title: Patched haploinsufficient mouse rhabdomyosarcoma overexpress secreted phosphoprotein 1 and matrix metalloproteinases.
abstract: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Improving the management of rhabdomyosarcoma requires a better understanding of growth regulation. Patched haploinsufficient (Ptch+/-) mice spontaneously develop soft tissue sarcomas that resemble human rhabdomyosarcomas. Using microarray profiling and quantitative real-time reverse transcriptase polymerase chain reaction, we identified candidate genes differentially expressed in Ptch+/- mouse rhabdomyosarcoma relative to mature muscle. Overexpressed genes include Secreted Phosphoprotein 1 (Spp1, Osteopontin), and Matrix Metalloproteinases-2 and -14 (Mmp2 and Mmp14). Spp1 is an integrin-binding phosphoglycoprotein upregulated in carcinomas, and Mmps regulate tumour invasion. Immunochemical analyses of murine and human rhabdomyosarcoma specimens confirmed increased expression of Spp1, Mmp2, Mmp14, nuclear factor-kappa B (NF-kappaB) p65 and its phosphorylated active isoform. Neutralising Spp1 antibody decreased Mmp14 RNA in murine rhabdomyosarcoma cultures, indicating a positive regulatory role for extracellular Spp1. Plasma from rhabdomyosarcoma patients display elevated levels of SPP1. These results implicate Spp1, NF-kappaB, and Mmp activation as a putative signalling pathway involved in rhabdomyosarcoma growth.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin Street, MC 3-3320 Houston, TX 77030, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: De Bortoli
authors.forename: Robert C
authors.initials: RC
authors.lastname: Castellino
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Skapura
authors.forename: Jianhe J
authors.initials: JJ
authors.lastname: Shen
authors.forename: Jack M
authors.initials: JM
authors.lastname: Su
authors.forename: Heidi V
authors.initials: HV
authors.lastname: Russell
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.forename: Tsz-Kwong
authors.initials: TK
authors.lastname: Man
authors.forename: John Y H
authors.initials: JY
authors.lastname: Kim
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D053495:Osteopontin; D020782:Matrix Metalloproteinases