Differential display analysis of fiver-induced carcinogenesis in rat: Cluefor involvement of integrin-mediated signal transduction

In this study: mRNA expression patterns during mesothelioma carcinogenesis in the peritoneal cavity were investigated. To this purpose, the mRNA expre ssion patterns of fiber-induced, mesothelioma and of fiber-treated tissues were compared to untreated tissues, respectively. Suppression subtractive h ybridization (SSH) and an array hybridization assay were used to perform di fferential display analyses. Genes found to be expressed differentially, ma inly represent proteins of signal transduction pathways and regulatory prot eins of the cell cycle. The genes for components of the AP-1 transcription factor c-jun, c-fos, and fra-1 fos-related antigen-1) are upregulated in no ntumorous tissue treated with asbestos. These data confirm in vivo the invo lvement of AP-1 expression as response to fiber treatment. in addition, ost eopontin, zyxin, and integrin-linked kinase were upregulated in tumors and in treated tissues. These genes code for proteins involved in the signal tr ansduction from the extracellular matrix to the nucleus. Using integrin-spe cific inhibitors, the apoptotic effects of crocidolite fibers could be supp ressed significantly From these results we hypothesize that direct effects of the fibers on the target tissue are mediated by interaction of the fiber s with the extracellular matrix molecules.