Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oncogenic fusion protein, Pax3/FKHR, is a more potent transcription factor relative to its normal counterpart, Pax3. Since Pax3 induced a mesenchymal to epithelial transition (MET) in human SaOS-2 osteosarcomas, we hypothesized that Pax3/FKHR would also induce a morphological change in SaOS-2 cells. We demonstrate here that Pax3/FKHR more potently induces a MET in SaOS-2 cells than Pax3. This greater potency was further evident where Pax3/FKHR, but not Pax3, induced a morphological alteration in U2-OS osteosarcoma cells. By microarray analysis, we determined that Pax3/FKHR altered the expression of gene targets in a manner quantitatively and qualitatively distinct from Pax3. Three classes of genes were identified: (i) genes induced or repressed by Pax3 and Pax3/FKHR, (ii) genes induced or repressed by Pax3/FKHR but not Pax3 and (iii) genes induced by Pax3/FKHR but repressed by Pax3. Chromatin immunoprecipitations confirmed the direct binding of Pax3/FKHR to the promoter region of several factors including cannabinoid receptor-1, EPHA2 and EPHA4. Verification of the microarray data also revealed coordinate alteration in the expression of factors involved in BMP4 signalling. Regulation of gene expression by Pax3 and Pax3/FKHR is, however, cell-type specific. BMP4 expression, for example, was repressed by both Pax3 and Pax3/FKHR in SaOS-2 cells, while in the rhabdomyosarcoma, RD, Pax3/FKHR, but not Pax3, induced BMP4 expression. Thus, our data reveal that Pax3/FKHR regulates a distinct but overlapping set of genes relative to Pax3 and that the global set of Pax3 and Pax3/FKHR gene targets is cell-type specific.
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PMID:Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR. 1568 35

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma likely results from abnormal proliferation and differentiation during skeletal myogenesis. Multiple genetic alterations are associated with the three RMS histopathological subtypes, embryonal, alveolar, and pleomorphic adult variant. Recently, we reported the novel amplification of the FGFR1 gene in a RMS tumor. The involvement of FGFR1 in RMS was now further studied in primary tumors and RMS cell lines by mutation screening, quantitative RNA expression, and methylation analyses. No mutation was found by DHPLC and sequencing of the entire FGFR1 coding sequence and exon-intron boundaries. However, FGFR1 over-expression was detected in all primary RMS tumors and cell lines tested. A hypomethylation of a CpG island upstream to FGFR1 exon 1 was identified in the primary RMS tumors, using sodium bisulfite modification method, suggesting a molecular mechanism to FGFR1 over-expression. Expression analysis of additional genes, AKT1, NOG and its antagonist BMP4, which interact downstream to FGFR1, demonstrated expression differences between primary RMS tumors and normal skeletal muscles. Our data suggest an important role for FGFR1 and FGFR1-downstream genes in RMS tumorigenesis and a possible association with the deregulation of proliferation and differentiation of skeletal myoblasts in RMS.
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PMID:FGFR1 over-expression in primary rhabdomyosarcoma tumors is associated with hypomethylation of a 5' CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes. 1769 96

Musculoskeletal malignancy is often accompanied by aberrant bone remodeling, leading to tumor cell invasion into skeletal tissues and causing severe pain. BMPs, FGF-2, and RANKL have been identified as promising regulators in physiological bone remodeling. In this study, we explored the expressional profile of BMPs, FGF-2, and RANKL in 1361 patients with 22 varieties of musculoskeletal tumors. Notably, the expression of FGF-2 and RANKL was under detected in all patients. Among BMP-1 to BMP-15, we found that BMP-1, -2, -4, -5, -6, and -7 were prevalent. In comparison with normal bones, osteosarcoma highly expressed BMP-1, -2, -4, and -7 with statistical significance. Synovial sarcoma upregulated BMP-4, -5, and -7; rhabdomyosarcoma increased BMP-1 and -4; and alveolar soft part sarcoma upregulated BMP-1, -4, and -7. To visualize the BMP-oriented interactions in a bone tumor microenvironment, we have developed novel software that analyzes numerous cell-to-cell and ligand-to-receptor interactions, i.e., Environmentome, delineating that osteosarcoma-secreted BMP-4 and synovial sarcoma-secreted BMP-7 potently interact with osteoblasts, osteocytes, osteoclast precursors, and mature osteoclasts. Specifically, quantification analysis revealed that the relationship between osteosarcoma and mature osteoclast/precursor, BMP4-BMPR2 and BMP4-ACVR2A interactions were most potent. Regarding the association between osteosarcoma and osteocyte/osteoblast, BMP4-ACVR1 and BMP4-BMPR2 were the key interactions. In the connection between synovial sarcoma and mature osteoclast/precursor, BMP7-ACVR2A and BMP7-BMPR2 interactions were most remarkable. With regard to the cellular link between synovial sarcoma and osteocyte/osteoblast, BMP7-BMPR2 was identified as a potent interaction. In conclusion, our new outlook suggests delivering the pathological events clinically underlie behind severe skeletal pain or fracture in musculoskeletal tumors. This article is protected by copyright. All rights reserved.
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PMID:Molecular profiling of bone remodeling occurring in musculoskeletal tumors. 3303 13