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Epigenetic inactivation of galanin receptor 1 in head and neck cancer.

ABSTRACT: One copy of the galanin receptor 1 (GALR1) locus on 18q is often deleted and expression is absent in some head and neck squamous cell carcinoma (HNSCC) cell lines. To determine if loss of heterozygosity and hypermethylation might silence the GALR1 gene, promoter methylation status and gene expression were assessed in a large panel of HNSCC cell lines and tumors.Promoter methylation of GALR1 in 72 cell lines and 100 primary tumor samples was analyzed using methylation-specific PCR. GALR1 expression and methylation status were analyzed further by real-time PCR and bisulfite sequencing analysis.The GALR1 promoter was fully or partially methylated in 38 of 72 (52.7%) HNSCC cell lines but not in the majority 18 of 20 (90.0%) of nonmalignant lines. GALR1 methylation was also found in 38 of 100 (38%) primary tumor specimens. Methylation correlated with decreased GALR1 expression. In tumors, methylation was significantly correlated with increased tumor size (P = 0.0036), lymph node status (P = 0.0414), tumor stage (P = 0.0037), cyclin D1 expression (P = 0.0420), and p16 methylation (P = 0.0494) and survival (P = 0.045). Bisulfite sequencing of 36 CpG sites upstream of the transcription start site revealed that CpG methylation within transcription factor binding sites correlated with complete suppression of GALR1 mRNA. Treatment with trichostatin A and 5-azacytidine restored GALR1 expression. In UM-SCC-23 cells that have total silencing of GALR1, exogenous GALR1 expression and stimulation with galanin suppressed cell proliferation.Frequent promoter hypermethylation, gene silencing, association with prognosis, and growth suppression after reexpression support the hypothesis that GALR1 is a tumor suppressor gene in HNSCC.

SUBMITTER: Misawa K

PROVIDER: S-EPMC3189853 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Epigenetic inactivation of galanin receptor 1 in head and neck cancer.

Misawa Kiyoshi K Ueda Yo Y Kanazawa Takeharu T Misawa Yuki Y Jang Ilwhan I Brenner John Chadwick JC Ogawa Tetsuya T Takebayashi Satoru S Grenman Reidar A RA Herman James G JG Mineta Hiroyuki H Carey Thomas E TE

Clinical cancer research : an official journal of the American Association for Cancer Research 20081201 23

<h4>Purpose</h4>One copy of the galanin receptor 1 (GALR1) locus on 18q is often deleted and expression is absent in some head and neck squamous cell carcinoma (HNSCC) cell lines. To determine if loss of heterozygosity and hypermethylation might silence the GALR1 gene, promoter methylation status and gene expression were assessed in a large panel of HNSCC cell lines and tumors.<h4>Experimental design</h4>Promoter methylation of GALR1 in 72 cell lines and 100 primary tumor samples was analyzed us ...[more]

PMID: 19047085

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Project description:BACKGROUND:Chronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC. METHODS:Methylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival. RESULTS:The mean number of methylated genes per sample was 2.05?±?2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5-9 methylated genes had a significantly lower survival rate than that of patients with 0-4 methylated genes (log-rank test, P=?0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P?=?0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P?=?0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P?=?0.028 and P?=?0.006, respectively). Moreover, Patients with 5-9 methylated genes were extremely lower of 5hmC levels (P?=?0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P?<?0.05 and P?<?0.05, respectively). CONCLUSION:We characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches.

Dataset Information

Epigenetic inactivation of galanin receptor 1 in head and neck cancer.

Publications

Epigenetic inactivation of galanin receptor 1 in head and neck cancer.

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