title: Differential expression of invasion promoting genes in childhood rhabdomyosarcoma.
abstract: Expression profiling of tumor tissue allows a systematic search for targeted therapies and offers relevant prognostic information. Molecular studies on rhabdomyosarcoma (RMS) revealed a more differentiated classification than the histological subgrouping into embryonal (RME) and alveolar (RMA) rhabdomyosarcoma, and reflected the chromosomal aberrations found in RMS. We addressed biological processes like cell migration and emerging drug resistance by expression profiling to identify mechanisms of metastasic invasion and differential response to chemotherapy in RMS. Gene expression analysis was performed in 19 RMS samples using the Affymetrix U133 Plus2 array. Validation of target genes was performed by qRT-PCR. Data were analyzed using Pathway analysis software. Involvement of these genes in invasion processes was evaluated in knock-down experiments using specific interference RNA and Matrigel(TM) invasion assay. In RMA tissues 211 of 534 genes were overexpressed, in RME tissues 323 genes were overexpressed. Pathway analysis software identified a group of genes involved in cell growth, morphology and motility. In patients with distant metastases especially transcription factors such as FOXF1 and LMO4 showed a high expression, which were described as determinants of tumor cell migration. Down-regulation of these factors inhibited the invasion of RMS cells >10-fold. Microarray technology is a powerful method not only to classify RMS samples, but also to identify major regulatory processes. Functional evaluation of LMO4 and FOXF1 identified targets of a molecular network for preventing metastatic invasion in RMS.
authors.affiliation: Department of Pediatric Surgery, University Children's Hospital, Hoppe-Seyler-Strasse 1, 72076 Tübingen, Germany. sorin.armeanu-ebinger@med.uni-tuebingen.de
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Karina
authors.initials: K
authors.lastname: Häbig
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.forename: Ewa
authors.initials: E
authors.lastname: Koscielniak
authors.forename: Jan
authors.initials: J
authors.lastname: Godzinski
authors.forename: Steven W
authors.initials: SW
authors.lastname: Warmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Guido
authors.initials: G
authors.lastname: Seitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D002465:Cell Movement / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D060588:LIM Domain Proteins; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis; D034622:RNA Interference; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; D014157:Transcription Factors