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.

Citation Format: Lan Yu, Mervi Toriseva, Andrew Erickson, Heikki Seikkula, Martti Nurmi, Pekka Taimen, Peter Boström, Tuomas Mirtti, Kalle Alanen, Markku Kallajoki, Johanna Tuomela, Mattias Nees, Pirkko Härkönen. Increased FGFRL1 expression is associated with prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5730. doi:10.1158/1538-7445.AM2017-5730