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Expression of DNA damage response biomarkers during oral carcinogenesis
1Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Abstract:
Emerging evidence suggests that an intact DNA damage response (DDR) serves as a potent barrier to malignant transformation. Using immunohistochemistry and patient-derived biopsy samples, we investigated whether the same may hold true during oral carcinogenesis. DNA damage accumulates early in the development of oral squamous cell carcinoma (OSCC) as evidenced by the detection of surrogate DDR biomarkers γ-H2A.X and phosphorylated CHK2-threonine-68 (phospho-CHK2(Thr68)) in epithelial hyperplasias. However, whereas γ-H2A.X expression peaked in dysplastic epithelium, its levels were significantly reduced in OSCCs (χ(2) = 7.655; P = .02). In contrast, there was a trend toward increased phospho-CHK2(Thr68) expression with increasing severity of the pathology. Nonetheless, combined expression of the biomarkers was significantly greater in the nontransformed tissues relative to OSCCs (χ(2) = 6.42; P = .04). Thus, our findings suggest that early therapeutic exploitation of the DDR may be worthy of investigation as a means by which to limit OSCC development.
Insights
The DNA damage response (DDR) acts as a barrier against cancer. In oral squamous cell carcinoma (OSCC), DDR biomarkers decrease, suggesting early DDR exploitation could limit OSCC development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The DNA damage response (DDR) is crucial in preventing malignant transformation.
- Oral carcinogenesis involves complex genetic and molecular alterations.
- Understanding DDR dynamics in oral squamous cell carcinoma (OSCC) is vital for early detection and intervention.
Purpose of the Study:
- To investigate the role of DDR biomarkers in oral carcinogenesis.
- To assess the expression patterns of γ-H2A.X and phospho-CHK2(Thr68) during OSCC development.
- To explore the potential of targeting DDR for OSCC prevention.
Main Methods:
- Immunohistochemistry was employed to analyze patient-derived biopsy samples.
- Expression levels of DDR biomarkers γ-H2A.X and phospho-CHK2(Thr68) were quantified.
- Statistical analysis was performed to correlate biomarker expression with disease severity.
Main Results:
- DNA damage accumulates early in oral carcinogenesis, indicated by increased γ-H2A.X and phospho-CHK2(Thr68) in hyperplasias.
- γ-H2A.X expression decreased significantly in OSCC compared to dysplastic epithelium.
- Combined expression of DDR biomarkers was higher in non-transformed tissues than in OSCCs.
Conclusions:
- The findings suggest a potential decline in DDR efficacy during late-stage OSCC development.
- Early therapeutic targeting of the DDR may be a promising strategy to limit OSCC progression.
- Further investigation into DDR modulation for OSCC prevention is warranted.
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