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Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer.

Bikle DD, Jiang Y, Nguyen T, Oda Y, Tu CL - Front Physiol (2016)

Bottom Line: 1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family.Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β-catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively.These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA.

ABSTRACT
1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis ((epid) Vdr (-∕-) and (epid) Casr (-∕-)). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β-catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr (-∕-) mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the (epid) Vdr (-∕-) or (epid) Casr (-∕-). But in mice with epidermal specific deletion of both Vdr and Casr ((epid) Vdr (-∕-)/(epid) Casr (-∕-) [DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the β-catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed.

No MeSH data available.


Related in: MedlinePlus

Regulation of HH and Wnt/β-catenin signaling by 1,25(OH)2D/VDR and calcium/Casr. The keratinocyte expresses VDR and is capable of making its own 1,25(OH)2D3 from the vitamin D3 produced from 7-dehydrocholesterol (DHC) under the influence of UVB, as it has both Cyp27a1/Cyp2r1 (which convert vitamin D3 to 25OHD3) and Cyp27b1 [which converts 25OHD3 to 1,25(OH)2D3]. The keratinocyte also expresses the calcium sensing receptor Casr required for calcium induced differentiation. 1,25(OH)2D/VDR suppresses Shh and Gli1 expression, inhibiting the HH pathway in keratinocytes. 1,25(OH)2D/VDR binds CTNNB1(β-catenin) and increases CDH1(E-cadherin) levels in the plasma membrane reducing the amount of β-catenin available for binding to TCF/LEF in the nucleus limiting its transcriptional activity. Calcium acting through its receptor is required for the formation of the E-cadherin/catenin complex in the plasma membrane. In combination these actions reduce the proliferative actions of Shh and Wnt/β-catenin signaling in keratinocytes, limiting their ability to induce tumors in the skin.
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Figure 1: Regulation of HH and Wnt/β-catenin signaling by 1,25(OH)2D/VDR and calcium/Casr. The keratinocyte expresses VDR and is capable of making its own 1,25(OH)2D3 from the vitamin D3 produced from 7-dehydrocholesterol (DHC) under the influence of UVB, as it has both Cyp27a1/Cyp2r1 (which convert vitamin D3 to 25OHD3) and Cyp27b1 [which converts 25OHD3 to 1,25(OH)2D3]. The keratinocyte also expresses the calcium sensing receptor Casr required for calcium induced differentiation. 1,25(OH)2D/VDR suppresses Shh and Gli1 expression, inhibiting the HH pathway in keratinocytes. 1,25(OH)2D/VDR binds CTNNB1(β-catenin) and increases CDH1(E-cadherin) levels in the plasma membrane reducing the amount of β-catenin available for binding to TCF/LEF in the nucleus limiting its transcriptional activity. Calcium acting through its receptor is required for the formation of the E-cadherin/catenin complex in the plasma membrane. In combination these actions reduce the proliferative actions of Shh and Wnt/β-catenin signaling in keratinocytes, limiting their ability to induce tumors in the skin.

Mentions: The β-catenin and HH pathways interact (Bienz, 2005; Pálmer et al., 2008). Using a constitutively active Smo [Gt(ROSA)26Sortm1(Smo∕EYFP)Amc] in keratinocytes to induce BCC, two groups (Yang et al., 2008; Youssef et al., 2012) found a rapid increase in genes of the Wnt/ β-catenin pathway. Dkk1 overexpression or deletion of Ctnnb1 prevented the development of BCC. Both HH and Wnt/ β-catenin pathway constituents were found to be over expressed in a series of human BCC (Youssef et al., 2012). Putative β-catenin /LEF1 response elements as well as VDRE mentioned earlier have been found in a number of HH pathway genes (Pálmer et al., 2008), which unlike the VDRE appear to be stimulated by activated β-catenin with an increase in Shh expression (Schneider et al., 2010). The role of VDR in the regulation of these two pathways is shown in Figure 1.


Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer.

