Tumor suppressor activity and inactivation of galanin receptor type 2 by aberrant promoter methylation in head and neck cancer.

Abstract

BACKGROUND:

There is accumulating evidence that galanin receptors (GALRs) may be tumor suppressors in head and neck squamous cell carcinoma (HNSCC). Promoter methylation status and gene expression were assessed in a large panel of head and neck primary tumors, based on the hypothesis that cytosine-guanine dinucleotide (CpG) hypermethylation might silence the galanin receptor 2 (GALR2) gene.

METHODS:

GALR2 expression was examined in a panel of cell lines by using quantitative reverse transcription polymerase chain reaction (RT-PCR). The methylation status of the GALR2 promoter was studied using quantitative methylation-specific PCR (Q-MSP). UM-SCC-1 was stably transfected to express GALR2.

RESULTS:

GALR2 expression was suppressed in UM-SCC cell lines, whereas nonmalignant cell lines exhibited stable expression. GALR2 methylation found in 31 of 100 (31.0%) tumor specimens was significantly correlated with the methylation status of both GALR1 and Galanin. The observed GALR2 promoter hypermethylation was statistically correlated with a decrease in disease-free survival (log-rank test, P=.045). A multivariate logistic-regression analysis revealed a high odds ratio for recurring methylation of GALR2 and the gene pair GALR2 and Galanin, 8.95 (95% confidence interval, 2.29-35.03; P=.024) and 9.05 (95% confidence interval, 1.76-46.50; P=.008), respectively. In addition, exogenous expression of GALR2 suppressed cell proliferation in UM-SCC-1 cells with hypermethylated Galanin and GALR2-proficient cell lines.

CONCLUSIONS:

Frequent promoter hypermethylation in association with prognosis, and growth suppression after re-expression, supports the hypothesis that GALR2 may act to suppress tumor activity. GALR2 is a potentially significant therapeutic target and prognostic factor for this cancer type.

• Authors: Yuki Misawa, Kiyoshi Misawa, Takeharu Kanazawa, Takayuki Uehara, Shori Endo, Daiki Mochizuki, Takashi Yamatodani, Thomas E Carey, Hiroyuki Mineta
• Journal: Cancer (Cancer) Vol. 120 Issue 2 Pg. 205-13 (Jan 15 2014) ISSN: 1097-0142 [Electronic] United States
• PMID: 24122450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 American Cancer Society.

Chemical References

• Receptor, Galanin, Type 1
• Receptor, Galanin, Type 2

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Squamous Cell (genetics, mortality, pathology)
• Cell Line, Tumor
• Cell Proliferation
• CpG Islands
• DNA Methylation
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Head and Neck Neoplasms (genetics, mortality, pathology)
• Humans
• Male
• Middle Aged
• Prognosis
• Promoter Regions, Genetic
• Receptor, Galanin, Type 1 (genetics)
• Receptor, Galanin, Type 2 (genetics, metabolism)
• Squamous Cell Carcinoma of Head and Neck