Loss of INK4a/Arf gene enhances ultraviolet radiation-induced cutaneous tumor development.

Publisher: Munksgaard Country of Publication: Denmark NLM ID: 9301549 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0625 (Electronic) Linking ISSN: 09066705 NLM ISO Abbreviation: Exp Dermatol Subsets: MEDLINE

Original Publication: Copenhagen : Munksgaard, c1992-

Cyclin-Dependent Kinase Inhibitor p16/*genetics ; Cyclin-Dependent Kinase Inhibitor p16/*metabolism ; Radiodermatitis/*etiology ; Skin Neoplasms/*etiology ; Ultraviolet Rays/*adverse effects; 8-Hydroxy-2'-Deoxyguanosine ; Animals ; Antigens, Ly/metabolism ; Cell Nucleus/metabolism ; Cyclooxygenase 2/metabolism ; Cytoplasm/metabolism ; Deoxyguanosine/analogs & derivatives ; Deoxyguanosine/metabolism ; Dinoprostone/metabolism ; Female ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Mice ; Mice, Knockout ; Myeloid Cells/metabolism ; Myeloid Cells/pathology ; NF-KappaB Inhibitor alpha/metabolism ; Radiodermatitis/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Prostaglandin E/metabolism ; Skin Neoplasms/metabolism ; Transcription Factor RelA/metabolism ; Tumor Necrosis Factor-alpha/metabolism

The CDKN2A locus encodes for tumor suppressor genes p16 ^INK4a and p14 ^Arf which are frequently inactivated in human skin tumors. The purpose of this study was to determine the relationship between loss of INK4a/Arf activity and inflammation in the development of ultraviolet (UV) radiation-induced skin tumors. Panels of INK4a/Arf ^-/- mice and wild-type (WT) mice were treated with a single dose of UVB (200 mJ/cm ² ). For long-term studies, these mice were irradiated with UVB (200 mJ/cm ² ) three times weekly for 30 weeks. At the end of the experiment, tissues were harvested from mice and assayed for inflammatory biomarkers and cytokines. A single dose of UVB resulted in a significant increase in reactive oxygen species (ROS) and 8-dihydroxyguanosine (8-oxo-dG) lesions in INK4a/Arf ^-/- mice compared to WT mice. When subjected to chronic UVB, we found that 100% of INK4a/Arf ^-/- mice had tumors, whereas there were no tumors in WT controls after 24 weeks of UVB exposure. The increase in tumor development correlated with a significant increase in nuclear factor (NF)-κB, cyclooxygenase-2 (COX-2), prostaglandin E 2 (PGE 2 ) and its receptors both in UVB-exposed skin and in the tumors. A significant increase was seen in inflammatory cytokines in skin samples of INK4a/Arf ^-/- mice following treatment with chronic UVB radiation. Furthermore, significantly more CD11b ⁺ Gr1 ⁺ myeloid cells were present in UVB-exposed INK4a/Arf ^-/- mice compared to WT mice. Our data indicate that by targeting UVB-induced inflammation, it may be possible to prevent UVB-induced skin tumors in individuals that carry CDKN2A mutation.
(© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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I01 BX003395 United States BX BLRD VA; P30 CA013148 United States CA NCI NIH HHS; R01 CA193885 United States CA NCI NIH HHS; R01 AR071157 United States AR NIAMS NIH HHS; R03 AR057483 United States AR NIAMS NIH HHS

Keywords: INK4a/Arf; inflammation; skin cancer; ultraviolet radiation

0 (Antigens, Ly)
0 (Cdkn2a protein, mouse)
0 (Cyclin-Dependent Kinase Inhibitor p16)
0 (IL1B protein, mouse)
0 (Interleukin-1beta)
0 (Interleukin-6)
0 (Ly6G antigen, mouse)
0 (Reactive Oxygen Species)
0 (Receptors, Prostaglandin E)
0 (Rela protein, mouse)
0 (Transcription Factor RelA)
0 (Tumor Necrosis Factor-alpha)
0 (interleukin-6, mouse)
139874-52-5 (NF-KappaB Inhibitor alpha)
88847-89-6 (8-Hydroxy-2'-Deoxyguanosine)
EC 1.14.99.1 (Cyclooxygenase 2)
G9481N71RO (Deoxyguanosine)
K7Q1JQR04M (Dinoprostone)

Date Created: 20170419 Date Completed: 20180720 Latest Revision: 20191210

20250114

PMC5901725

10.1111/exd.13356

28418604