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11Beta-hydroxysteroid dehydrogenase 1 expression in squamous cell carcinomas of the head and neck
S Gronau1, D Koenig Greger, M Jerg
1Department of Otorhinolaryngology, University of Ulm, Germany. silke.gronau@medizin.uni-ulm.de
Abstract:
11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been identified as a major detoxification enzyme of one of the most potent tobacco smoke-derived carcinogens, NNK. If not metabolized by 11beta-HSD1, activation of NNK by cytochrome p450 mono-oxidase 2D6 (CYP2D6) results in an electrophile intermediate responsible for DNA damage. Interindividual variability in the expression of 11beta-HSD1 and CYP2D6 has been found to influence the susceptibility to lung cancer. The aim of this study was to compare 11beta-HSD1 mRNA expression and CYP2D6 metabolizer status in pharyngeal tissues of patients with oropharyngeal carcinoma and controls. In 20 patients with oropharyngeal cancer and 15 non-smoking controls, the 11beta-HSD1 mRNA expression was assessed with RT-PCR. The frequency of genetic polymorphisms of the CYP2D6 gene was assessed using RFLP. It was found that 11beta-HSD1 mRNA is expressed in human pharyngeal mucosa. It is upregulated in mucosa exposed to tobacco smoke. In tumour tissues, 11beta-HSD1 expression was significantly lower than in non-affected mucosa. The frequency distribution of CYP2D6 gene polymorphisms was similar in patients and controls. Chronic tobacco abuse results in 11beta-HSD1 enzyme induction. A reduction of 11beta-HSD1 expression in tumour tissues could be a consequence of malignantly transformed cells. It remains unclear if the lower 11beta-HSD1 expression gives rise to an increased rate of additional mutations.
Insights
11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) detoxifies tobacco carcinogens. Its expression is lower in oropharyngeal tumors, potentially increasing cancer risk due to DNA damage from NNK, especially in tobacco users.
Area of Science:
- Biochemistry
- Oncology
- Toxicology
Background:
- 11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) is crucial for detoxifying NNK, a potent tobacco carcinogen.
- Variations in 11beta-HSD1 and CYP2D6 influence lung cancer susceptibility.
- Oropharyngeal carcinoma risk is linked to carcinogen metabolism.
Purpose of the Study:
- To compare 11beta-HSD1 mRNA expression and CYP2D6 metabolizer status in patients with oropharyngeal carcinoma versus controls.
- To investigate the role of these enzymes in tobacco smoke-related head and neck cancer.
Main Methods:
- Quantitative RT-PCR to assess 11beta-HSD1 mRNA expression in pharyngeal tissues.
- Restriction Fragment Length Polymorphism (RFLP) to determine CYP2D6 genetic polymorphisms.
- Study included 20 oropharyngeal cancer patients and 15 non-smoking controls.
Main Results:
- 11beta-HSD1 mRNA is expressed in human pharyngeal mucosa and upregulated by tobacco smoke exposure.
- Tumor tissues showed significantly lower 11beta-HSD1 expression compared to non-affected mucosa.
- CYP2D6 polymorphism frequencies were similar between patients and controls.
Conclusions:
- Chronic tobacco use induces 11beta-HSD1, but its reduced expression in tumors may be due to malignant transformation.
- The impact of lower 11beta-HSD1 expression on mutation rates in oropharyngeal cancer requires further investigation.
- Enzyme activity and genetic variations play a role in tobacco-induced oropharyngeal cancer development.