The expression of insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is decreased in various tumours, but the role of IGFBP-rP1 in lung cancer is not yet clear. In this study, IGFBP-rP1 expression in lung cancer cell lines was evaluated and reduced expression of IGFBP-rP1 was found. In tissue microarrays containing 138 primary tumours and 20 normal lung tissues analysed by immunohistochemistry, 58 tumours (42%) exhibited no expression of IGFBP-rP1, while all 20 normal lung tissues showed high expression. In squamous cell lung cancer, low expression of IGFBP-rP1 was significantly linked to high-grade tumours. Treatment with 5-aza-2'-deoxycytidine restored the expression of IGFBP-rP1 in three of four lung cancer cell lines. Sequencing of PCR products of sodium bisulphite-treated genomic DNA from the three lung cancer cell lines revealed a heterogeneous methylation pattern in the region of exon 1 and intron 1. Stable transfection of IGFBP-rP1 full-length cDNA into the H2170 lung cancer cell line led to increased expression of IGFBP-rP1 protein. IGFBP-rP1-positive transfectants exhibited remarkably reduced colony-forming ability in soft agar, suppression of tumour growth rate in nude mice, and increased apoptotic cell number as well as activated caspase-3 expression level. The data suggest that IGFBP-rP1 is a tumour suppressor inactivated by DNA methylation in human lung cancer.

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Lung cancer is one of the most common malignancies and is the leading cause of cancer-related death in the world. Despite the major progress made in cancer treatment during the last decades, the prognosis of lung cancer has not greatly improved due to its high frequency of recurrence. To achieve new therapeutic approaches for this fatal disease, a better understanding of the molecular mechanisms underlying the complex process of tumorigenesis in lung cancer is therefore required.In order to identify new candidate genes in lung carcinogenesis, we performed suppression subtractive hybridization (SSH) to reveal lung cancer associated genes in previous studies. 1,2 Comparing the gene expression between normal human bronchial epithelial cells (HBEC) and a lung squamous carcinoma cell line, we cloned 2 cDNA libraries that represented mainly the genes that are overexpressed and underexpressed in HBEC and the tumor cell line, respectively. The clone HBEC-15 with high similarity to the human Connexin 26 gene (gap junction protein, beta 2) was found in the library enriched for the genes that were downregulated in tumor cell lines.Connexins (Cxs) are member of a multigene family of at least 20 highly conserved proteins that compose a hexameric transmembrane functional channel called a connexon. 3 Gap junctions are formed by the interaction of connexons or hemichannels on adjacent cells. Intercellular communication mediated by gap junctions plays an important role in a variety of cellular processes including homeostasis, morphogenesis, cell differentiation and growth control. Modulation of gap junction communication can be achieved by multiple mechanisms such as alteration in transcription, translation, stability and posttranslational processing. It has been reported that Cx is expressed in a tissue-specific manner during development and adult life, and the reduction or alteration in the level or types of connexin expressed in a given cell type is correlated with tumor progression and metastasis. 4

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