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      Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis.

      Clinical cancer research : an official journal of the American Association for Cancer Research

      Humans, Adult, Aged, Aged, 80 and over, Base Sequence, Carcinoma, Squamous Cell, genetics, pathology, Cell Division, Cell Line, Tumor, Cloning, Molecular, DNA Methylation, DNA Primers, DNA, Neoplasm, Female, Gene Silencing, Head and Neck Neoplasms, Leukoplakia, Oral, Male, Middle Aged, Molecular Sequence Data, Mouth Neoplasms, Polymerase Chain Reaction, Precancerous Conditions, Promoter Regions, Genetic, Receptors, Retinoic Acid, drug effects, Tretinoin, pharmacology

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          Abstract

          Retinoic acid receptor-beta(2) (RAR-beta(2)) expression is suppressed in oral premalignant lesions and head and neck squamous cell carcinomas (HNSCCs). This study was conducted to determine whether RAR-beta(2) gene expression in such lesions can be silenced by promoter methylation. RAR-beta(2) 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-beta(2) promoter was methylated in 67, 56, and 53% of HNSCC tumors, HNSCC cell lines, and microdissected oral leukoplakia specimens, respectively. RAR-beta(2) hypermethylation was confirmed by sodium bisulfite-PCR combined with restriction enzyme digestion analysis and by random cloning and sequencing of bisulfite-treated DNA isolates. Significantly higher RAR-beta(2) hypermethylation levels were found in tumor tissue compared with adjacent normal tissue (P = 0.002). RAR-beta(2) methylation in the cell lines was correlated with loss of RAR-beta(2) 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-beta(2) inducibility by all-trans-retinoic acid (ATRA) in some of the cell lines, which posses a methylated RAR-beta(2) promoter. In some cell lines, this effect was associated with increased growth inhibition after combined treatment with 5-aza-CdR and ATRA. RAR-beta(2) silencing by methylation is an early event in head and neck carcinogenesis; 5-Aza-CdR can restore RAR-beta(2) 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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