FGFRL1 is a regulator of FGFR and AR signaling networks in prostate cancer [RNA-seq]

ABSTRACT: Purpose: This study investigates the role of fibroblast growth factor receptor-like 1 (FGFRL1) in regulating androgen receptor (AR) and fibroblast growth factor receptor (FGFR) signaling pathways in advanced prostate cancer (PCa). Methodology: Clinical samples from two independent datasets (n=48 and n=492) were analyzed to compare the expression levels of FGFRL1, AR, and FGFR1 in PCa versus normal samples. Transient knockdown (KD) experiments using siRNA were conducted in LNCaP and 22RV1 PCa cell lines to reduce FGFRL1 expression by 60-80%. FGFR downstream signaling was assessed following R1881+FGF2 stimulation. Additionally, ChIP and RNA sequencing were used to explore FGFRL1's role in AR transcriptional binding and pathway analysis. Immunohistochemistry of FGFR1 and FGFRL1 staining of tumor microarrays (n=141) were quantified for their localization pattern. Immunofluorescence and subcellular protein fractionation followed by immunoblotting were used to quantify FGFR1, FGFRL1, AR and p-AR localization in the nucleus of PCa cell lines. Results: The study found elevated levels of FGFRL1 and AR, and decreased FGFR1 expression in PCa samples compared to normal prostate samples. FGFRL1 KD led to significantly reduced AR binding to androgen response elements (AREs), despite the presence of synthetic androgen R1881. This reduction in AR activity was linked to decreased expression of AR-regulated proteins, such as CAMKK2 and pAKT. FGFRL1 KD also resulted in decreased AR phosphorylation at Ser81 and reduced nuclear translocation of FGFR1. Stimulation with R1881 and FGF2 increased FGFR downstream signaling upon FGFRL1 KD, as indicated by elevated pFRS2a and pERK1/2 levels. In the PCa patient cohort (n=141), FGFR1 and FGFRL1 localization patterns were correlated, with significant positive correlations between nuclear FGFRL1 and FGFR1. Significance: This study provides novel insights into the role of FGFRL1 in modulating AR and FGFR signaling in PCa. By demonstrating that FGFRL1 KD affects AR binding and FGFR1 nuclear translocation, the research highlights potential targets for developing new combinatorial therapies for advanced PCa, particularly castration-resistant prostate cancer (CRPC). Understanding the interplay between FGFR and AR signaling may offer new strategies for overcoming resistance in PCa treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319336 | GEO | 2026/05/20

REPOSITORIES: GEO