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Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer

Oncogene volume 18, pages 7234–7243 (1999)Cite this article

Abstract

FGFRs (fibroblast growth factor receptors) are encoded by four genes (FGFR1 – 4). Alternative splicing results in various receptor isoforms. The FGFR2-IIIb variant is present in a wide variety of epithelia, including the bladder epithelium. Recently, we have shown that FGFR2-IIIb is downregulated in a subset of transitional cell carcinomas of the bladder, and that this downregulation is associated with a poor prognosis. We investigated possible tumour suppressive properties of FGFR2-IIIb by transfecting two human bladder tumour cell lines, J82 and T24, which have no endogenous FGFR2-IIIb expression, with FGFR2-IIIb cDNA. No stable clones expressing FGFR2-IIIb were isolated with the J82 cell line. For the T24 cell line, stable transfectants expressing FGFR2-IIIb had reduced growth in vitro and formed fewer tumours in nude mice which, in addition, grew more slowly. The potential mechanisms leading to decreased FGFR2-IIIb mRNA levels were also investigated. The 5′ region of the human FGFR2 gene was isolated and found to contain a CpG island which was partially methylated in more than half the cell lines and tumours which do not express FGFR2-IIIb. No homozygous deletion was identified in any of the tumours or cell lines with reduced levels of FGFR2-IIIb. Mutational analysis of the entire coding region of FGFR2-IIIb at the transcript level was performed in 33 bladder tumours. In addition to normal FGFR2-IIIb mRNA, abnormal transcripts were detected in two tumour samples. These abnormal mRNAs resulted from exon skipping which affected the region encoding the kinase domain. Altogether, these results show that FGFR2-IIIb has tumour growth suppressive properties in bladder carcinomas and suggest possible mechanisms of FGFR2 gene inactivation.

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Abbreviations

FGFR2-IIIb:

fibroblast growth factor receptor 2-IIIb

PCR:

polymerase chain reaction

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Acknowledgements

We would like to thank Dr Yutaka Hattori and Dr Masaaki Terada, for providing the K-samIIC1/FGFR2-IIIb cDNA, Dr Jennifer Southgate for the gift of cell lysates, Dr Marie-Aude Lefrère Belda for the interpretation of the histology, Dr Jean-Charles Ahomadegbe, Michel Barrois and Dr Hélène Feracci for helpful advice and Dr Jacqueline Jouanneau for critical reading of the manuscript. This work was supported by the Association Claude Bernard, Université Paris XII, AP-HP (PHRC no: AOA94015), CNRS, Ligue Contre le Cancer (Comité de Paris), the GEFLUC and NIH grant 2RO1 CA 49417-06. D Ricol was awarded a fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche, D Cappellen from ARC and S Gil Diez de Medina from the Ligue Contre le Cancer-Comité du Val de Marne.

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Authors and Affiliations

  1. UMR 144, Centre National de la Recherche Scientifique, Institut Curie, Section de Recherche, 26 rue d'Ulm, Paris, 75248, Cedex 05, France

    David Ricol, David Cappellen, Ahmed El Marjou, Sixtina Gil-Diez-de-Medina, Jeanne-Marie Girault, Jean Paul Thiery & François Radvanyi

  2. Groupe d'Etude des Tumeurs Urologiques et Service d'Urologie, Centre Hospitalier Universitaire Henri Mondor,

    Sixtina Gil-Diez-de-Medina & Dominique Chopin

  3. AP-HP, 94010 Créteil Cedex, France

    Sixtina Gil-Diez-de-Medina & Dominique Chopin

  4. Genetics Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan

    Teruhiko Yoshida

  5. Division de Cancérologie Expérimentale, Institut de Recherches Servier, 92150, Suresnes, France

    Gilles Ferry & Gordon Tucker

  6. UMR 147, Centre National de la Recherche Scientifique, Institut Curie, Section de Recherche, 26 rue d'Ulm, Paris, 75248, Cedex 05, France

    Marie-France Poupon

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  1. David Ricol
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  2. David Cappellen
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Ricol, D., Cappellen, D., El Marjou, A. et al. Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer. Oncogene 18, 7234–7243 (1999). https://doi.org/10.1038/sj.onc.1203186

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