Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer

FGFRs (fibroblast growth factor receptors) are encoded by four genes (FGFR1 -4). Alternative splicing results in various receptor isoforms, The FGFR2-I IIb variant is present in a wide variety of epithelia, including the bladde r epithelium. Recently, we have shown that FGFR2-IIIb is downregulated in a subset of transitional cell carcinomas of the bladder, and that this downr egulation is associated with a poor prognosis. We investigated possible tum our suppressive properties of FGFR2-IIIb by transfecting two human bladder tumour cell lines, J82 and T24, which have no endogenous FGFR2-IIIb express ion, with FGFR2-IIIb cDNA, No stable clones expressing FGFR2-IIIb were isol ated with the J82 cell line, For the T24 cell line, stable transfectants ex pressing FGFR2-IIIb had reduced growth in vitro and formed fewer tumours in nude mice which, in addition, grew more slowly. The potential mechanisms l eading to decreased FGFR2-IIIb mRNA levels mere also investigated, The 5' r egion of the human FGFR2 gene was isolated and found to contain a CpG islan d which was partially methylated in more than half the cell lines and tumou rs which do not express FGFR2-IIIb, No homozygous deletion was identified i n any of the tumours or cell lines with reduced levels of FGFR2-IIIb, Mutat ional analysis of the entire coding region of FGFR2-IIIb at the transcript level was performed in 33 bladder tumours, In addition to normal FGFR2-IIIb mRNA, abnormal transcripts were detected in two tumour samples, These abno rmal mRNAs resulted from exon skipping which affected the region encoding t he kinase domain. Altogether, these results show that FGFR2-IIIb has tumour growth suppressive properties in bladder carcinomas and suggest possible m echanisms of FGFR2 gene inactivation.