Background: UV radiation induces significant DNA damage in keratinocytes and is a known risk factor for skin\ncarcinogenesis. However, it has been reported previously that repeated and simultaneous exposure to UV and heat\nstress increases the rate of cutaneous tumour formation in mice. Since constant exposure to high temperatures and\nUV are often experienced in the environment, the effects of exposure to UV and heat needs to be clearly addressed\nin human epidermal cells.\nMethods: In this study, we determined the effects of repeated UVB exposure 1 kJ/m2 followed by heat (39 �°C) to\nhuman keratinocytes. Normal human ex vivo skin models and primary keratinocytes (NHEK) were exposed once a\nday to UVB and/or heat stress for four consecutive days. Cells were then assessed for changes in proliferation,\napoptosis and gene expression at 2 days post-exposure, to determine the cumulative and persistent effects of UV\nand/or heat in skin keratinocytes.\nResults: Using ex vivo skin models and primary keratinocytes in vitro, we showed that UVB plus heat treated\nkeratinocytes exhibit persistent DNA damage, as observed with UVB alone. However, we found that apoptosis was\nsignificantly reduced in UVB plus heat treated samples. Immunohistochemical and whole genome transcription\nanalysis showed that multiple UVB plus heat exposures induced inactivation of the p53-mediated stress response.\nFurthermore, we demonstrated that repeated exposure to UV plus heat induced SIRT1 expression and a decrease in\nacetylated p53 in keratinocytes, which is consistent with the significant downregulation of p53-regulated\npro-apoptotic and DNA damage repair genes in these cells.\nConclusion: Our results suggest that UVB-induced p53-mediated cell cycle arrest and apoptosis are reduced in the\npresence of heat stress, leading to increased survival of DNA damaged cells. Thus, exposure to UVB and heat stress\nmay act synergistically to allow survival of damaged cells, which could have implications for initiation skin\ncarcinogenesis.
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