Expression of nuclear survivin in normal skin and squamous cell carcinoma: a possible role in tumour invasion.

BACKGROUND: Survivin is detected in few adult normal cells and it is highly expressed in cancer. Nuclear survivin facilitates cell cycle entry, whereas the mitochondrial pool protects cells from apoptosis. Survivin is overexpressed in keratinocyte stem cells (KSCs) and protects them from apoptosis. METHODS: As KSCs are at the origin of squamous cell carcinoma (SCC), we evaluated survivin expression in normal and cancerous skin in vivo by immunohistochemistry and western blotting. HaCaT cells overexpressing survivin and wound-healing assay are used. Analysis of variance and Student's T-tests are used for statistical analysis. RESULTS: Survivin is localised in both the cytoplasm and nucleus of normal adult and young keratinocytes. Nuclear survivin is detected in one every 10 of 11 basal keratinocytes. When present in suprabasal cells, nuclear survivin is coexpressed with K10 but not with K15 or p75-neurotrophin receptor (p75NTR), a transit amplifying cell marker. Nuclear, but not cytoplasmic, survivin expression markedly increases in actinic keratosis and in SCC in situ, as compared with normal epidermis, and it is highest in poorly differentiated SCC. In SCC tumours, nuclear survivin-positive cells are mainly K10/p75NTR-negative and K15-positive. In poorly differentiated tumours, survivin mostly localises in the deep infiltrating areas. When overexpressed in keratinocytes, survivin increases cell migration. CONCLUSION: High survivin expression and the subcellular localisation of survivin correlate with keratinocyte differentiation and are associated with undifferentiated and more invasive SCC phenotype.

p75 neurotrophin receptor mediates apoptosis in transit-amplifying cells and its overexpression restores cell death in psoriatic keratinocytes.

p75 neurotrophin receptor (p75NTR) belongs to the TNF-receptor superfamily and signals apoptosis in many cell settings. In human epidermis, p75NTR is mostly confined to the transit-amplifying (TA) sub-population of basal keratinocytes. Brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4), which signals through p75NTR, induces keratinocyte apoptosis, whereas ß-amyloid, a ligand for p75NTR, triggers caspase-3 activation to a greater extent in p75NTR transfected cells. Moreover, p75NTR co-immunoprecipitates with NRAGE, induces the phosphorylation of c-Jun N-terminal kinase (JNK) and reduces nuclear factor kappa B (NF-κB) DNA-binding activity. p75NTR also mediates pro-NGF-induced keratinocyte apoptosis through its co-receptor sortilin. Furthermore, BDNF or ß-amyloid cause cell death in TA, but not in keratinocyte stem cells (KSCs) or in p75NTR silenced TA cells. p75NTR is absent in lesional psoriatic skin and p75NTR levels are significantly lower in psoriatic than in normal TA keratinocytes. The rate of apoptosis in psoriatic TA cells is significantly lower than in normal TA cells. BDNF or ß-amyloid fail to induce apoptosis in psoriatic TA cells, and p75NTR retroviral infection restores BDNF- or ß-amyloid-induced apoptosis in psoriatic keratinocytes. These results demonstrate that p75NTR has a pro-apoptotic role in keratinocytes and is involved in the maintenance of epidermal homeostasis.

The Skin Neurotrophic Network in Health and Disease / La Red Neurotrófica Cutánea en Piel Sana y Enferma

Neurotrophins (NTs) belong to a family of structurally and functionally related proteins that, depending on the tissue context and the receptors involved, promote neuronal cell survival and differentiation or cell death. NTs also exert important functions in other organs besides the nervous system, including the skin. The presence in the skin of diverse cell types which are able to secrete and/or to respond to stimulation by NTs creates a unique network of molecular signaling in the cutaneous microenvironment. This review summarizes currently available data on the expression and function of NTs and their receptors in several cell types in the skin (namely, keratinocytes, melanocytes and fibroblasts). The role of the skin NT network in the development and maintenance of some relevant skin diseases is presented and the potential implications for therapeutic intervention are discussed (AU)

Las neurotrofinas (NT) pertenecen a una familia de proteínas relacionadas estructural y funcionalmente que, dependiendo del tejido y del receptor implicados, promueven la supervicencia y diferenciación neuronal o la apoptosis. Las NT también ejercen importantes funciones en otros órganos, aparte del sistema nervioso, incluyendo la piel. La presencia de diversos tipos celulares en la piel que son capaces de segregar o responder al estímulo de las NT, crea una red única de señalización molecular en el microambiente cutáneo. Esta revisión resume los datos disponibles actualmente sobre la expresión y función de las NT y sus receptores en diversos tipos celulares de la piel (a saber: queratinocitos, melanocitos, fibroblastos). Se discute el papel de la red de NT cutáneas en el desarrollo y mantenimiento de algunas enfermedades cutáneas relevantes, así como las implicaciones potenciales para una intervención terapéutica (AU)

The skin neurotrophic network in health and disease.

Neurotrophins (NTs) belong to a family of structurally and functionally related proteins that, depending on the tissue context and the receptors involved, promote neuronal cell survival and differentiation or cell death. NTs also exert important functions in other organs besides the nervous system, including the skin. The presence in the skin of diverse cell types which are able to secrete and/or to respond to stimulation by NTs creates a unique network of molecular signaling in the cutaneous microenvironment. This review summarizes currently available data on the expression and function of NTs and their receptors in several cell types in the skin (namely, keratinocytes, melanocytes and fibroblasts). The role of the skin NT network in the development and maintenance of some relevant skin diseases is presented and the potential implications for therapeutic intervention are discussed.

Expression and function of neurotrophins and their receptors in human melanocytes.

Melanocytes and cells of the nervous system are of common ectodermal origin and neurotrophins (NT) have been shown to be released by human keratinocytes. We investigated the expression and function of NT [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, NT-4/-5] and their receptors in human melanocytes. Human melanocytes produce all NT in different amounts, whereas they only release NT-4. NT-4 release is downregulated, whereas NT-3 is upregulated by ultraviolet (UVB) irradiation. Melanocytes treated with phorbol 12-myristate 13-acetate (PMA) express TrkA and TrkB, but not TrkC. NT fail to stimulate melanocyte proliferation, whereas they stimulate the synthesis of tyrosinase and tyrosinase-related protein-1 (TRP-1). Finally, NT-3, NT-4 and NGF increase melanin production. Taken together, these results demonstrate an intriguing interaction between melanocytes and the nervous system. We speculate that NT could be considered the target of therapy for disorders of skin pigmentation.