We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by β-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 β-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergises with β-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear β-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high β-catenin and low VDR levels. In mice, EB1089 prevents β-catenin induced trichofolliculomas, while in the absence of VDR β-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.
We found that one-third of human sebaceous tumors examined had double-nucleotide substitutions in the same LEF1 allele, irrespective of DNA mismatch repair status. The mutations impaired both LEF1 binding to beta-catenin and transcriptional activation, and are the first tumor-associated mutations that inactivate Wnt signaling. Mutant LEF1 not only inhibited expression of beta-catenin target genes but also stimulated expression of sebocyte markers, suggesting that it may determine the differentiated characteristics of sebaceous tumors.
The tissue angiotensin (Ang) system, which acts independently of the circulating renin Ang system, is supposed to play an important role in tissue repair in the heart and kidney. In the skin, the role of the system for wound healing has remained to be ascertained. Our study demonstrated that oral administration of selective AngII type-1 receptor (AT(1)) blocker suppressed keratinocyte re-epithelization and angiogenesis during skin wound healing in rats. Immunoprecipitation and Western blot analysis indicated the existence of AT(1) and AngII type-2 receptor (AT(2)) in cultured keratinocytes and myofibroblasts. In a bromodeoxyuridine incorporation study, induction of AT(1) signaling enhanced the incorporation into keratinocytes and myofibroblasts. Wound healing migration assays revealed that induction of AT(1) signaling accelerated keratinocyte re-epithelization and myofibroblasts recovering. In these experiments, induction of AT(2) signaling acted vice versa. Taken together, our study suggests that skin wound healing is regulated by balance of opposing signals between AT(1) and AT(2).
Angiotensin II receptors are the specific receptors of angiotensin II of the renin-angiotensin system. The existence and role of the receptors in the skin have not been determined. We immunohistochemically studied the expression of angiotensin receptors in the human skin. The results demonstrated the expression of angiotensin type 1 receptor (AT1) in the normal human suprabasal epidermis. The expression pattern suggests the role of AT1 in association with differentiation. In addition, we studied the expression of AT1 in squamous cell carcinoma (SCC) of the skin, SCC of the lip, and keratoacanthoma (KA). Our experiments showed that high, intermediate, and low levels of AT1 were observed in 37 (74.0%), 7 (14.0%), and 2 (4.0%) of 50 cases of SCC of the skin, respectively, and the negative periphery pattern was observed in 17 (77.3%) of 22 cases of KA. These observations suggest that the immunohistochemical study of AT1 is useful to distinguish SCC from KA. Studying the role and distribution of AT1 may help in understanding the pathophysiology of the skin.
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