The absence of Brm exacerbates photocarcinogenesis.

Brm is an ATPase subunit of the SWI/SNF chromatin-remodelling complex. Previously, we identified a novel hotspot mutation in Brm in human skin cancer, which is caused by exposure to ultraviolet radiation (UVR). As SWI/SNF is involved in DNA repair, we investigated whether Brm-/- mice had enhanced photocarcinogenesis. P53+/- and Brm-/-p53+/- mice were also examined as the p53 tumor suppressor gene is mutated early during human skin carcinogenesis. Mice were exposed to a low-dose irradiation protocol that caused few skin tumors in wild-type mice. Brm-/- mice with both p53 alleles intact had an increased incidence of skin and ocular tumors compared to Brm+/+p53+/+ controls. Brm loss in p53+/- mice did not further enhance skin or ocular cancer incidence beyond the increased photocarcinogenesis in p53+/- mice. However, the skin tumors that arose early in Brm-/- p53+/- mice had a higher growth rate. Brm-/- did not prevent UVR-induced apoptotic sunburn cell formation, which is a protective response. Unexpectedly, Brm-/- inhibited UVR-induced immunosuppression, which would be predicted to reduce rather than enhance photocarcinogenesis. In conclusion, the absence of Brm increased skin and ocular photocarcinogenesis. Even when one allele of p53 is lost, Brm has additional tumor suppressing capability.

Topical 'Sydney' propolis protects against UV-radiation-induced inflammation, lipid peroxidation and immune suppression in mouse skin.

BACKGROUND: Propolis is a honeybee product that has been used in traditional medicine for antioxidant, immune-stimulating, anti-inflammatory and anti-cancer effects. Here, the potential of the topical application of a crude ethanolic extract of Sydney propolis to protect against UV-radiation-induced impairments associated with an increased risk of photocarcinogenesis has been tested in the hairless mouse. METHODS: Solutions providing between 10 and 200 mg/kg propolis were applied to the skin following UV irradiation. The inflammation from exposure to UV (290-400 nm) was quantitated by measurement of increased skinfold thickness; lipid peroxidation was assayed by the induction of thiobarbituric acid reactive species in the skin; immune function was measured by the contact hypersensitivity (CHS) reaction and supported by the changes in epidermal cytokine expression. RESULTS: Propolis protected significantly and dose-dependently against both sunburn oedema and the suppression of CHS, and (at 100 mg/kg) against lipid peroxidation. The overexpression of IL-10 and the depletion of IL-12 characteristic of photoimmune suppression were markedly reduced by propolis. Further, the upregulation of IL-6 was decreased, and the associated induction of haem oxygenase was shown to play a role in propolis skin protection. CONCLUSIONS: Sydney propolis was able to effectively reduce cutaneous inflammation, immunosuppression and lipid peroxidation induced by UV exposure. It is concluded that Sydney propolis might have strong beneficial protective effects against photodamage and skin cancer development in humans.

Snail transcription factors in keratinocytes: Enough to make your skin crawl.

Keratinocytes are the cells in vertebrates that form the frontline barrier to the environment, and are also the most common origin of human cancer. They normally retain tight cell-cell adhesion and low motility, allowing them to terminally differentiate as they stratify. However, they must be able to respond to tissue damage by migrating into and across wounds. This requires reduced mutual adhesion, suppressed terminal differentiation and increased motility, processes driven by the Snail family of transcriptional repressors. The quantity, location and activity of Snail proteins are regulated by growth factors and cytokines to mediate these responses and invoke an inflammatory response. Subversion of these same pathways can promote carcinoma invasion and metastasis. Signaling network facts: • Snail1 and Snail2 in keratinocytes are important in promoting migration, inflammation and carcinogenesis, and suppressing terminal differentiation. • Extracellular stimuli, including TGFR and EGFR ligands, regulate Snails transcriptionally, via SMAD and MAPK pathways, and post-translationally, by modulating GSK3 and PAK1 activity, which determine Snail stability and intracellular location. • Snails directly repress transcription of genes important for cell-cell adhesion and cornified envelope formation. • Down-regulation of epithelial cadherins by Snails allows LIMDPs to relocate from adherens junctions to the cytoplasm, where they stimulate MAPK pathways, and to the nucleus, where they bind directly to Snails and act as corepressors. • Snail2 is essential for re-epithelialization of healing wounds and can be up-regulated in the keratinocytes at wound margins by p38, ERK1/2 and ERK5 MAPKs, and the arylhydrocarbon receptor. • Further information on signaling related to Snail proteins can be found online at KEGG: http://www.genome.jp/kegg-bin/show pathway?hsa04520 http://www.genome.jp/kegg-bin/show_pathway?hsa04350 http://www.genome.jp/kegg-bin/show pathway?hsa04012.