The Human IIIb-mRNA Splice Variant of FGF-receptor-1 Reduces the Transforming Potential of Pancreatic Cancer Cells in vitro and in vivo

摘要

Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play an important role in malignant diseases by being involved in several biological processes like angiogenesis and mitogenesis. Interactions between FGFs and their receptors take place between Ig-domain II and III. The second half of Ig-domain in determines the conformation and thus has major influence on FGF ligand affinity. This important area is encoded by 3 possible exons. Exon IIIa results in a truncated receptor without intracellular domain, while IIIb and IIIc are functional transmembraneous receptors with intracellular kinase activity. Cells of epithelial origin mostly express the IIIb variant, whereas cells of mesenchymal origin more often express the IIIc variant. A higher expression of FGFR1-IIIc and a reduced expression of FGFR1-IIIb was detected in solid tumors. We recently demonstrated that the IIIc variant of FGFR1 (FGFR1-IIIc) dramatically enhanced the transforming potential after expression in normal TAKA-1 pancreatic ductal cells which do not express endogenous FGFR1. Human pancreatic carcinoma tissue show an over-expression of FGFR1-IIIc and in cultured pancreatic cancer cell lines FGFR1-IIIc is predominantly expressed.