Hedgehog-independent overexpression of transforming growth factor-beta1 in rhabdomyosarcoma of Patched1 mutant mice.
The tumor suppressor gene PATCHED1 (PTCH1) is a member of the hedgehog signaling pathway and causatively associated with several human sporadic and familial cancers, including those of the skin, muscle and brain. Inactivation of one Ptch1 allele in the mouse results in the development of medulloblastoma and rhabdomyosarcoma (RMS), the latter being a malignant tumor of skeletal muscle origin. To identify genes involved in the pathogenesis of Ptch1-associated RMS, we have monitored the expression of 588 genes in RMS and normal skeletal muscle (SM) of heterozygous Ptch1neo67/+ mice using cDNA array technology. RMS displayed increased transcript levels of several genes such as transforming growth factor-beta1 (Tgfb1), insulin-like growth factor 2 (Igf2), villin 2 (Vil2), integrin beta1 (Itgb1), Sloan-Kettering viral oncogene homolog (Ski), and insulin-like growth factor binding protein 3 (Igfbp3), as well as numerous genes coding for structural components of myogenic cells such as myosin light polypeptide 4 (Myl4), myosin light polypeptide 6 (Myl6), and vimentin (Vim). Detailed promoter analysis revealed a putative Gli binding site in the second promoter region (P2) of the murine Tgfb1 gene. However, using reporter assay we show that the P2 promoter is not responsive to hedgehog signaling. We furthermore describe that Tgfb1 expression could not be activated in C2C12 myoblasts in the presence of murine Shh-N peptide and that Tgfb1 is equally expressed in both wild-type and Ptch1-deficient mouse embryos. In line with this, TGFB1 was strongly expressed in human RMS cell lines independently of the GLI1 expression status. In summary, our results suggest that aberrant expression of Tgfb1 may be involved in RMS development in a way that is independent of hedgehog signaling.
Eichenmüller
Melanie
M
Pediatric Surgical Clinic, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, D-80337 Munich, Germany.
Bauer
Regine
R
Von Schweinitz
Dietrich
D
Hahn
Heidi
H
Kappler
Roland
R
D000818:Animals; D001665:Binding Sites; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D053823:Hedgehog Proteins / Q000502:physiology*; D006579:Heterozygote; D051379:Mice; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010455:Peptides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010455:Peptides; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D053773:Transforming Growth Factor beta1