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Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage.

ABSTRACT: Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm-/- mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm-/- mice, with both or a single Trp53 allele were exposed to UV for 2 or 25 weeks. In wild type mice the central cornea and stroma became atrophic with increasing time of exposure while the peripheral regions became hyperplastic, presumably as a reparative process. Brm-/-, Trp53+/-, and particularly the Brm-/- Trp53+/- mice had an exaggerated hyperplastic regeneration response in the corneal epithelium and stroma so that the central epithelial atrophy or stromal loss was reduced. UV induced hyperplasia of the epidermis and corneal epithelium, with an increase in the number of dividing cells as determined by Ki-67 expression. This response was considerably greater in both the Brm-/- Trp53+/+ and Brm-/- Trp53+/- mice indicating that Brm protects from UV-induced enhancement of cell division, even with loss of one Trp53 allele. Cell division was disorganized in Brm-/- mice. Rather than being restricted to the basement membrane region, dividing cells were also present in the suprabasal regions of both tissues. Brm appears to be a tumour suppressor gene that protects from skin and ocular photocarcinogenesis. These studies indicate that Brm protects from UV-induced hyperplastic growth in both cutaneous and corneal keratinocytes, which may contribute to the ability of Brm to protect from photocarcinogenesis.

SUBMITTER: Hassan NM

PROVIDER: S-EPMC4177874 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage.

Hassan Nur Mohammad Monsur NM Painter Nicole N Howlett C Rolfe CR Farrell Andrew W AW Di Girolamo Nick N Lyons J Guy JG Halliday Gary M GM

PloS one 20140925 9

Ultraviolet radiation (UV) from sunlight is the primary cause of skin and ocular neoplasia. Brahma (BRM) is part of the SWI/SNF chromatin remodeling complex. It provides energy for rearrangement of chromatin structure. Previously we have found that human skin tumours have a hotspot mutation in BRM and that protein levels are substantially reduced. Brm-/- mice have enhanced susceptibility to photocarcinogenesis. In these experiments, Brm-/- mice, with both or a single Trp53 allele were exposed to ...[more]

PMID: 25254962

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Project description:Background:Keloids are benign fibroproliferative skin lesions that are difficult to treat and become a lifetime predicament for patients. Several treatment modalities have been put forth, but as yet no satisfactory approach to the prevention or treatment of keloids has been identified. The process of epithelial-to-mesenchymal transition (EMT) has been implicated in keloid scarring, as keloid keratinocytes display an EMT-like phenotype. This study investigated the potential of pirfenidone, an antifibrotic agent, to counteract EMT-like alterations in keloid keratinocytes, including gene expression, cell migratory and proliferative functions. Methods:Normal and keloid keratinocytes were isolated from discarded normal skin tissues and from resected keloid tissues, respectively. Cells were quiesced for 24 h without epidermal growth factor DS-Qi1MCDigital and were exposed to transforming growth factor-beta1 (TGF-?1; 10 ng/mL), with or without pirfenidone (400 ?g/mL), for an additional 24 h. The effects of pirfenidone on cytotoxicity, cell migration, cell proliferation, and on expression of genes and proteins involved in EMT were assayed. Statistical significance was determined by two-way ANOVA using Sigma Plot. Results:We found that pirfenidone did not elicit any cytotoxic effect at concentrations up to 1000 ?g/mL. A statistically significant dose-dependent decrease in basal cell proliferation rate was noted in both normal and keloid keratinocytes when exposed to pirfenidone at concentrations ranging from 200 to 1000 ?g/mL. Pirfenidone significantly decreased basal cell migration in both normal and keloid keratinocytes, but a significant decrease in TGF-?1-induced cell migration was seen only in keloid keratinocytes. Significant inhibition of the expression of TGF-?1-induced core EMT genes, namely hyaluronan synthase 2, vimentin, cadherin-11, and wingless-type MMTV integration site family, member 5A along with fibronectin-1, was observed in both normal and keloid keratinocytes treated with pirfenidone. In addition, the protein levels of vimentin and fibronectin were significantly reduced by pirfenidone (400 ?g/mL) in both normal and keloid keratinocytes. Conclusions:For the first time, this study shows the efficacy of pirfenidone in inhibiting the EMT-like phenotype in keratinocytes derived from keloids, suggesting that pirfenidone may counteract a critical contributor of keloid progression and recurrence.

Dataset Information

Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage.

Publications

Brm inhibits the proliferative response of keratinocytes and corneal epithelial cells to ultraviolet radiation-induced damage.

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