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Therapy Testing in a Spheroid-based 3D Cell Culture Model for Head and Neck Squamous Cell Carcinoma
Published on: April 20, 2018
RAR beta2 suppression in head and neck squamous cell carcinoma correlates with site, histology and age
Judit Olasz1, Alíz Juhász, Eva Remenár
1Department of Pathogenetics, National Institute of Oncology, 1122 Budapest, Hungary.
Abstract:
Retinoids as important growth and differentiation regulating agents have a potential role in the chemoprevention of head and neck squamous cell carcinoma (HNSCC). Despite the promising preclinical and early clinical findings, limitations of application are raised by intrinsic resistance acquired during carcinogenesis. Retinoic acid receptor beta2 (RAR beta2) is one of the proximate mediators of retinoid signalling and its expression is often diminished in early stages of head and neck carcinogenesis. One form of retinoid resistance has been associated with the methylation-induced silencing of the RAR beta gene. We studied primary HNSCC samples of different anatomical sites in respect of methylation, expression and allelic loss of RAR beta gene. A strong correlation (p<0.01) was found between hyper-methylation and reduced expression of RAR beta2, however the allelic loss at 3p24, the locus of RAR beta, did not considerably influence its mRNA level. Hypopharynx tumors showed significantly lower hypermethylation (p<0.05) and higher mRNA expression levels of RAR beta2 compared to the tumors located at other sites of the head and neck. We could also provide evidence that poorly differentiated grade 3 tumors had significantly higher RAR beta2 expression and lower methylation levels (p<0.05) than better differentiated grade 1 and grade 2 tumors. In addition, we found a good correlation between the methylation degree of the RAR beta2 promoter and the ages of patients. Collectively, our results suggest that evaluation of several factors such as tumor location, age, histology and methylation state of the RAR beta gene might contribute to the selection of patients for retinoid-based chemoprevention.
Insights
Retinoid resistance in head and neck cancer may be linked to RAR beta2 gene silencing. Methylation levels, tumor site, and grade influence RAR beta2 expression, suggesting factors for retinoid chemoprevention patient selection.
Area of Science:
- Oncology
- Molecular Biology
- Chemoprevention
Background:
- Retinoids regulate growth and differentiation, showing potential in head and neck squamous cell carcinoma (HNSCC) chemoprevention.
- Intrinsic retinoid resistance, often linked to diminished Retinoic Acid Receptor beta2 (RAR beta2) expression, limits therapeutic application in HNSCC.
- Methylation-induced silencing of the RAR beta gene is a key mechanism contributing to retinoid resistance.
Purpose of the Study:
- To investigate the methylation status, expression levels, and allelic loss of the RAR beta gene in primary HNSCC samples.
- To explore the correlation between RAR beta2 gene alterations and HNSCC characteristics, including tumor location, differentiation grade, and patient age.
- To identify factors that could aid in selecting patients for retinoid-based chemoprevention strategies.
Main Methods:
- Analysis of methylation, mRNA expression, and allelic loss of the RAR beta gene in primary HNSCC samples from various anatomical sites.
- Statistical correlation analysis to assess relationships between RAR beta2 gene status and clinicopathological features.
- Comparison of methylation and expression levels across different tumor locations, differentiation grades, and patient age groups.
Main Results:
- A significant inverse correlation was observed between RAR beta2 gene hyper-methylation and its mRNA expression (p<0.01).
- Allelic loss at the RAR beta locus (3p24) did not significantly impact RAR beta2 mRNA levels.
- Hypopharyngeal tumors exhibited lower hyper-methylation and higher RAR beta2 expression compared to other head and neck sites (p<0.05).
- Poorly differentiated (grade 3) tumors showed higher RAR beta2 expression and lower methylation than well-differentiated tumors (p<0.05).
- A correlation was found between RAR beta2 promoter methylation degree and patient age.
Conclusions:
- Tumor location, histological grade, and RAR beta gene methylation status are significant factors influencing RAR beta2 expression in HNSCC.
- These findings suggest that evaluating these factors may improve patient selection for retinoid-based chemoprevention.
- Understanding the methylation dynamics of RAR beta2 is crucial for overcoming retinoid resistance in HNSCC treatment.
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