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The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.

Pálmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM - PLoS ONE (2008)

Bottom Line: We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation.Many epidermal genes induced by beta-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef.We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.

ABSTRACT
We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by beta-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef. The VDR is required for beta-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergizes with beta-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear beta-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high beta-catenin and low VDR levels. In mice, EB1089 prevents beta-catenin induced trichofolliculomas, while in the absence of VDR beta-catenin induces tumours resembling BCCs. We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

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VDR modulates β-catenin induced skin tumours.(A, B) K14ΔNβ-cateninER (D4) transgenic mice were treated with vehicle, 4OHT, EB1089 or 4OHT+EB1089 for 21 days. (A) Macroscopic appearance of tails. (B) H&E stained tail skin sections. Arrows indicate parakeratosis and increased cornified layers. (C) H&E stained tail skin sections of wild type and K14ΔNβ-cateninER (D4) transgenic mice that were heterozygous (+/−) or homozygous (−/−)  for VDR, following 4OHT treatment for 21 days. Arrows indicate ectopic HF formation. eHF: ectopic hair follicles; DP: dermal papilla; eDP: ectopic dermal papilla. (D, E) Human trichofolliculoma (D) and infiltrative basal cell carcinoma (E). Serial sections were stained with H&E or immunolabelled for β-catenin (red) and VDR (green) with Hoescht counterstain (blue). Immunolabelling corresponds to boxed regions of H&E stained sections. Arrowheads show nuclear β-catenin and VDR. Scale bars: 100 µm (B–E), 50 µm (inserts in d, e), 10 µm (Hoescht staining inserts d,e). (F) Diagram summarizing dual role of β-catenin as a coactivator of TCF/Lef and VDR in adult epidermis. Hair follicle differentiation requires both the canonical Wnt pathway and ligand activated VDR. In the absence of VDR differentiation is impaired, favoring tumor formation. CoR: co-repressor; β: β-catenin; red triangle: endogenous vitamin D3; red star: vitamin D analog EB1089. eHF: ectopic hair follicles.
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pone-0001483-g005: VDR modulates β-catenin induced skin tumours.(A, B) K14ΔNβ-cateninER (D4) transgenic mice were treated with vehicle, 4OHT, EB1089 or 4OHT+EB1089 for 21 days. (A) Macroscopic appearance of tails. (B) H&E stained tail skin sections. Arrows indicate parakeratosis and increased cornified layers. (C) H&E stained tail skin sections of wild type and K14ΔNβ-cateninER (D4) transgenic mice that were heterozygous (+/−) or homozygous (−/−) for VDR, following 4OHT treatment for 21 days. Arrows indicate ectopic HF formation. eHF: ectopic hair follicles; DP: dermal papilla; eDP: ectopic dermal papilla. (D, E) Human trichofolliculoma (D) and infiltrative basal cell carcinoma (E). Serial sections were stained with H&E or immunolabelled for β-catenin (red) and VDR (green) with Hoescht counterstain (blue). Immunolabelling corresponds to boxed regions of H&E stained sections. Arrowheads show nuclear β-catenin and VDR. Scale bars: 100 µm (B–E), 50 µm (inserts in d, e), 10 µm (Hoescht staining inserts d,e). (F) Diagram summarizing dual role of β-catenin as a coactivator of TCF/Lef and VDR in adult epidermis. Hair follicle differentiation requires both the canonical Wnt pathway and ligand activated VDR. In the absence of VDR differentiation is impaired, favoring tumor formation. CoR: co-repressor; β: β-catenin; red triangle: endogenous vitamin D3; red star: vitamin D analog EB1089. eHF: ectopic hair follicles.

Mentions: If VDR/β-catenin interactions stimulate HF differentiation, then EB1089 may inhibit β-catenin induced tumour formation. Prolonged activation of β-catenin signalling in the D4 line of K14ΔNβ-cateninER transgenic mice results in the conversion of almost all of the follicles into benign tumours known as trichofolliculomas [6], and as a result the tails of 4OHT treated mice are swollen, lumpy and ulcerated (Figure 5A). Simultaneous treatment with EB1089 and 4OHT normalised the gross appearance of the tail (Figure 5A). Histological evaluation confirmed that EB1089 blocked trichofolliculoma development, inhibiting parakeratosis, stimulating IFE differentiation and restoring normal anagen (Figure 5B and data not shown). The protective effect of EB1809 was not due to inhibition of proliferation (Figure S3G–K). We conclude that EB1089 treatment inhibits the formation of HF tumours by promoting HF differentiated gene expression.


The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.

Pálmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM - PLoS ONE (2008)

VDR modulates β-catenin induced skin tumours.(A, B) K14ΔNβ-cateninER (D4) transgenic mice were treated with vehicle, 4OHT, EB1089 or 4OHT+EB1089 for 21 days. (A) Macroscopic appearance of tails. (B) H&E stained tail skin sections. Arrows indicate parakeratosis and increased cornified layers. (C) H&E stained tail skin sections of wild type and K14ΔNβ-cateninER (D4) transgenic mice that were heterozygous (+/−) or homozygous (−/−)  for VDR, following 4OHT treatment for 21 days. Arrows indicate ectopic HF formation. eHF: ectopic hair follicles; DP: dermal papilla; eDP: ectopic dermal papilla. (D, E) Human trichofolliculoma (D) and infiltrative basal cell carcinoma (E). Serial sections were stained with H&E or immunolabelled for β-catenin (red) and VDR (green) with Hoescht counterstain (blue). Immunolabelling corresponds to boxed regions of H&E stained sections. Arrowheads show nuclear β-catenin and VDR. Scale bars: 100 µm (B–E), 50 µm (inserts in d, e), 10 µm (Hoescht staining inserts d,e). (F) Diagram summarizing dual role of β-catenin as a coactivator of TCF/Lef and VDR in adult epidermis. Hair follicle differentiation requires both the canonical Wnt pathway and ligand activated VDR. In the absence of VDR differentiation is impaired, favoring tumor formation. CoR: co-repressor; β: β-catenin; red triangle: endogenous vitamin D3; red star: vitamin D analog EB1089. eHF: ectopic hair follicles.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198947&req=5

pone-0001483-g005: VDR modulates β-catenin induced skin tumours.(A, B) K14ΔNβ-cateninER (D4) transgenic mice were treated with vehicle, 4OHT, EB1089 or 4OHT+EB1089 for 21 days. (A) Macroscopic appearance of tails. (B) H&E stained tail skin sections. Arrows indicate parakeratosis and increased cornified layers. (C) H&E stained tail skin sections of wild type and K14ΔNβ-cateninER (D4) transgenic mice that were heterozygous (+/−) or homozygous (−/−) for VDR, following 4OHT treatment for 21 days. Arrows indicate ectopic HF formation. eHF: ectopic hair follicles; DP: dermal papilla; eDP: ectopic dermal papilla. (D, E) Human trichofolliculoma (D) and infiltrative basal cell carcinoma (E). Serial sections were stained with H&E or immunolabelled for β-catenin (red) and VDR (green) with Hoescht counterstain (blue). Immunolabelling corresponds to boxed regions of H&E stained sections. Arrowheads show nuclear β-catenin and VDR. Scale bars: 100 µm (B–E), 50 µm (inserts in d, e), 10 µm (Hoescht staining inserts d,e). (F) Diagram summarizing dual role of β-catenin as a coactivator of TCF/Lef and VDR in adult epidermis. Hair follicle differentiation requires both the canonical Wnt pathway and ligand activated VDR. In the absence of VDR differentiation is impaired, favoring tumor formation. CoR: co-repressor; β: β-catenin; red triangle: endogenous vitamin D3; red star: vitamin D analog EB1089. eHF: ectopic hair follicles.
Mentions: If VDR/β-catenin interactions stimulate HF differentiation, then EB1089 may inhibit β-catenin induced tumour formation. Prolonged activation of β-catenin signalling in the D4 line of K14ΔNβ-cateninER transgenic mice results in the conversion of almost all of the follicles into benign tumours known as trichofolliculomas [6], and as a result the tails of 4OHT treated mice are swollen, lumpy and ulcerated (Figure 5A). Simultaneous treatment with EB1089 and 4OHT normalised the gross appearance of the tail (Figure 5A). Histological evaluation confirmed that EB1089 blocked trichofolliculoma development, inhibiting parakeratosis, stimulating IFE differentiation and restoring normal anagen (Figure 5B and data not shown). The protective effect of EB1809 was not due to inhibition of proliferation (Figure S3G–K). We conclude that EB1089 treatment inhibits the formation of HF tumours by promoting HF differentiated gene expression.

Bottom Line: We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation.Many epidermal genes induced by beta-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef.We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.

ABSTRACT
We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by beta-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef. The VDR is required for beta-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergizes with beta-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear beta-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high beta-catenin and low VDR levels. In mice, EB1089 prevents beta-catenin induced trichofolliculomas, while in the absence of VDR beta-catenin induces tumours resembling BCCs. We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

Show MeSH
Related in: MedlinePlus