Carcinogenesis Advance Access originally published online on July 7, 2009
Carcinogenesis 2009 30(9):1597-1605; doi:10.1093/carcin/bgp160
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Deficient deletion of apoptotic cells by macrophage migration inhibitory factor (MIF) overexpression accelerates photocarcinogenesis
1 Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
2 Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
3 Department of Medical Information, Hokkaido Information University, Ebetsu 069-8585, Japan
* To whom correspondence should be addressed. Tel: +81 76 434 7305; Fax: +81 76 434 5028; Email: shimizut{at}med.u-toyama.ac.jp
Chronic ultraviolet (UV) exposure can increase the occurrence of p53 mutations, thus leading to a dysregulation of apoptosis and the initiation of skin cancer. Therefore, it is extremely important that apoptosis is induced quickly after UV irradiation, without any dysregulation. Recent studies have suggested a potentially broader role for macrophage migration inhibitory factor (MIF) in growth regulation via its ability to antagonize p53-mediated gene activation and apoptosis. To further elucidate the possible role of MIF in photocarcinogenesis, the acute and chronic UVB effect in the skin was examined using macrophage migration inhibitory factor transgenic (MIF Tg) and wild-type (WT) mice. The MIF Tg mice exposed to chronic UVB irradiation began to develop skin tumors after 
14 weeks, whereas the WT mice began to develop tumors after 18 weeks. A higher incidence of tumors was observed in the MIF Tg in comparison with the WT mice after chronic UVB irradiation. Next, we clarified whether the acceleration of photo-induced carcinogenesis in the MIF Tg mice was mediated by the inhibition of apoptosis There were fewer sunburned cells in the epidermis of the MIF Tg mice than the WT mice after acute UVB exposure. The epidermis derived from the MIF Tg mice exhibited substantially decreased levels of p53, bax and p21 after UVB exposure in comparison with the WT mice. Collectively, these findings suggest that chronic UVB exposure enhances MIF production, which may inhibit the p53-dependent apoptotic processes and thereby induce photocarcinogenesis in the skin.
Abbreviations: CPD, cyclobutane pyrimidine dimmer; IL, interleukin; MIF, macrophage migration inhibitory factor; MIF Tg, macrophage migration inhibitory factor transgenic; mRNA, messenger RNA; PBS, phosphate-buffered saline; TUNEL, terminal deoxynucleotidyl transferase nick end labeling; TNF, tumor necrosis factor; UV, ultraviolet; WT, wild-type
These authors contributed equally to this work. Received March 2, 2009; revised June 15, 2009; accepted June 20, 2009.