Rhabdomyosarcoma (RMS) is a highly malignant tumor that is histologically related to skeletal muscle, yet genetic and molecular lesions underlying its genesis and progression remain largely unknown. In this study we have compared the molecular profiles of two different mouse models of RMS, each associated with a defined primary genetic defect known to play a role in rhabdomyosarcomagenesis in man. We report that RMS of heterozygous Patched1 (Ptch1) mice show less aggressive growth and a greater degree of differentiation than RMS of heterozygous p53 mice. By means of cDNA microarray analysis we demonstrate that RMS in Ptch1 mutants predominantly express a number of myogenic markers, including myogenic differentiation 1, myosin heavy chain, actin, troponin and tropomyosin, as well as genes associated with Hedgehog/Patched signaling like insulin-like growth factor 2, forkhead box gene Foxf1 and the growth arrest and DNA-damage-inducible gene Gadd45a. In sharp contrast, RMS in p53 mutants display higher expression levels of cell cycle-associated genes like cyclin B1, cyclindependent kinase 4 and the proliferation marker Ki-67. These results demonstrate that different causative mutations lead to distinct gene expression profiles in RMS, which appear to reflect their different biological characteristics. Our results provide a first step towards a molecular classification of different forms of RMS. If the described differences can be confirmed in human RMS our results will contribute to a new molecular taxonomy of this cancer, which will be critical for gene mutation-and expression-specific therapy.
Abstract. 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 Ptch1 neo67/+ mice using cDNA array technology. RMS displayed increased transcript levels of several genes such as transforming growth factor-ß1 (Tgfb1), insulin-like growth factor 2 (Igf2), villin 2 (Vil2), integrin ß1 (Itgb1), Sloan-Kettering viral oncogene homolog (Ski), and insulinlike 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.
4.1.1.Aktivierung der IGF2/ Igf2-Expression bei der Tumorentstehung.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.