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Loss of INK4a/Arf gene enhances ultraviolet radiation-induced cutaneous tumor development
Israr Ahmad1, Purushotham Guroji1, Amanda H DeBrot1
1Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract:
The CDKN2A locus encodes for tumor suppressor genes p16INK4a and p14Arf 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/cm2 ). For long-term studies, these mice were irradiated with UVB (200 mJ/cm2 ) 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 E2 (PGE2 ) 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.
Insights
Loss of tumor suppressor genes p16INK4a and p14Arf accelerates ultraviolet radiation-induced skin tumors by promoting inflammation. Targeting this inflammation may prevent skin cancer in individuals with CDKN2A mutations.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- The CDKN2A locus encodes tumor suppressor proteins p16INK4a and p14Arf, frequently inactivated in human skin tumors.
- Loss of INK4a/Arf function is implicated in cancer development, but its role in ultraviolet (UV) radiation-induced skin tumorigenesis and inflammation requires further elucidation.
Purpose of the Study:
- To investigate the relationship between the loss of INK4a/Arf activity and inflammation in the development of UV radiation-induced skin tumors.
- To determine if targeting UVB-induced inflammation can prevent skin tumors in mice with CDKN2A mutations.
Main Methods:
- Comparative study using INK4a/Arf-/- and wild-type (WT) mice subjected to single and chronic UVB irradiation.
- Assay of inflammatory biomarkers, cytokines, reactive oxygen species (ROS), and DNA damage (8-oxo-dG).
- Quantification of tumor incidence, immune cell infiltration (CD11b+ Gr1+), and molecular markers (NF-κB, COX-2, PGE2).
Main Results:
- Single UVB dose increased ROS and 8-oxo-dG lesions in INK4a/Arf-/- mice.
- Chronic UVB exposure led to 100% tumor development in INK4a/Arf-/- mice versus 0% in WT controls.
- Tumor development correlated with increased NF-κB, COX-2, PGE2, inflammatory cytokines, and myeloid cell infiltration in INK4a/Arf-/- mice.
Conclusions:
- Loss of INK4a/Arf function promotes UVB-induced skin inflammation and accelerates tumor development.
- UVB-induced inflammation, characterized by NF-κB and COX-2 pathways, plays a critical role in skin tumorigenesis.
- Targeting UVB-induced inflammation presents a potential strategy for preventing skin tumors in individuals with CDKN2A mutations.
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