title: Insulin-like growth factor binding protein-4 gene silencing in lung adenocarcinomas.
abstract: 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.
authors.affiliation: Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Sato
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakaeda
authors.forename: Jun
authors.initials: J
authors.lastname: Ishii
authors.forename: Korehito
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimoyamada
authors.forename: Koji
authors.initials: K
authors.lastname: Okudela
authors.forename: Michihiko
authors.initials: M
authors.lastname: Tajiri
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohmori
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogura
authors.forename: Tetsukan
authors.initials: T
authors.lastname: Woo
authors.forename: Munetaka
authors.initials: M
authors.lastname: Masuda
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Hirata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Takuya
authors.initials: T
authors.lastname: Yazawa
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D019175:DNA Methylation; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics* / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018974:Insulin-Like Growth Factor Binding Protein 4; D019394:Ki-67 Antigen