family of coactivators (Y. Oda and D. D. Bikle, University of California, San Francisco, unpublished results, 2004). In normal keratinocytes, DRIP205 levels decrease, whereas SRC3 levels increase with differentiation (77). This transition does not take place in SCCs (77). Thus, we hypothesize that the failure of SCCs to switch coactivator complexes from DRIP to SRC explains the ability of 1,25(OH)2D3 to induce 24OHase but not genes required for differentiation.
The recent availability of mice lacking either VDR or 1OHase has expanded our understanding of the role of 1,25(OH)2D3 in epidermal differentiation. Although the most striking feature of the VDR-null mouse is the development of alopecia (likewise found in many patients with mutations in the VDR), these mice also exhibit a defect in epidermal differentiation as shown by reduced levels of involucrin, profilaggrin, and loricrin, and loss of keratohyalin granules (78). Similarly 1OHase-null mice show a reduction in levels of the epidermal differentiation markers (79). Furthermore, 1OHase null mice have a retarded recovery of barrier function when the barrier is disrupted, which on ultrastructural examination is associated with an impaired reestablishment of the calcium gradient in the epidermis (79). This has not been observed in VDR-null mice. However, 1OHase-null mice do not have a defect in hair follicle cycling. VDR-null mice also show an increased susceptibility to tumor formation. Using a model for mammary cancer induction in which medroxyprogesterone pellets are implanted before oral administration of DMBA at ages 5.5 and 7 wk, Zinser et al. (80) found that 85% of the VDR-null mice developed tumors (primarily papillomas but some BCCs), whereas none of the wild type mice did. This experiment has not yet been tried in the 1OHase-null mice or been repeated using more standard models for skin carcinogenesis. However, the data point to a protective effect of VDR and perhaps also for 1,25(OH)2D3 with respect to chemically induced skin cancer. Increased predisposition of humans with VDR mutations to develop skin cancers has not been reported but is worth monitoring.
Summary
Keratinocyte proliferation and differentiation are tightly controlled processes critical for maintenance of the epidermal functions of skin, including maintenance of the barrier to external insults and internal losses. Calcium and 1,25(OH)2D3 participate in the regulation of these processes. Keratinocytes contain both CaRs and VDRs and possess the metabolic machinery to make their own 1,25(OH)2D3 (via 1OHase). Although most of our information on the mechanisms by which such regulation occurs comes from in vitro studies, the abnormalities in the epidermis in rodents lacking CaR, VDR, or 1OHase attest to the importance of calcium and 1,25(OH)2D3 in regulating keratinocyte differentiation in vivo. Calcium and 1,25(OH)2D3 interact in their regulation of keratinocyte differentiation. A sustained increase in [Ca2+]i is required for differentiation to occur. Extracellular calcium acutely increases [Ca2+]i via CaR but exerts a more prolonged effect on [Ca2+]i via activation and induction of PLC and the opening of various calcium channels. 1,25(OH)2D3 potentiates these effects by inducing the CaR and PLC family. Through the sustained rise in [Ca2+]i, genes producing the proteins required for differentiation are induced in a manner potentiated by 1,25(OH)2D3 acting on these genes through their own VDREs. The sequential turning on and off of genes during the course of differentiation can be understood as occurring through 3 mechanisms: 1) the loss of the full-length CaR and VDR with differentiation, 2) the synergism between calcium and 1,25(OH)2D3 first in gene induction but subsequently in stimulating mRNA degradation, and 3) the transition from DRIP to SRC coactivator binding to the VDR with differentiation in that the VDRE of genes induced during differentiation appear to be selective for the VDR-SRC complex. Skin cancer develops when these processes go awry. The transformed cells become resistant to the antiproliferative, prodifferentiating actions of calcium and 1,25(OH)2D3. This is not due to the loss of either CaR or VDR in most cases. Instead, the problem lies distal to these receptors. Clues lie in the overexpression of PLC-1, which seems to promote proliferation instead of differentiation when overexpressed, and DRIP205, which seems to maintain the proproliferative actions of 1,25(OH)2D3, while blocking the shift to coactivator complexes that mediate its prodifferentiating actions. Overexpression of ras may also contribute by leading to the phosphorylation of RXR and so diminishing the effectiveness of the VDR-RXR partnership in transcriptional regulation. Much remains to be understood. Although dietary vitamin D appears to have little effect on the development of skin cancer, 1,25(OH)2D3 and its analogs, perhaps in combination with other agents, including retinoids, may prove useful in preventing and treating skin cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 The studies reviewed here were supported by grants to the author from the American Institute for Cancer Research (98079 and 03A113), the National Institutes of Health (RO1 AR38386, RO1 50023, PO1 AR39448), and a Veterans Affairs Merit Review Award.
4 Abbreviations used: 1,25(OH)2D3, 1,25 dihydroxyvitamin D3 (calcitriol); 7-DHC, 7-dehydrocholesterol; 1OHase, 25OHD-1-hydroxylase; 24OHase, 25-hydroxyvitamin D-24 hydroxylase; 25OHase, vitamin D-25 hydroxylase; BCC, basal cell carcinoma; [Ca2+]i, intracellular free calcium; [Ca2+]0 extracellular free calcium; CaR, calcium receptor; DG, diacylglycerol; DMBA, dimethyl benzanthracene; IP3, inositol trisphosphate; PLC, phospholipase C; RXR, retinoid X receptor; SCC, squamous cell carcinoma; VDR, vitamin D receptor; VDRE, VDR element; vitamin D-3, cholecalciferol.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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