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This study highlights the crucial role of ligand-independent actions of the vitamin D receptor (VDR) in maintaining hair cycle and skin homeostasis. In VDR-KO rats, which lack the VDR gene, there is significant alopecia and skin abnormalities, including hyperkeratosis and increased trans-epidermal water loss. In contrast, rats with a mutant VDR (R270L/H301Q) that cannot bind ligands do not exhibit these issues, indicating that VDR's non-liganded actions are essential. The study found that VDR-KO rats have altered gene and protein expression, particularly in the Shh, Wnt, and Bmp signaling pathways, with decreased hair keratins and increased epidermal keratins. These findings underscore the importance of non-liganded VDR in keratinocyte differentiation, proliferation, and cell death in hair follicles and the epidermis.

The document reviewed the role of the hedgehog (Hh) signalling pathway in skin development and cancer, particularly basal cell carcinoma (BCC), which affected 750,000 Americans annually. It highlighted how mutations in genes like PATCHED (PTCH), sonic hedgehog (Shh), and smoothened (Smo) expanded the understanding of BCC's genetic basis. The Shh pathway was crucial for stem cell maintenance and hair follicle and sebaceous gland development in the skin, though it played a minimal role in adult tissues. The review summarized studies on the Shh pathway's involvement in skin development and cancer, described animal models based on this pathway, and discussed chemoprevention strategies for BCCs, providing insights into molecular target-based prevention and treatment of skin cancer.

Cutaneous gene therapy research, conducted over more than 20 years, explored both direct and indirect gene transfer methods using viral and nonviral vectors to treat inherited skin diseases and potentially systemic disorders. Despite reaching clinical phases, challenges such as gene expression loss and immune reactions persisted. The study highlighted the potential of epidermal and hair follicle stem cells in skin regeneration and gene therapy, with telomerase influencing hair growth and cell proliferation. Clinical trials, such as those for junctional epidermolysis bullosa, showed potential for long-term expression and phenotypic correction. The research also explored hair follicle gene therapy, noting that adenoviral-mediated expression of Sonic hedgehog (Shh) could enhance hair growth, suggesting potential benefits for alopecia treatment. The document concluded that advancements in vector development and gene expression control could make cutaneous gene therapy a viable option for various diseases.

The document discussed the three most common types of skin cancer: malignant melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Malignant melanoma was noted as the most lethal, originating from melanocytes. BCC, the most common cancer, was debated to arise from hair follicle keratinocytes and was associated with mutations in the sonic hedgehog (SHH) pathway, suggesting a link to failed organogenesis. SCC, also from keratinocytes, was described as more aggressive than BCC, with the potential for lethal metastases, unlike BCC, which rarely metastasizes. The document explored both in vivo and in vitro models for studying these cancers.