Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma

Erina Nakamura, Ken Ichi Kozaki, Hitoshi Tsuda, Emina Suzuki, Atiphan Pimkhaokham, Gou Yamamoto, Tarou Irie, Tetsuhiko Tachikawa, Teruo Amagasa, Johji Inazawa, Issei Imoto

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Abstract

Array-based comparative genomic hybridization (array-CGH) has good potential for the high-throughput identification of genetic aberrations in cell genomes. In the course of a program to screen a panel of 21 oral squamous-cell carcinoma (OSCC) cell lines for genome-wide copy-number aberrations by array-CGH using our in-house bacterial artificial chromosome arrays, we identified a frequent homozygous deletion at 4q35 loci with approximately 1 Mb in extent. Among the seven genes located within this region, the expression of the melatonin receptor 1 A (MTNR1A) messenger RNA (mRNA) was not detected or decreased in 35 out of the 39 (89%) OSCC cell lines, but was detected in immortalized normal oral epithelial cell line, and was restored in gene-silenced OSCC cells without its homozygous loss after treatment with 5-aza-2′-deoxycytidine. The hypermethylation of the CpG (cytosine and guanine separated by phosphate) island in the promoter region of MTNR1A was inversely correlated with its expression in OSCC lines without a homozygous deletion. Methylation of this CpG island was also observed in primary OSCC tissues. In an immunohistochemical analysis of 50 primary OSCC tumors, the absence of immunoreactive MTNR1A was significantly associated with tumor size and a shorter overall survival in patients with OSCC tumors, and seems to be an independent prognosticator in a multivariate analysis. Exogenous restoration of MTNR1A expression inhibited the growth of OSCC cells lacking its expression. Together with the known tumor-suppressive function of melatonin and MTNR1A in various tumors, our results indicate MTNR1A to be the most likely target for epigenetic silencing at 4q35 and to play a pivotal role during oral carcinogenesis.

Original languageEnglish
Pages (from-to)1390-1400
Number of pages11
JournalCancer Science
Volume99
Issue number7
DOIs
Publication statusPublished - Jul 2008
Externally publishedYes

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Melatonin Receptors
Tumor Suppressor Genes
Squamous Cell Carcinoma
Cell Line
Comparative Genomic Hybridization
decitabine
Neoplasms
Genome
Bacterial Artificial Chromosomes
CpG Islands
Cytosine
Guanine
Melatonin
Islands
Genetic Promoter Regions
Epigenomics
Methylation
Genes
Carcinogenesis
Multivariate Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nakamura, E., Kozaki, K. I., Tsuda, H., Suzuki, E., Pimkhaokham, A., Yamamoto, G., ... Imoto, I. (2008). Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma. Cancer Science, 99(7), 1390-1400. https://doi.org/10.1111/j.1349-7006.2008.00838.x

Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma. / Nakamura, Erina; Kozaki, Ken Ichi; Tsuda, Hitoshi; Suzuki, Emina; Pimkhaokham, Atiphan; Yamamoto, Gou; Irie, Tarou; Tachikawa, Tetsuhiko; Amagasa, Teruo; Inazawa, Johji; Imoto, Issei.

In: Cancer Science, Vol. 99, No. 7, 07.2008, p. 1390-1400.

Research output: Contribution to journalArticle

Nakamura, E, Kozaki, KI, Tsuda, H, Suzuki, E, Pimkhaokham, A, Yamamoto, G, Irie, T, Tachikawa, T, Amagasa, T, Inazawa, J & Imoto, I 2008, 'Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma', Cancer Science, vol. 99, no. 7, pp. 1390-1400. https://doi.org/10.1111/j.1349-7006.2008.00838.x
Nakamura, Erina ; Kozaki, Ken Ichi ; Tsuda, Hitoshi ; Suzuki, Emina ; Pimkhaokham, Atiphan ; Yamamoto, Gou ; Irie, Tarou ; Tachikawa, Tetsuhiko ; Amagasa, Teruo ; Inazawa, Johji ; Imoto, Issei. / Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma. In: Cancer Science. 2008 ; Vol. 99, No. 7. pp. 1390-1400.
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