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Alteration of p53-binding protein 1 expression during skin carcinogenesis: association with genomic instability
Yuki Naruke1, Masahiro Nakashima, Keiji Suzuki
1Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki Unviersity Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Abstract:
Epidermal cells are the first cells to be exposed to environmental genotoxic agents such as ultraviolet and ionizing radiations, which induce DNA double strand breaks (DSB) and activate DNA damage response (DDR) to maintain genomic integrity. Defective DDR can result in genomic instability (GIN) which is considered to be a central aspect of any carcinogenic process. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins. Because 53BP1 molecules localize at the sites of DSB and rapidly form nuclear foci, the presence of 53BP1 nuclear foci can be considered as a cytological marker for endogenous DSB reflecting GIN. The levels of GIN were analyzed by immunofluorescence studies of 53BP1 in 56 skin tumors that included 20 seborrheic keratosis, eight actinic keratosis, nine Bowen's disease, nine squamous cell carcinoma, and 10 basal cell carcinoma. This study demonstrated a number of nuclear 53BP1 foci in human skin tumorigenesis, suggesting a constitutive activation of DDR in skin cancer cells. Because actinic keratosis showed a high DDR type of 53BP1 immunoreactivity, GIN seems to be induced at the precancerous stage. Furthermore, invasive cancers exhibited a high level of intense, abnormal 53BP1 nuclear staining with nuclear accumulation of p53, suggesting a disruption of DDR leading to a high level of GIN in cancer cells. The results of this study suggest that GIN has a crucial role in the progression of skin carcinogenesis. The detection of 53BP1 expression by immunofluorescence can be a useful histological marker to estimate the malignant potential of human skin tumors.
Insights
Genomic instability (GIN) is crucial in skin cancer progression. 53BP1 nuclear foci indicate DNA damage response activation, serving as a marker for GIN and malignant potential in skin tumors.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Epidermal cells face genotoxic agents, triggering DNA damage response (DDR) to maintain genomic integrity.
- Defective DDR leads to genomic instability (GIN), a key factor in cancer development.
- 53BP1 protein localizes to DNA double-strand breaks (DSB) and forms nuclear foci, acting as a marker for GIN.
Purpose of the Study:
- To analyze genomic instability levels in various human skin tumors using 53BP1 as a biomarker.
- To investigate the role of 53BP1 and DDR in the progression of skin carcinogenesis.
- To evaluate 53BP1 immunofluorescence as a potential marker for estimating the malignant potential of skin tumors.
Main Methods:
- Immunofluorescence studies were performed to detect 53BP1 nuclear foci.
- 53BP1 levels were analyzed in 56 skin tumors, including seborrheic keratosis, actinic keratosis, Bowen's disease, squamous cell carcinoma, and basal cell carcinoma.
- Nuclear accumulation of p53 was also assessed in invasive cancers.
Main Results:
- A significant number of 53BP1 nuclear foci were observed in human skin tumors, indicating constitutive DDR activation.
- Actinic keratosis, a precancerous lesion, showed high 53BP1 immunoreactivity, suggesting GIN induction at this stage.
- Invasive cancers displayed intense, abnormal 53BP1 staining and p53 accumulation, pointing to disrupted DDR and high GIN.
Conclusions:
- Genomic instability plays a critical role in the progression of skin carcinogenesis.
- 53BP1 nuclear foci serve as a reliable cytological marker for endogenous DSB and GIN.
- 53BP1 detection via immunofluorescence can be a valuable histological tool for assessing the malignant potential of skin tumors.
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