Bikle DD, Jiang Y, Nguyen T, Oda Y, Tu CL - Front Physiol (2016)

Regulation of HH and Wnt/β-catenin signaling by 1,25(OH)2D/VDR and calcium/Casr. The keratinocyte expresses VDR and is capable of making its own 1,25(OH)2D3 from the vitamin D3 produced from 7-dehydrocholesterol (DHC) under the influence of UVB, as it has both Cyp27a1/Cyp2r1 (which convert vitamin D3 to 25OHD3) and Cyp27b1 [which converts 25OHD3 to 1,25(OH)2D3]. The keratinocyte also expresses the calcium sensing receptor Casr required for calcium induced differentiation. 1,25(OH)2D/VDR suppresses Shh and Gli1 expression, inhibiting the HH pathway in keratinocytes. 1,25(OH)2D/VDR binds CTNNB1(β-catenin) and increases CDH1(E-cadherin) levels in the plasma membrane reducing the amount of β-catenin available for binding to TCF/LEF in the nucleus limiting its transcriptional activity. Calcium acting through its receptor is required for the formation of the E-cadherin/catenin complex in the plasma membrane. In combination these actions reduce the proliferative actions of Shh and Wnt/β-catenin signaling in keratinocytes, limiting their ability to induce tumors in the skin.
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Related In: Results  -  Collection

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Show All Figures
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Figure 1: Regulation of HH and Wnt/β-catenin signaling by 1,25(OH)2D/VDR and calcium/Casr. The keratinocyte expresses VDR and is capable of making its own 1,25(OH)2D3 from the vitamin D3 produced from 7-dehydrocholesterol (DHC) under the influence of UVB, as it has both Cyp27a1/Cyp2r1 (which convert vitamin D3 to 25OHD3) and Cyp27b1 [which converts 25OHD3 to 1,25(OH)2D3]. The keratinocyte also expresses the calcium sensing receptor Casr required for calcium induced differentiation. 1,25(OH)2D/VDR suppresses Shh and Gli1 expression, inhibiting the HH pathway in keratinocytes. 1,25(OH)2D/VDR binds CTNNB1(β-catenin) and increases CDH1(E-cadherin) levels in the plasma membrane reducing the amount of β-catenin available for binding to TCF/LEF in the nucleus limiting its transcriptional activity. Calcium acting through its receptor is required for the formation of the E-cadherin/catenin complex in the plasma membrane. In combination these actions reduce the proliferative actions of Shh and Wnt/β-catenin signaling in keratinocytes, limiting their ability to induce tumors in the skin.
Mentions: The β-catenin and HH pathways interact (Bienz, 2005; Pálmer et al., 2008). Using a constitutively active Smo [Gt(ROSA)26Sortm1(Smo∕EYFP)Amc] in keratinocytes to induce BCC, two groups (Yang et al., 2008; Youssef et al., 2012) found a rapid increase in genes of the Wnt/ β-catenin pathway. Dkk1 overexpression or deletion of Ctnnb1 prevented the development of BCC. Both HH and Wnt/ β-catenin pathway constituents were found to be over expressed in a series of human BCC (Youssef et al., 2012). Putative β-catenin /LEF1 response elements as well as VDRE mentioned earlier have been found in a number of HH pathway genes (Pálmer et al., 2008), which unlike the VDRE appear to be stimulated by activated β-catenin with an increase in Shh expression (Schneider et al., 2010). The role of VDR in the regulation of these two pathways is shown in Figure 1.

Bottom Line: 1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family.Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β-catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively.These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted.

View Article: PubMed Central - PubMed

Affiliation: Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA.

ABSTRACT
1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis ((epid) Vdr (-∕-) and (epid) Casr (-∕-)). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β-catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr (-∕-) mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the (epid) Vdr (-∕-) or (epid) Casr (-∕-). But in mice with epidermal specific deletion of both Vdr and Casr ((epid) Vdr (-∕-)/(epid) Casr (-∕-) [DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the β-catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed.

No MeSH data available.


Related in: MedlinePlus