C/EBPα expression is downregulated in human nonmelanoma skin cancers and inactivation of C/EBPα confers susceptibility to UVB-induced skin squamous cell carcinomas
| Autor: | Robert C. Smart, Songyun Zhu, Rakesh Ranjan, Yu-Ying He, Jonathan R. Hall, Elizabeth A. Thompson, John S. House, Jeanne Burr, David M. Owens |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Pathology medicine.medical_specialty Cell cycle checkpoint Neoplasms Radiation-Induced Skin Neoplasms DNA damage Ultraviolet Rays Human skin Dermatology Biology Biochemistry Article 03 medical and health sciences Mice 0302 clinical medicine medicine Skin Squamous Cell Carcinoma CCAAT-Enhancer-Binding Protein-alpha Animals Humans skin and connective tissue diseases Molecular Biology Cells Cultured 030304 developmental biology Skin 0303 health sciences Mice Hairless Epidermis (botany) integumentary system Cell Cycle Cell Biology Cell cycle medicine.disease Genes p53 3. Good health Keratosis Actinic Mice Inbred C57BL medicine.anatomical_structure 030220 oncology & carcinogenesis Mutation Cancer research Carcinoma Squamous Cell Skin cancer Keratinocyte Precancerous Conditions |
| Zdroj: | The Journal of investigative dermatology. 131(6) |
| ISSN: | 1523-1747 |
| Popis: | Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBPα (CCAAT/enhancer-binding protein-α) in the DNA damage response network, where C/EBPα is induced following UVB DNA damage, regulates the G(1) checkpoint, and diminished or ablated expression of C/EBPα results in G(1) checkpoint failure. In the current study we observed that C/EBPα is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBPα expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBPα similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBPα. To determine the significance of C/EBPα in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBPα (CKOα) were exposed to UVB. CKOα mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKOα mice displayed keratinocyte cell cycle checkpoint failure in vivo in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBPα is silenced in human SCC and loss of C/EBPα confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB. |
| Databáze: | OpenAIRE |
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