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: Hanako Sato, Masashi Sakaeda, Jun Ishii, Korehito Kashiwagi, Hiroaki Shimoyamada, Koji Okudela, Michihiko Tajiri, Takahiro Ohmori, Takashi Ogura, Tetsukan Woo, Munetaka Masuda, Kazuaki Hirata, Hitoshi Kitamura, Takuya Yazawa
• Journal: Pathology international (Pathol Int) Vol. 61 Issue 1 Pg. 19-27 (Jan 2011) ISSN: 1440-1827 [Electronic] Australia
• PMID: 21166939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors. Pathology International © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

Chemical References

• EGR1 protein, human
• Early Growth Response Protein 1
• Insulin-Like Growth Factor Binding Protein 4
• Ki-67 Antigen

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Binding Sites
• DNA Methylation
• Early Growth Response Protein 1 (genetics, metabolism)
• Gene Silencing
• Humans
• Immunohistochemistry
• Insulin-Like Growth Factor Binding Protein 4 (genetics, metabolism)
• Ki-67 Antigen (metabolism)
• Lung Neoplasms (genetics, metabolism, pathology)
• Polymerase Chain Reaction
• Promoter Regions, Genetic