c‐Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas

Genomic amplification of the c‐Jun proto‐oncogene has been identified in ∼30% of dedifferentiated liposarcomas ( DDLPS ), but the functional contribution of c‐Jun to the progression of DDLPS remains poorly understood. In previous work we showed that knock‐down of c‐Jun by RNA interference impaired the in vitro proliferation and in vivo growth of a DDLPS cell line ( LP6 ) with genomic amplification of the c‐Jun locus. Here, we used gene expression analysis and functional studies in a broad panel of cell lines to further define the role of c‐Jun in DDLPS and other soft tissue sarcomas. We show that c‐Jun knock‐down impairs transition through the G 1 phase of the cell cycle in multiple DDLPS cell lines. We also found that high levels of c‐Jun expression are both necessary and sufficient to promote DDLPS cell migration and invasion in vitro . Our data suggest that high levels of c‐Jun enhance motility in part by driving the expression of ENPP2 /Autotaxin. c‐Jun over‐expression has minimal effects on in vitro proliferation but substantially enhances the in vivo growth of weakly tumourigenic DDLPS cell lines. Finally, we provide evidence that c‐Jun genomic amplification and over‐expression may have similar functional consequences in other types of soft tissue sarcoma. Our data suggest a model in which relatively low levels of c‐Jun are sufficient for in vitro proliferation, but high levels of c‐Jun enhance invasiveness and capacity for in vivo tumour growth. These observations provide an explanation for the selective advantage provided by c‐Jun genomic amplification in vivo and suggest that sarcomas with elevated c‐Jun levels are likely to have a particularly high malignant potential. Data from exon array and RNA ‐Seq experiments have been deposited in the GEO database (Accession No. GSE57531 ). Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd