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BMI-1 Promotes Ewing Sarcoma Tumorigenicity Independent of CDKN2A Repression

¹ Division of Hematology-Oncology, Department of Pediatrics, Childrens Hospital Los Angeles, and Departments of ² Pediatrics and ³ Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California

Requests for reprints: Elizabeth R. Lawlor, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027. Phone: 323-361-8579; Fax: 323-361-4902; E-mail: elawlor{at}chla.usc.edu.

Key Words: BMI-1 • Ewing • tumorigenicity • p16

Deregulation of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we have investigated if the Ewing sarcoma family of tumors (ESFT) expresses BMI-1 and whether it functions as an oncogene in this highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by ESFT cells and that, although it does not significantly affect proliferation or survival, BMI-1 actively promotes anchorage-independent growth in vitro and tumorigenicity in vivo. Moreover, we find that BMI-1 promotes the tumorigenicity of both p16 wild-type and p16-null cell lines, demonstrating that the mechanism of BMI-1 oncogenic function in ESFT is, at least in part, independent of CDKN2A repression. Expression profiling studies of ESFT cells following BMI-1 knockdown reveal that BMI-1 regulates the expression of hundreds of downstream target genes including, in particular, genes involved in both differentiation and development as well as cell-cell and cell-matrix adhesion. Gain and loss of function assays confirm that BMI-1 represses the expression of the adhesion-associated basement membrane protein nidogen 1. In addition, although BMI-1 promotes ESFT adhesion, nidogen 1 inhibits cellular adhesion in vitro. Together, these data support a pivotal role for BMI-1 ESFT pathogenesis and suggest that its oncogenic function in these tumors is in part mediated through modulation of adhesion pathways. [Cancer Res 2008;68(16):6507–15]