FGF signalling facilitates cervical cancer progression

• Published in: The FEBS journal Vol. 289; no. 12; pp. 3440 - 3456
• Main Authors: Mahmood, Hiba‐Tun‐Noor Afshan, Tomas Bort, Elena, Walker, Anthony J., Grose, Richard P., Chioni, Athina‐Myrto
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2022
• Subjects: Cancer; Cell activation; Cervical cancer; Cervix; FGFR signaling; Fibroblast growth factor 2; Fibroblast growth factor 4; Fibroblast growth factor receptor 1; Fibroblast growth factor receptor 4; Fibroblast growth factor receptor 7; Fibroblast growth factor receptors; Gene expression; Growth factors; Human papillomavirus; Invasiveness; metastasis; Molecular modelling; Signaling; Transcription factors; metastasis; cervical cancer; FGFR signaling
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16331

Cervical cancer is one of the most frequently diagnosed cancers in women worldwide. While cervical cancer is caused by human papillomavirus (HPV), not all females infected with HPV develop the disease, suggesting that other factors might facilitate its progression. Growing evidence supports the involvement of the fibroblast growth factor receptor (FGFR) axis in several cancers, including gynecological. However, for cervical cancer, the molecular mechanisms that underpin the disease remain poorly understood, including the role of FGFR signaling. The aim of this study was to investigate FGF(R) signaling in cervical cancer through bioinformatic analysis of cell line and patient data and through detailed expression profiling, manipulation of the FGFR axis, and downstream phenotypic analysis in cell lines (HeLa, SiHa, and CaSki). Expression (protein and mRNA) analysis demonstrated that FGFR1b/c, FGFR2b/c, FGFR4, FGF2, FGF4, and FGF7 were expressed in all three lines. Interestingly, FGFR1 and 2 localized to the nucleus, supporting that nuclear FGFRs could act as transcription factors. Importantly, 2D and 3D cell cultures demonstrated that FGFR activation can facilitate cell functions correlated with invasive disease. Collectively, this study supports an association between FGFR signaling and cervical cancer progression, laying the foundations for the development of therapeutic approaches targeting FGFR in this disease. Here, we interrogate FGF(R) expression and signalling both in clinical databases and in cervical cancer cell lines. 2D and 3D cell cultures demonstrate that activation of the FGFR axis and downstream activation of ERK facilitates cell proliferation and migration, alongside inhibiting apoptosis. Interestingly, FGFR1/2 localizes to the nucleus, supporting that nuclear FGFRs could act as transcription factors. Collectively, this work supports an association between FGFR signalling and cervical cancer progression.