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Transcriptional silencing of Cyclooxygenase-2 by hyper-methylation of the 5′ CpG island in human gastric carcinoma cells

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Authors
Song, Sang-Hyun; Jong, Hyun-Soon; Choi, Hyun Ho; Inoue, Hiroyasu; Tanabe, Tadashi; Kim, Noe Kyeong; Bang, Yung-Jue
Issue Date
2001-06
Citation
Cancer Research, Vol.61 No.11, pp.4628-4635
Abstract
It has been well established that overexpression of Cyclooxygenase-2 (Cox-a) in epithetial cells inhibits apoptosis and increases the invasiveness of malignant cells, favoring tumorigenesis and metastasis, However, the molecular mechanism that regulates Cox-2 expression has not been well defined in gastric carcinoma. In this study, we examined whether the Cox-2 expression could be regulated by hyper-methylation of the Cox-2 CPG bland (spanning from -590 to +186 with respect to the transcription initiation site) in human gastric carcinoma cell lines. By Southern analysis, we found that three gastric cells (SNU-601, -620, and -719) without Cox-2 expression demonstrated hyper-methylation at the Cox-2 CpG island, A detailed methylation pattern using bisulfite sequencing analysis revealed that all of the CpG sites were completely methylated in SNU-601. Treatment with demethylating agents effectively reactivated the expression of Cox-2 and restored IL-1 beta sensitivity in the previously resistant SNU-601. By transient transfection experiments, we demonstrate that constitutively active Cox-2 promoter activities were exhibited even without an exogenous stimulation in SNU-601, Furthermore, when the motif of the nuclear factor for interleukin-6 expression site, the cyclic AMP response element, or both was subjected to point mutation, the constitutive luciferase activity was markedly reduced. In addition, Cox-2 promoter activity was completely blocked by irt vitro methylation of all of the CpG sites in the Cox-2 promoter region with SssI (CpG) methylase in SNU-601, Taken together, these results indicate that transcriptional repression of Cox-2 is caused by hyper-methylation of the Cox-2 CpG island in gastric carcinoma cell lines.
ISSN
0008-5472
URI
https://hdl.handle.net/10371/173030
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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