Role for amplification and expression of Glypican-5 in rhabdomyosarcoma

被引:80
作者
Williamson, Daniel
Selfe, Joanna
Gordon, Tony
Lu, Yong-Jie
Pritchard-Jones, Kathy
Murai, Kasumi
Jones, Phil
Workman, Paul
Shipley, Janet
机构
[1] Inst Canc Res, Mol Cytogenet Team, Sutton SM2 5NG, Surrey, England
[2] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England
[3] Addenbrookes Hosp, Hutchison Med Res Council Res Ctr, Med Res Council Canc Cell Unit, Cambridge, England
基金
英国医学研究理事会;
关键词
D O I
10.1158/0008-5472.CAN-06-1650
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 mill-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 mill-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.
引用
收藏
页码:57 / 65
页数:9
相关论文
共 47 条
[1]  
Anderson J, 1999, GENE CHROMOSOME CANC, V26, P275, DOI 10.1002/(SICI)1098-2264(199912)26:4<275::AID-GCC1>3.3.CO
[2]  
2-V
[3]   Hepatocyte growth factor/scatter factor stimulates migration of muscle precursors in developing mouse tongue [J].
Bandow, K ;
Ohnishi, T ;
Tamura, M ;
Semba, I ;
Daikuhara, Y .
JOURNAL OF CELLULAR PHYSIOLOGY, 2004, 201 (02) :236-243
[4]   Glypican-3: A novel serum and histochemical marker for hepatocellular carcinoma [J].
Capurro, M ;
Wanless, IR ;
Sherman, M ;
Deboer, G ;
Shi, W ;
Miyoshi, E ;
Filmus, J .
GASTROENTEROLOGY, 2003, 125 (01) :89-97
[5]   Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling [J].
Capurro, MI ;
Xiang, YY ;
Lobe, C ;
Filmus, J .
CANCER RESEARCH, 2005, 65 (14) :6245-6254
[6]   Heparan sulphate proteoglycans modulate fibroblast growth factor-2 binding through a lipid raft-mediated mechanism [J].
Chu, CL ;
Buczek-Thomas, JA ;
Nugent, MA .
BIOCHEMICAL JOURNAL, 2004, 379 :331-341
[7]   A census of human cancer genes [J].
Futreal, PA ;
Coin, L ;
Marshall, M ;
Down, T ;
Hubbard, T ;
Wooster, R ;
Rahman, N ;
Stratton, MR .
NATURE REVIEWS CANCER, 2004, 4 (03) :177-183
[8]   Glypican 4 modulates FGF signalling and regulates dorsoventral forebrain patterning in Xenopus embryos [J].
Galli, A ;
Roure, A ;
Zeller, R ;
Dono, R .
DEVELOPMENT, 2003, 130 (20) :4919-4929
[9]  
Gordon AT, 2000, GENE CHROMOSOME CANC, V28, P220, DOI 10.1002/(SICI)1098-2264(200006)28:2<220::AID-GCC11>3.3.CO
[10]  
2-K