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Elevated expression of the NOV (Nephroblastoma overexpressed) gene, also known as CCN3, has been detected in clinical samples of the skeletal muscle cancer rhabdomyosarcoma, with the highest expression found in the alveolar subtype (aRMS).The role of NOV in RMS pathogenesis and how NOV expression is regulated in RMS cells is not completely understood.In this study, we linked elevated NOV levels in aRMS cells to PAX3-FKHR, a chromosomal translocation-derived fusion transcription factor expressed in ~80% of aRMS tumors.We found reduced NOV levels in aRMS cells following siRNA knockdown of PAX3-FKHR, and increased NOV levels in C2 myoblasts following ectopic expression of PAX3-FKHR.Promoter, EMSA, and ChIP analyses confirmed that the NOV gene was a direct target for PAX3-FKHR transcriptional activation through a paired domain DNA sequence in the first intron of the NOV gene.Knockdown and ectopic expression of NOV decreased survival and increased differentiation in aRMS cells, respectively.In addition, we found that exogenously supplied NOV protein promoted aRMS cell adhesion,migration, and Matrigel invasion.Taken together, data from this study have (1) provided a mechanistic basis for the NOV over-expression in aRMS cells, and (2) identified NOV as an autocrine/paracrine factor that contributes to the aggressive behavior of aRMS cells, perhaps through a positive feedback loop.Thus NOV may be an attractive target for therapeutic intervention in aRMS.