Data from BMI-1 Promotes Ewing Sarcoma Tumorigenicity Independent of <i>CDKN2A</i> Repression

Abstract

<div>Abstract<p>Deregulation of the polycomb group gene <i>BMI-1</i> 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 <i>in vitro</i> and tumorigenicity <i>in vivo</i>. Moreover, we find that <i>BMI-1</i> 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 <i>CDKN2A</i> 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 <i>in vitro</i>. Together, these data support a pivotal role for <i>BMI-1</i> 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]</p></div>