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비소세포성 폐암에서 인슐린 양 성장 인자 결합 단백질 -3의 발현 조절 기전

Other Titles
 Regulatory Mechanism of Insulin-Like Growth Factor Binding Protein-3 in Non-Small Cell Lung Cancer 
 장윤수  ;  이호영  ;  김세규  ;  김성규  ;  안철민  ;  장준  ;  김형중  ;  김영삼 
Journal Title
Issue Date
Insulin-like growth factor (IGF) ; Insulin-like growth factor binding protein-3 (IGFBP-3) ; Methylation of CpG islands ; Methyl CpG binding protein-2 (MeCP2) ; Non-small cell lung cancer(NSCLC)
BACKGROUND: Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) inhibits the proliferation of non-small cell lung cancer (NSCLC) cells by inducing apoptosis. METHODS: In this study, we investigated whether hypermethylation of IGFBP-3 promoter play an important role in the loss of IGFBP-3 expression in NSCLC. We also studied the mechanisms that mediate the silencing of IGFBP-3 expression in the cell lines which have hypermethylated IGFBP-3 promoter. RESULTS: The IGFBP-3 promoter has hypermethylation in 7 of 15 (46.7%) NSCLC cell lines and 16 (69.7%) of 23, 7 (77.8%) of 9, 4 (80%) of 5, 4 (66.7 %) of 6, and 6 (100%) of 6 tumor specimens from patients with stage I, II, IIIA, IIIB, and IV NSCLC, respectively. The methylation status correlated with the level of protein and mRNA in NSCLC cell lines. Expression of IGFBP-3 was restored by the demethylating agent 5´-aza-2´-deoxycytidine (5´-aza-dC) in a subset of NSCLC cell lines. The Sp-1/ Sp-3 binding element in the IGFBP-3 promoter, important for promoter activity, was methylated in the NSCLC cell lines which have reduced IGFBP-3 expression and the methylation of this element suppressed the binding of the Sp-1 transcription factor. A ChIP assay showed that the methylation status of the IGFBP-3 promoter influenced the binding of Sp-1, methyl-CpG binding protein-2 (MeCP2), and histone deacetylase (HDAC) to Sp-1/Sp-3 binding element, which were reversed by by 5´-aza-dC. In vitro methylation of the IGFBP-3 promoter containing the Sp-1/Sp-3 binding element significantly reduced promoter activity, which was further suppressed by the overexpression of MeCP2. This reduction in activity was rescued by 5´-aza-dC. CONCLUSION: These findings indicate that hypermethylation of the IGFBP-3 promoter is one mechanism by which IGFBP-3 expression is silenced and MeCP2, with recruitment of HDAC, may play a role in silencing of IGFBP-3 expression. The frequency of this abnormality is also associated with advanced stages among the patients with NSCLC, suggesting that IGFBP-3 plays an important role in lung carcinogenesis/progression and that the promoter methylation status of IGFBP-3 may be a marker for early molecular detection and/or for monitoring chemoprevention efforts.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sung Kyu(김성규)
Kim, Se Kyu(김세규)
Kim, Young Sam(김영삼) ORCID logo https://orcid.org/0000-0001-9656-8482
Kim, Hyung Jung(김형중) ORCID logo https://orcid.org/0000-0003-2498-0683
Ahn, Chul Min(안철민)
Lee, Ho Yung(이호영)
Chang, Joon(장준) ORCID logo https://orcid.org/0000-0003-4542-6841
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