Insulin-like growth factor binding protein-4 gene silencing in lung adenocarcinomas
Article first published online: 3 NOV 2010
© 2010 The Authors. Pathology International © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd
Volume 61, Issue 1, pages 19–27, January 2011
How to Cite
Sato, H., Sakaeda, M., Ishii, J., Kashiwagi, K., Shimoyamada, H., Okudela, K., Tajiri, M., Ohmori, T., Ogura, T., Woo, T., Masuda, M., Hirata, K., Kitamura, H. and Yazawa, T. (2011), Insulin-like growth factor binding protein-4 gene silencing in lung adenocarcinomas. Pathology International, 61: 19–27. doi: 10.1111/j.1440-1827.2010.02612.x
- Issue published online: 19 DEC 2010
- Article first published online: 3 NOV 2010
- Received 31 July 2010. Accepted for publication 21 September 2010.
- early growth response-1;
- insulin-like growth factor binding protein-4;
- lung adenocarcinoma;
- tumor differentiation
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.