Reduced TGF-beta1 expression and its target genes in human insulinomas

Aiming to identify signalling pathways relevant for ss-cell growth we performed an explorative micro-array analysis comparing the gene expression profiles of three human insulinomas and one normal pancreatic islet preparation. This revealed an insulinoma-associated down-regulation of the transforming growth factor beta 1 (TGF-beta1) and its target genes. Comparative quantitative real-time PCR (qRT-PCR) including an expanded sample number of both insulinomas (n=9) and pancreatic islet preparations (n=4) confirmed the decreased TGF-beta1 expression and its target molecules (TGFBI, NNMT, RPN2) in insulinomas. Similarly, TGF-beta1 immunofluorescence analysis revealed reduced expression in insulinomas when compared to pancreatic islets. In contrast, TGFBR2 (transforming growth factor beta receptor II) was found up-regulated. However, the consistent down-regulation of the TGF-beta1 targets TGFBI (transforming growth factor, beta-induced), NNMT (nicotinamide N-methyltransferase), RPN2 (ribophorin II) indicates that the parallel up-regulation of TGFBR2 does not compensate for the only marginal TGF-beta1 expression levels in insulinomas. TGFBR2 expression was confirmed at the protein level in insulinomas. SMAD2/3 protein expression was found at higher levels in human pancreatic islets when compared with insulinomas by dual colour confocal microscopy. TGF-beta1 signalling is known to be involved in cell replication and is abrogated in ductal pancreatic tumours. The down-regulation of TGF-beta1 expression and its target molecules in insulinomas is a new aspect of this cytokine. Our data underline parallels in endocrine and exocrine pancreatic tumour development, which may implicate common progenitor cells.