EWS/ATF1 expression induces sarcomas from neural crest-derived cells in mice.
J Clin Invest, 2013/2;123(2):600-10.
Yamada K[1], Ohno T, Aoki H, Semi K, Watanabe A, Moritake H, Shiozawa S, Kunisada T, Kobayashi Y, Toguchida J, Shimizu K, Hara A, Yamada Y
Affiliations
PMID: 23281395
Impact factor: 19.456
Abstract
Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.
MeSH terms
Activating Transcription Factor 1; Animals; Base Sequence; Cell Line, Tumor; Cell Lineage; Cell Proliferation; Gene Expression; Gene Fusion; Genes, fos; Humans; Mice; Mice, Transgenic; Neural Crest; Oncogene Proteins, Fusion; RNA, Small Interfering; RNA-Binding Protein EWS; Sarcoma, Clear Cell; Transcription Factors
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download