Patched haploinsufficient mouse rhabdomyosarcoma overexpress secreted phosphoprotein 1 and matrix metalloproteinases.
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.
De Bortoli
Massimiliano
M
Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin Street, MC 3-3320 Houston, TX 77030, USA.
Castellino
Robert C
RC
Skapura
Darlene G
DG
Shen
Jianhe J
JJ
Su
Jack M
JM
Russell
Heidi V
HV
Hicks
M John
MJ
Man
Tsz-Kwong
TK
Kim
John Y H
JY
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*
D018076:DNA, Complementary; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D053495:Osteopontin; D020782:Matrix Metalloproteinases