Prostate cancer (PCa) is the most diagnosed cancer in men in developed
countries. Fibroblast growth factor receptors (FGFRs) have been
demonstrated to play an important role in PCa initiation and
progression. Fibroblast growth factor receptor like 1 (FGFRL1) is the
most recently identified member of the FGFR family. Its extracellular
domain shares high similarity to FGFR1-4 but it lacks the cytoplasmic
domain with tyrosine kinase activity. Thus, FGFRL1 is able to bind FGF
ligands but the subsequent intracellular signaling cascade is defective.
We observed up-regulation of FGFRL1 mRNA expression in PCa in a public
genome-wide cancer transcriptome data base (cBioPortal). To validate the
expression data and to investigate the putative role of upregulated
FGFRL1 protein in normal prostate and PCa, tissue microarrays containing
different types of benign and malignant prostate tissue were used.
Altered FGFRL1 protein expression was correlated with clinical
parameters; and both in vitro and in vivo experiments were applied to
study the biological functions FGFRL1 in PCa cell lines. Our results
confirmed that FGFRL1 expression is upregulated in PCa compared to
normal prostate. More specifically, increased cytoplasmic and nuclear
FGFRL1 expression was associated with high Gleason score and Ki67
expression, while membrane-associated FGFRL1 showed the opposite
correlation. To investigate the effects of androgens on FGFRL1 in vitro,
PCa cells were treated with dihydrotestosterone and/or MDV3100, an
androgen receptor inhibitor. Dihydrotestosterone increased FGFRL1
expression and MDV3100 inhibited endogenous FGFRL1 expression, but not
when stimulated by dihydrotestosterone, suggesting indirect
androgen-mediated regulation. The in vitro studies also showed that
FGFRL1 is able to attenuate the phosphorylation of FRS2α and ERK1/2 by
FGF ligands, providing evidence for the assumed decoy function of
membranous FGFRL1. However, knock-down of FGFRL1 in PC3M cells resulted
in reduced cell growth in tumor xenografts. Additionally, mRNA
sequencing on PC3M cells with FGFRL1 knock-down revealed differential
expression of about 250 molecules, including several metalloproteinases
and FGFR1, compared to control cells (FDR<0.1 and -1>logFC>1).
In conclusion, we suggest that upregulation and altered subcellular
localization of FGFRL1, in PCa, directly or indirectly, promotes tumor
growth and progression. The results suggest that FGFRL1 is a potent
regulator of gene expression and may be involved in diverse functions
depending on its cellular localization.