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Article

Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression

1
Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland
2
GenomeScan, 2333 BZ Leiden, The Netherlands
3
Nuffield Department of Surgical Sciences, University of Oxford, Oxford 0X3 9DU, UK
4
Department of Urology, University of Turku and Turku University Hospital, 20520 Turku, Finland
5
Department of Pathology, Turku University Hospital, 20520 Turku, Finland
6
HUS Diagnostic Center and Research Program in Systems Oncology (ONCOSYS), Helsinki University Hospital and University of Helsinki, 00014 Helsinki, Finland
7
Department of Biochemistry and Molecular Biology, Medical University in Lublin, 20-093 Lublin, Poland
*
Author to whom correspondence should be addressed.
Current address: Henan Provincial People’s Hospital, Henan Provincial Reproductive Hospital, People’s Hospital of Zhengzhou University, Zhengzhou 450003, China.
These authors contributed equally to this work.
§
Current address: Computational Biology, Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland.
Current address: Department of Surgery, Central Finland Central Hospital, 40620 Jyväskylä, Finland.
Deceased.
Academic Editor: Constantin N. Baxevanis
Cancers 2022, 14(2), 278; https://doi.org/10.3390/cancers14020278
Received: 25 November 2021 / Revised: 28 December 2021 / Accepted: 29 December 2021 / Published: 7 January 2022
(This article belongs to the Special Issue Models, Mechanisms, and Biomarkers of Prostate Cancer Progression)
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. PCa is primarily regulated by androgens, but other mechanisms, such as fibroblast growth factor receptor (FGFR) signaling, are also involved. In some patients, PCa relapses after surgical removal of prostate, and androgen deprivation therapy (ADT) is used as the first-line treatment. Unfortunately, the patients often lose response to ADT and progress by other mechanisms to castration-resistant, currently non-curable PCa. In our study, we aimed to identify better diagnostic markers and therapeutic targets against PCa. We analyzed patient PCa tissue samples from radical prostatectomies and biopsies, and used physiologically relevant 3D organoids and mouse xenografts to study FGFR signaling in PCa. We found that FGFRL1, a protein belonging to the FGFR family, plays a role in PCa. Our results suggest that FGFRL1 has significant effects on PCa progression and has potential as a prognostic biomarker.
Fibroblast growth factor receptors (FGFRs) 1–4 are involved in prostate cancer (PCa) regulation, but the role of FGFR-like 1 (FGFRL1) in PCa is unclear. FGFRL1 expression was studied by qRT-PCR and immunohistochemistry of patient tissue microarrays (TMAs) and correlated with clinical patient data. The effects of FGFRL1 knockdown (KD) in PC3M were studied in in vitro culture models and in mouse xenograft tumors. Our results showed that FGFRL1 was significantly upregulated in PCa. The level of membranous FGFRL1 was negatively associated with high Gleason scores (GSs) and Ki67, while increased cytoplasmic and nuclear FGFRL1 showed a positive correlation. Cox regression analysis indicated that nuclear FGFRL1 was an independent prognostic marker for biochemical recurrence after radical prostatectomy. Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1. In accordance with clinical data, FGFRL1-KD markedly suppressed PC3M xenograft growth. Transcriptomics of FGFRL1-KD cells and xenografts revealed major changes in genes regulating differentiation, ECM turnover, and tumor–stromal interactions associated with decreased growth in FGFRL1-KD xenografts. Our results suggest that FGFRL1 upregulation and altered cellular compartmentalization contribute to PCa progression. The nuclear FGFRL1 could serve as a prognostic marker for PCa patients. View Full-Text
Keywords: prostate cancer; FGFRL1 (FGFR5); FGFR signaling; tumor–stromal interactions; biochemical recurrence; prostate cancer progression prostate cancer; FGFRL1 (FGFR5); FGFR signaling; tumor–stromal interactions; biochemical recurrence; prostate cancer progression
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Figure 1

MDPI and ACS Style

Yu, L.; Toriseva, M.; Afshan, S.; Cangiano, M.; Fey, V.; Erickson, A.; Seikkula, H.; Alanen, K.; Taimen, P.; Ettala, O.; Nurmi, M.; Boström, P.J.; Kallajoki, M.; Tuomela, J.; Mirtti, T.; Beumer, I.J.; Nees, M.; Härkönen, P. Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression. Cancers 2022, 14, 278. https://doi.org/10.3390/cancers14020278

AMA Style

Yu L, Toriseva M, Afshan S, Cangiano M, Fey V, Erickson A, Seikkula H, Alanen K, Taimen P, Ettala O, Nurmi M, Boström PJ, Kallajoki M, Tuomela J, Mirtti T, Beumer IJ, Nees M, Härkönen P. Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression. Cancers. 2022; 14(2):278. https://doi.org/10.3390/cancers14020278

Chicago/Turabian Style

Yu, Lan, Mervi Toriseva, Syeda Afshan, Mario Cangiano, Vidal Fey, Andrew Erickson, Heikki Seikkula, Kalle Alanen, Pekka Taimen, Otto Ettala, Martti Nurmi, Peter J. Boström, Markku Kallajoki, Johanna Tuomela, Tuomas Mirtti, Inès J. Beumer, Matthias Nees, and Pirkko Härkönen. 2022. "Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression" Cancers 14, no. 2: 278. https://doi.org/10.3390/cancers14020278

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