Carcinogenesis Advance Access originally published online on July 8, 2009
Carcinogenesis 2009 30(9):1645-1650; doi:10.1093/carcin/bgp172
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Dual role for Id2 in chemical carcinogen-induced skin tumorigenesis
1 Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences
2 Division of Dermatology, Department of Sensory and Locomotor Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
3 Department of Animal Development and Physiology, Graduate School of Biostudies
4 Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research
5 Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
6 Research and Education Program for Life Science, University of Fukui, Fukui 910-1193, Japan
* To whom correspondence should be addressed. Tel: +81 776 61 8312; Fax: +81 776 61 8164; Email: yokota{at}u-fukui.ac.jp
Inhibitor of DNA binding 2 (Id2) is a negative regulator of basic helix-loop-helix transcription factors and is involved in the control of cellular differentiation and proliferation. By using a two-step chemical carcinogenesis protocol, we evaluated the role of Id2 in skin tumor formation in mice. Twenty weeks after the initiation, the number of tumors formed in the Id2–/– mice was 3.5-fold higher than that in their wild-type littermates, whereas the diameter of tumors in the Id2–/– mice was about half of that of the tumors in the wild-type mice. In the Id2–/– mice, epidermal 
T cells, which play a key role in immunosurveillance against skin tumor development, were barely detectable. Although histological analyses demonstrated no apparent difference in tumor cell type, tumor vessel formation or apoptosis, the proportion of proliferating cells was reduced in the tumors in the Id2–/– mice compared with those in the wild-type mice. In the wild-type mice, the expression of Id2 was enhanced in skin tumors compared with that in ear epidermal cells. Biochemical analysis demonstrated that cyclin D1 was reduced at the protein level in the tumors in the Id2–/– mice, whereas other factors such as cyclin E and p27 were not altered significantly. Our results reveal that Id2 plays a dual role in skin tumorigenesis by suppressing tumor development through the establishment of epidermal T cell-mediated skin immunosurveillance and by promoting tumor cell proliferation via the control of the cyclin D1 protein level.
Abbreviations: CDK, cyclin-dependent kinase; DMBA, dimethylbenz(a)anthracene; Erk, extracellular signal-regulated kinase; HLH, helix-loop-helix; Id, inhibitors of DNA binding; Id2, Inhibitor of DNA binding 2; mRNA, messenger RNA; TPA, 12-O-tetradecanoylphorbol-13-acetate
Received December 23, 2008; revised June 22, 2009; accepted June 25, 2009.