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Molecular Oncology, Markers, Clinical Correlates |
Departments of 1 Thoracic/Head and Neck Medical Oncology, 2 Leukemia, 3 Biostatistics, and 4 Clinical Cancer Prevention, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, and 5 Department of Pathology, Osaka City University Medical School, Osaka, Japan
Purpose: Retinoic acid receptor-ß2 (RAR-ß2) expression is suppressed in oral premalignant lesions and head and neck squamous cell carcinomas (HNSCCs). This study was conducted to determine whether RAR-ß2 gene expression in such lesions can be silenced by promoter methylation.
Experimental Design: RAR-ß2 methylation was analyzed in DNA samples from 22 pairs of primary HNSCC and adjacent normal epithelium, 124 samples of oral leukoplakia, and 18 HNSCC cell lines using methylation-specific PCR. RAR-ß2 promoter was methylated in 67, 56, and 53% of HNSCC tumors, HNSCC cell lines, and microdissected oral leukoplakia specimens, respectively. RAR-ß2 hypermethylation was confirmed by sodium bisulfite-PCR combined with restriction enzyme digestion analysis and by random cloning and sequencing of bisulfite-treated DNA isolates.
Results: Significantly higher RAR-ß2 hypermethylation levels were found in tumor tissue compared with adjacent normal tissue (P = 0.002). RAR-ß2 methylation in the cell lines was correlated with loss of RAR-ß2 expression (P = 0.013) and inversely related to the presence of mutated p53 (P = 0.025). The demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) restored RAR-ß2 inducibility by all-trans-retinoic acid (ATRA) in some of the cell lines, which posses a methylated RAR-ß2 promoter. In some cell lines, this effect was associated with increased growth inhibition after combined treatment with 5-aza-CdR and ATRA.
Conclusions: RAR-ß2 silencing by methylation is an early event in head and neck carcinogenesis; 5-Aza-CdR can restore RAR-ß2 inducibility by ATRA in most cell lines, and the combination of 5-aza-CdR and ATRA is more effective in growth inhibition than single agents.
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