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Roles of different IRES-dependent FGF2 isoforms in the acquisition of the major aggressive features of human metastatic melanoma

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Abstract

Fibroblast growth factor 2 (FGF2) is involved in many physiological and pathological processes. Fgf2 deregulation contributes to the acquisition of malignant features of melanoma and other cancers. FGF2 is an alternative translation product expressed as five isoforms, a low-molecular-weight (18 KDa) and four high-molecular-weight (22, 22.5, 24, 34 KDa) isoforms, with different subcellular distributions. An internal ribosomal entry site (IRES) in its mRNA controls the translation of all the isoforms with the exception for the cap-dependent 34 KDa. The 18-KDa isoform has been extensively studied, while very few is known about the roles of high molecular weight isoforms. FGF2 is known to promote melanoma development and progression. To disclose the differential contribution of FGF2 isoforms in melanoma, we forced the expression of IRES-dependent low-molecular-weight (LMW, 18 KDa) and high-molecular-weight (HMW, 22, 22.5, 24 KDa) isoforms in a human metastatic melanoma cell line. This comparative study highlights that, while LMW isoform confers stem-like features to melanoma cells and promotes angiogenesis, HMW isoforms induce higher migratory ability and contribute to tumor perfusion by promoting vasculogenic mimicry (VM) when endothelial cell-driven angiogenesis is lacking. To conclude, FGF2 isoforms mainly behave in specific, antithetical manners, but can cooperate in different steps of tumor progression, providing melanoma cells with major malignant features.

Key message

  • FGF2 is an alternative translation product expressed as different isoforms termed LMW and HMW.

  • FGF2 is involved in melanoma development and progression.

  • HMW FGF2 isoforms enhance in vitro motility of melanoma cells.

  • LMW FGF2 confers stem-like features and increases in vivo metastasization.

  • LMW FGF2 promotes angiogenesis while HMW FGF2 induces vasculogenic mimicry.

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Acknowledgments

Financial support: Associazione Italiana Ricerca sul Cancro (AIRC), grant IG 2013 N. 14266.

We thank Prof. Daniele Bani, Dr. Laura Calosi, Dr. Stefano Catarinicchia, for histological analysis and Mr. Marco Cutrì for technical support.

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Authors and Affiliations

  1. Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50134, Florence, Italy

    Elena Andreucci, Francesca Bianchini, Alessio Biagioni, Mario Del Rosso, Laura Papucci, Nicola Schiavone & Lucia Magnelli

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  1. Elena Andreucci
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  2. Francesca Bianchini
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  3. Alessio Biagioni
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  7. Lucia Magnelli
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Correspondence to Laura Papucci or Nicola Schiavone.

Ethics declarations

All procedures involving animals were performed in accordance with national guidelines and approved by the ethical committee of Animal Welfare Office of Italian Work Ministry (DECRETO N° 53/2014- B, 17th Feb. 2014).

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The authors declare that they have no conflict of interest.

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Andreucci, E., Bianchini, F., Biagioni, A. et al. Roles of different IRES-dependent FGF2 isoforms in the acquisition of the major aggressive features of human metastatic melanoma. J Mol Med 95, 97–108 (2017). https://doi.org/10.1007/s00109-016-1463-7

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  • DOI: https://doi.org/10.1007/s00109-016-1463-7

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