This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Williamson, D. Articles by Shipley, J. Search for Related Content PubMed PubMed Citation Articles by Williamson, D. Articles by Shipley, J.

Role for Amplification and Expression of Glypican-5 in Rhabdomyosarcoma

¹ Molecular Cytogenetics Team, ² Paediatric Oncology, ³ Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom; and ⁴ Medical Research Council Cancer Cell Unit, Hutchison/Medical Research Council Research Centre, Addenbrooke's Hospital, Cambridge, United Kingdom

Requests for reprints: Janet Shipley, Molecular Cytogenetics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-20-8722-4273; Fax: 44-20-8722-4278; E-mail: janet.shipley{at}icr.ac.uk.

Overexpression of genes, through genomic amplification and other mechanisms, can critically affect the behavior of tumor cells. Genomic amplification of the 13q31-32 region is reported in many tumors, including rhabdomyosarcomas that are primarily pediatric sarcomas resembling developing skeletal muscle. The minimum overlapping region of amplification at 13q31-32 in rhabdomyosarcomas was defined as containing two genes: Glypican-5 (GPC5) encoding a cell surface proteoglycan and C13orf25 encompassing the miR-17-92 micro-RNA cluster. Genomic copy number and gene expression analyses of rhabdomyosarcomas indicated that GPC5 was the only gene consistently expressed and up-regulated in all cases with amplification. Constitutive overexpression and knockdown of GPC5 expression in rhabdomyosarcoma cell lines increased and decreased cell proliferation, respectively. A correlation between expression levels of nascent pre-rRNA and GPC5 (P = 0.001), but not a C13orf25 transcript containing miR-17-92, in primary samples supports an association of GPC5 with proliferative capacity in vivo. We show that GPC5 increases proliferation through potentiating the action of the growth factors fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and Wnt1A. GPC5 enhanced the intracellular signaling of FGF2 and HGF and altered the cellular distribution of FGF2. The mesoderm-inducing effect of FGF2 and FGF4 in Xenopus blastocysts was also enhanced. Our data are consistent with a role of GPC5, in the context of sarcomagenesis, in enhancing FGF signaling that leads to mesodermal cell proliferation without induction of myogenic differentiation. Furthermore, the properties of GPC5 make it an attractive target for therapeutic intervention in rhabdomyosarcomas and other tumors that amplify and/or overexpress the gene. [Cancer Res 2007;67(1):57–65]

This article has been cited by other articles:

				R. S. Huang, S. Duan, E. O. Kistner, C. M. Hartford, and M. E. Dolan Genetic variants associated with carboplatin-induced cytotoxicity in cell lines derived from Africans Mol. Cancer Ther., September 1, 2008; 7(9): 3038 - 3046. [Abstract] [Full Text] [PDF]

				F. G. Barr and W. H. Meyer Rhabdomyosarcoma: An Overview of Biology, Clinical Features, and the Current Children's Oncology Group Studies ASCO Educational Book, January 1, 2008; 2008(1): 465 - 470. [Abstract] [Full Text] [PDF]