Role for Amplification and Expression of Glypican-5 in Rhabdomyosarcoma

Abstract

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]

Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

“…GPC6 encodes a smaller protein (∼350 aa) and contains nov-nsSNVs at positions that are highly conserved (GERP score above 5) in 2 of 16 nonhypermutated tumors as well as in 1 hypermutated tumor. GPC6 encodes a glypican, a class of cell surface coreceptors for proteases implicated in cell growth and division (23)(24)(25).…”

Diagnostic and prognostic significance of glypican 5 and glypican 6 gene expression levels in gastric adenocarcinoma

“…The results of that study demonstrated a higher GPC5 expression in tumoral compared to that in normal skeletal muscle tissues; this overexpression triggered cell proliferation by modifying the cell surface distribution of FGF2, HGF and Wnt1A receptors (27). A recent publication indicated that GPC5 regulates rhabdomyosarcoma cell proliferation by activating the Hedgehog (Hh) signaling pathway.…”

“…Similar to other glypican members, the overexpression and knockdown of GPC5 expression in rhabdomyosarcoma have been shown to cause increased and decreased cell proliferation, respectively. It was demonstrated that GPC5 increases cell proliferation through potentiating the action of FGF2, hepatocyte growth factor (HGF) and Wnt1A (27). Reduced GPC6 expression has been reported in retinoblastoma.…”

Altered expression of miR‐17‐5p in CD4+ lymphocytes of relapsing–remitting multiple sclerosis patients

“…Glypicans are bound to the surface of plasma membranes and play an important role in the control of cell division and growth regulation. Deregulation of proteoglycans has been reported especially in sarcomas [44]. Glypican 5 and miR-17-92 are co-expressed in cancer and expanding over the genomic region, which is amplified in many tumors [44].…”

“…Deregulation of proteoglycans has been reported especially in sarcomas [44]. Glypican 5 and miR-17-92 are co-expressed in cancer and expanding over the genomic region, which is amplified in many tumors [44]. However, whether these gene products are directly interacting with each other is not known.…”