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Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has been shown to have decreased expression in several solid cancers. However, the role of IGFBP-rP1 in lung cancer is not yet clear. The aims of this study were: 1) to analyze the expression of IGFBP-rP1 and explore the mechanisms responsible for the downregulation of IGFBP-rP1 in lung cancer; 2) to investigate the tumor suppressive function of IGFBP-rP1 in lung cancer. We analyzed the mRNA expression of IGFBP-rP1 in 17 lung cancer cell lines including all 4 types of lung cancer by using Northern blot analysis together with RT-PCR, and found that IGFBP-rP1 mRNA expression markedly decreased in lung cancer cell lines compared to normal bronchial epithelia cells. In tissue microarrays comprising 138 primary lung tumors, 58 cases (42%) exhibited no expression of IGFBP-rP1. The mRNA expression of IGFBP-rP1 was restored in 4 lung cancer cell lines after these cell lines were treated with the demethylation agent 5-aza-2’-deoxycytidine. No deletion or LOH turned out by using Southern blot analysis and LOH analysis. For the functional analysis, IGFBP-rP1 was stably transfected into a lung cancer cell line H2170, and the constitutive protein expression of IGFBP-rP1 was confirmed by Western blot analysis. IGFBP-rP1 positive clones remarkably influenced the ability of colony formation in soft agar test and, moreover, suppressed the tumorigenicity of the cells in nude mice. Additionally, the number of apoptotic cells and caspase-3 expression were increased in IGFBP-rP1 transfectant. We suggest that IGFBP-rP1 is a potential tumor suppressor through induction of apoptosis and also hypermethylation in lung cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]