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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)
Published on: December 19, 2019
Dual role for Id2 in chemical carcinogen-induced skin tumorigenesis
Atsushi Tokuriki1, Tomonori Iyoda, Kayo Inaba
1Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
Abstract:
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 gammadelta 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 gammadelta T cell-mediated skin immunosurveillance and by promoting tumor cell proliferation via the control of the cyclin D1 protein level.
Insights
Inhibitor of DNA binding 2 (Id2) deficiency increases skin tumor number but reduces tumor size in mice. Id2 plays a dual role in skin cancer by regulating T cell immunosurveillance and tumor cell proliferation.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Inhibitor of DNA binding 2 (Id2) is a key regulator of cell differentiation and proliferation.
- Id2 influences basic helix-loop-helix transcription factors, impacting cellular processes.
- The role of Id2 in skin tumorigenesis and its underlying mechanisms require further elucidation.
Purpose of the Study:
- To investigate the role of Id2 in skin tumor formation using a chemical carcinogenesis model in mice.
- To analyze the impact of Id2 deficiency on tumor development, immunosurveillance, and cell proliferation.
- To explore the molecular mechanisms by which Id2 influences skin tumorigenesis.
Main Methods:
- A two-step chemical carcinogenesis protocol was employed in Id2-deficient (Id2(-/-)) and wild-type mice.
- Tumor incidence, size, and histological features were assessed.
- Epidermal gammadelta T cell populations, cell proliferation, apoptosis, and protein levels of cell cycle regulators (cyclin D1, cyclin E, p27) were analyzed.
Main Results:
- Id2(-/-) mice exhibited a 3.5-fold increase in tumor number but a reduced tumor diameter compared to wild-type mice.
- Epidermal gammadelta T cells, crucial for skin immunosurveillance, were significantly reduced in Id2(-/-) mice.
- Tumors in Id2(-/-) mice showed reduced cell proliferation and decreased cyclin D1 protein levels, despite no significant differences in tumor type, vascularization, or apoptosis.
Conclusions:
- Id2 exhibits a dual role in skin tumorigenesis: it suppresses tumor development via gammadelta T cell-mediated immunosurveillance and promotes tumor cell proliferation by regulating cyclin D1.
- Loss of Id2 impairs skin immunosurveillance, leading to increased tumor initiation.
- Id2 promotes tumor cell proliferation, potentially through the modulation of cyclin D1 levels.
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