The PAX3-FKHR Fusion Gene of Rhabdomyosarcoma Cooperates with Loss of p16INK4A to Promote Bypass of Cellular Senescence
- 15 July 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (14), 6691-6699
- https://doi.org/10.1158/0008-5472.can-06-3210
Abstract
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of <30%. ARMS is characterized by a chromosomal translocation generating the PAX3-FKHR fusion gene. However, ectopic expression of PAX3-FKHR often induces inhibition of cell proliferation, or cell death, when expressed in nonmuscle cells. This prompted us to explore the effect of expressing PAX3-FKHR in more relevant cells, specifically primary human skeletal muscle cells because these cells can be converted to a tumorigenic state that mimics rhabdomyosarcoma. PAX3-FKHR expression promoted both fetal and postnatal primary human skeletal muscle cell precursors to bypass the senescence growth arrest checkpoint. This bypass was accompanied by epigenetic DNA methylation of the p16INK4A promoter and correspondingly a loss of expression of this tumor suppressor. Knockdown of p16INK4A cooperated with PAX3-FKHR to drive proliferation past senescence, whereas reintroduction of wild-type p16INK4A in post-senescent cells caused growth arrest. Thus, PAX3-FKHR acts in concert with loss of p16INK4A to promote inappropriate proliferation of skeletal muscle cells. This association between PAX3-FKHR expression and p16INK4A loss was seen in human ARMS tumor tissue, as both human rhabdomyosarcoma cell lines and tissue microarrays showed a trend toward down-regulation of p16INK4A protein in alveolar subsets. We surmise that the generation of the PAX3-FKHR fusion protein may require loss of p16INK4A to promote malignant proliferation of skeletal muscle cells as an early step in ARMS tumorigenesis. [Cancer Res 2007;67(14):6691–9]Keywords
This publication has 25 references indexed in Scilit:
- Cellular Senescence, Epigenetic Switches and c-MycCell Cycle, 2006
- Identification and Epitope Enhancement of a PAX-FKHR Fusion Protein Breakpoint Epitope in Alveolar Rhabdomyosarcoma Cells Created by a Tumorigenic Chromosomal Translocation Inducing CTL Capable of Lysing Human TumorsCancer Research, 2006
- Genetic Modeling of Human RhabdomyosarcomaCancer Research, 2005
- Analysis of the transforming and growth suppressive activities of the PAX3-FKHR oncoproteinOncogene, 2004
- Soft tissue sarcomas of childhoodCancer Treatment Reviews, 2004
- Hallmarks of senescence in carcinogenesis and cancer therapyOncogene, 2004
- Rhabdomyosarcoma – working out the pathwaysOncogene, 1999
- Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivationOncogene, 1998
- Analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, andCDKN2C) in childhood rhabdomyosarcomaGenes, Chromosomes and Cancer, 1996
- Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcomaNature Genetics, 1993