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Insulin‐like growth factor binding protein‐4 gene silencing in lung adenocarcinomas
Author(s) -
Sato Hanako,
Sakaeda Masashi,
Ishii Jun,
Kashiwagi Korehito,
Shimoyamada Hiroaki,
Okudela Koji,
Tajiri Michihiko,
Ohmori Takahiro,
Ogura Takashi,
Woo Tetsukan,
Masuda Munetaka,
Hirata Kazuaki,
Kitamura Hitoshi,
Yazawa Takuya
Publication year - 2011
Publication title -
pathology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.73
H-Index - 74
eISSN - 1440-1827
pISSN - 1320-5463
DOI - 10.1111/j.1440-1827.2010.02612.x
Subject(s) - gene silencing , dna methylation , cancer research , methylation , insulin like growth factor binding protein , biology , growth factor , epigenetics , adenocarcinoma , insulin like growth factor , immunohistochemistry , insulin like growth factor 2 , microbiology and biotechnology , gene expression , cancer , gene , immunology , receptor , genetics
Gene silencing by promoter hypermethylation plays an important role in molecular pathogenesis. We previously reported that insulin‐like growth factor (IGF) binding protein‐4 (IGFBP‐4), which inhibits IGF‐dependent growth, is expressed via early growth response‐1 (EGR‐1) and is often silenced in cultivated lung cancer cells. The purpose of the present study was to clarify clinicopathological factors associated with IGFBP‐4 gene silencing in lung adenocarcinomas. Seventy‐six surgically resected adenocarcinomas (20 well‐, 35 moderately‐, and 21 poorly‐differentiated) were subjected to methylation‐specific polymerase chain reaction (PCR) analysis for EGR‐1‐binding sites located in the IGFBP‐4 promoter and immunohistochemistry for IGFBP‐4, EGR‐1, and Ki‐67. Thirty‐two adenocarcinomas (42%) revealed IGFBP‐4 promoter hypermethylation, and the severity inversely correlated with the level of IGFBP‐4 expression ( P < 0.0001) and tumor differentiation (well versus poor, P = 0.0278; well/moderate versus poor, P = 0.0395). Furthermore, there was a negative correlation between Ki‐67 labeling index and IGFBP‐4 expression ( P = 0.0361). These findings suggest that the expression of IGFBP‐4 in adenocarcinoma cells in vivo is downregulated by epigenetic silencing in association with tumor differentiation, resulting in disruption of the mechanism of IGFBP‐4‐mediated growth inhibition.